Pharmacokinetic properties

Fluconazole

General pharmacokinetics

Available in both oral and intravenous preparations, oral fluconazole is rapidly and fully absorbed (bioavailability >90%). Bioequivalence is established between tablets, oral suspension and rectal suppositories. Absorption of fluconazole is not impacted by food or gastric pH. Time to maximum plasma concentration is 1 - 2 hours after oral dose. Plasma concentrations are proportional to dose (range 50 - 400 mg). Steady state concentrations are reached in 5 - 10 days (day 2 if a loading dose is administered). Plasma half-life is approximately 30 hours (markedly reduced in children: 12 - 25 hours), allowing fluconazole to be administered once daily.
Fluconazole has low protein binding (11 -12%) and may be affected by renal function. Fluconazole is considered a very hydrophilic drug and is widely distributed into tissues and cerebrospinal fluid (apparent volume of distribution: 0.56 - 0.82 L/kg).
Elimination is primarily by renal excretion, with 80% of fluconazole being excreted unchanged in urine and only 11% as metabolites. Fluconazole is a potent inhibitor of CYP2C9, a moderate inhibitor of CYP3A4 and inhibits CYP2C19 only to minor extent.
A dose reduction of 50% is recommended in patients with renal failure. Hemodialysis decreases plasma concentrations of fluconazole, requiring 1 full dose after every dialysis session.

References

[1] Product Information: DIFLUCAN(R) oral tablets, IV injection, oral suspension, fluconazole oral tablets, IV injection, oral suspension. Pfizer Inc, New York, NY, 2008.

[2] Blum RA, D'Andrea DT, Florentino BM, et al: Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann Intern Med 1991; 114:755-757.

[3] Stevens DA: The new generation of antifungal drugs. Eur J Clin Microbiol Infect Dis 1988; 7:732-735.

[4] Pfaff G, Zimmermann T, Lach P, et al: Pharmacokinetics and tolerance of fluconazole suppositories in healthy volunteers. Arzneimittelforschung 1993; 43:391-395.

[5] Debruyne D: Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses. Clin Pharmacokinet 1997; 33:52-77.

[6] Foulds G, Brennan DR, Wajszczuk C, et al: Fluconazole penetration into cerebrospinal fluid in humans. J Clin Pharmacol 1988; 28:363-366.

[7] Humphrey MJ, Jevons S, & Tarbit MH: Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal agent, in animals and humans. Antimicrob Agents Chemother 1985; 28:648-653.

[8] Krzeska I, Yeates RA, & Pfaff G: Single dose intravenous Pharmacokinetics of fluconazole in infants. Drugs Exp Clin Res 1993; 19:267-271.

[9] Brammer KW & Coates PE: Pharmacokinetics of fluconazole in pediatric patients. Eur J Clin Microbiol Infect Dis 1994; 13:325-329.

[10] Arredondo G, Martinez-Jorda R, Calvo R, et al: Protein binding of itraconazole and fluconazole in patients with chronic renal failure. Intern J Clin Pharmacol Ther 1994; 32:361-364.

[11] Walsh TJ & Pizzo A: Treatment of systemic fungal infections: Recent progress and current problems. Eur J Clin Microbiol Infect Dis 1988; 7:460-475.

[12] Byers M, Chapman S, Feldman S, et al: Fluconazole pharmacokinetics in the cerebrospinal fluid of a child with candida tropicalis meningitis. Pediatr Infect Dis J 1992; 11:895-896.

[13] Tucker RM, Williams PL, Arathoon EG, et al: Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemother 1988; 32:369-373.

[14] Stern JJ, Hartman BJ, Sharkey P, et al: Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients. Am J Med 1988; 85:477-480.

[15] Chin T, Fong IW, & Vandenbroucke A: Pharmacokinetics of fluconazole in serum and cerebrospinal fluid in a patient with AIDS and cryptococcal meningitis. Pharmacotherapy 1990; 10:305-307.

[16] Savin RC, Drake L, Babel D, et al: Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail. J Am Acad Dermatol 1998; 38(6 pt 2):S110-S116.

[17] Faergemann J: Pharmacokinetics of fluconazole in skin and nails. J Am Acad Dermatol 1999; 40(6 pt 2):S14-S20.

[18] Faergemann J & Laufen H: Levels of fluconazole in normal and diseased nails during and after treatment of onychomycoses in toe-nails with fluconazole 150 mg once weekly. Acta Derm Venereol 1996; 76:219-221.

[19] Rieder-Nelissen CM, Hasse J, Yeates RA, et al: Fluconazole concentrations in pulmonary tissue and pericardial fluid. Infection 1997; 25:62-64.

[20] Dudley MN: Clinical pharmacology of fluconazole. Pharmacotherapy 1990; 10(suppl):141-145.

[21] Ebden P, Neill P, & Farrow PR: Sputum levels of fluconazole in humans. Antimicrob Agents Chemother 1989; 33:963-964.

[22] Dahl NV, Foote EF, Searson KM, et al: Pharmacokinetics of intraperitoneal fluconazolde during continuous cycling peritoneal dialysis. Ann Pharmacother 1998; 32:1284-1289.

[23] Yagasaki K, Gando S, Matsuda N, et al: Pharmacokinetics and the most suitable dosing regimen of fluconazole in critically ill patients receiving continuous hemodiafiltration. Intensive Care Med 2003; 29:1844-1848.

Absorption

BIOAVAILABILITY

  • Healthy volunteers: >90% (oral administration compared with intravenous administration) [1]
  • Influence pH: absorption not affected drugs known to increase gastric pH [2]

FOOD EFFECTS

Absorption is not affected by food. Fluconazole can be administered without regard to meals [1,3]

BIOEQUIVALENCE

Oral fluconazole (both 100 and 200 mg tablet single dose) is bioequivalent to both oral suspension strenghts [1]
Oral fluconazole (both 25 and 200 mg capsule single dose) is bioequivalent to both rectal suppository strenghts [4]

PLASMA CONCENTRATIONS

Peak plasma concentrations (Cmax)

Adults:

Healthy volunteers (fasted): 6.72 mg/L (range 4.12 - 8.08) after a 400 mg single oral dose [1].
Cmax and AUC are dose-proportional for single doses of 50 - 400 mg in fasted healthy volunteers [1].

Lactating women (n=10): 2.61 mg/L (range 1.57 to 3.65 mg/L) after a 150 mg single oral tablet [1].

Geriatric patients (n=22, age: > 65 years): 1.54 mg/mL after a 50 mg single oral dose [1].

Pediatric patients:

  • Multiple intravenous doses (age: 5 - 15 years) [1]:
    2 mg/kg (n=5): 5.5 mg/L
    4 mg/kg (n=6): 11.4 mg/L
    8 mg/kg (n=8): 14.1 mg/L
  • Single oral dose (age 9 months - 13 years) [1]:
    2 mg/kg (n=16): 2.9 mg/L
    8 mg/kg (n=15): 9.8 mg/L
Time to peak plasma concentrations (Tmax)

Healthy volunteers (fasted): 1 - 2 hours after oral administration [1]
Geriatric patients (n=22, age: > 65 years): 1.3 hours after a 50 mg single oral dose [1]

Area under the curve (AUC)

Patients suffering from oropharyngeal candidiasis:
105 mg/L/hr after 100 mg oral suspension [5]
151 mg/L/hr after a 200 mg rectal suppository [5]

Geriatric patients (n=22, age: > 65 years): 76.4 +/- 20.3 mg/L/hr after a 50 mg single oral dose [1]

Steady state plasma concentrations

Reached within 5 - 10 days after oral doses of 50 - 400 mg/day [1]
Reached within 7 days after 100 mg/day (healthy volunteers) [6]

A loading dose (day 1) of twice the usual daily dose resulted in plasma concentrations of approximately 90% of steady state concentrations by the second day [1]

Distribution

VOLUME OF DISTRIBUTION

Healthy volunteers (fasted): 0.56 - 0.82 L/kg [7]. The apparent Vd approximates that of total body water.

Pediatric patients:

  • Multiple intravenous doses (age: 5 - 15 years, Vd at steady state concentrations) [1]:
    2 mg/kg (n=4): 0.722 L/kg
    4 mg/kg (n=5): 0.729 L/kg
    8 mg/kg (n=7): 1.069 L/kg
  • Mean Vd in infants: 0.76 to 2.6 L/kg [8,9]

PROTEIN BINDING

Protein binding is low: 11 - 12% [1], may be affected by renal dysfunction [10]

DISTRIBUTION SITES

Penetration into all body fluids studied after single/multiple oral dose for up to 14 days (see Table 1) [1].

Table 1.

Tissue/Fluid Fluconazole Tissue (Fluid) to Plasma Concentration (ratio)*
Blister fluid 1
Blister skin 2
Cerebrospinal Fluid ** 0.5 - 0.9
Nails 1
Normal skin 10
Saliva 1
Sputum 1
Vaginal tissue 1
Vaginal fluid 0.4 - 0.7
Urine 10

* Subjects with normal renal function
** Independent of degree of meningeal inflammation

Cerebrospinal fluid (CSF)

Patients with fungal meningitis: approximately 80% of plasma concentration [1]
Patients with inflamed and normal meningitis: 50 - 88% of plasma concentration [11, 12, 13]
Patients with meningitis: 2.6 - 10.5 mg/L of plasma concentration 2 - 12 hours post-dose [13, 14, 15]

Nail

Healthy/affected nails: detectable within 14 days after start therapy for treatment of onychomycosis of fingernails. Steady state was reached after 3 - 5 months and detectable until 4 months after last dose [16].

Following oral administration 150 mg per week for a maximum of 12 months, mean nail concentration was 3.09 mcg/g after one month.
Highest concentration was achieved after 6 months of treatment: 8.54 mcg/g. After treatment discontinuation mean nail concentration in healthy and diseased nails was 1.7 and 2.08 mcg/g (3 months) and 1.4 and1.9 mcg/g (6 months), respectively [17, 18].

Lung

Pulmonary tissue concentrations: 4.64 mg/kg (1 hour), 4.54 mg/kg (2 hours), 3.50 mg/kg (12 hours) and 3.40 mg/kg (13 hours) after iv administration [19]

Pericardial

Pericardial concentrations: 3.3.86 mg/l (1 hour), 3.57 mg/l (2 hours), 2.35 mg/l (12 hours) and 2.13 mg/l (13 hours) after iv administration [19]

Skin

Highest in strateum corneum layer of skin (followed by sweat and epidermis-dermis layer), as reported in healthy volunteers receiving 50 mg/day orally for 12 weeks or 150 mg once weekly for 2 weeks. Tissue concentrations exceed serum concentrations [17].
Well absorbed and distributed into subcutaneous tissue and epidermis [20]

Sputum

Sputum concentrations: 3.71 mg/L (4 hours) and 2.23 mg/L (24 hours): similar to plasma concentrations [21]

Vaginal

Vaginal tissue/plasma ratio: 0.94 - 1.14 (48 hours after 150 mg single oral dose, n=27)
Vaginal fluid/plasma ratio: 0.36 - 0.71 (72 hours after same dose, n=14) [1]

Metabolism

METABOLISM SITES

Fluconazole is primarily excreted by the kidneys, with approximately 80% of the administered dose appearing in the urine as unmetabolised drug. Only 11% of total drug is excreted in a metabolised form in urine (indicating liver metabolism) [1,7]

METABOLITES

1,2,3-triazole and two N-dealkylated products [1,7]

BIOTRANSFORMATION

Potent inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4. Weak inhibitor of CYP2C19 [1]

Excretion

CLEARANCE

Renal clearance

Healthy volunteers: 0.27 - 0.63 mL/min/kg [7,8]

Geriatric patients (n=22, age: > 65 years): 0.124 mL/min/kg after a 50 mg single oral dose [1]

Pediatric patients:

  • Multiple intravenous doses (age: 5 - 15 years) [1]
    2 mg/kg (n=4): 0.49 mL/min/kg
    4 mg/kg (n=5): 0.59 mL/min/kg
    8 mg/kg (n=7): 0.66 mL/min/kg
  • Single oral dose (age 9 months - 13 years) [1]
    2 mg/kg (n=14): 0.4 mL/min/kg
    8 mg/kg (n=15): 0.51 mL/min/kg

Neonates (gestational age 26 - 29 weeks): 0.18 mL/min/kg (within 36 hours of birth), 0.218 (6 days) and 0.333 mL/min/kg (12 days) [1]

Renal Excretion

Healthy volunteers: 80% of administered dose unchanged in urine (11% as metabolites) [1]

Geriatric patients (n=22, age >65 years): 22% of total drug is excreted in a metabolised form in urine after a 50 mg single oral dose [1]

TOTAL BODY CLEARANCE

Healthy volunteers: 0.23 mL/min/kg

ELIMINATION HALF-LIFE

Healthy volunteers (fasted), parent compound: approximately 30 hours (range 20 - 50 hours) after oral administration [1]

Geriatric patients (n=22, age: > 65 years): 46.2 hours after a 50 mg single oral dose [1]

Renal impairment

Average 8.7 hours (range 6.75 - 10.3) in 7 patients undergoing hemodiafiltration [22].
A dose reduction of 50% is recommended in patients with renal failure [1]

Pediatrics
  • Multiple intravenous doses (age: 5 - 15 years) [1]
    2 mg/kg: 17.4 hours
    4 mg/kg: 15.2 hours
    8 mg/kg: 17.6 hours
  • Single oral dose (age 9 months - 13 years)
    2 mg/kg: 25 hours
    8 mg/kg: 19.5 hours

Premature newborns (gestational age 26 - 29 weeks): 73.6 hours (within 26 hours of birth), 53.2 hours (6 days) and 46.6 hours (12 days) [1]

Prematures and neonates: prolonged to approximately 71 hours during the first weeks of life, stabilizing around 21 hours during the first years of life (approximately 30 hours in fasted, healthy volunteers) [5]

EXTRACORPOREAL ELIMINATION

Hemodialysis: Dialyzable

Hemodialysis of 3 hours decreased plasma concentrations with 50% [1]

Peritoneal: Dialyzable

Intraperitoneal administration: Cmax of fluconazole was 7 hours; peritoneal bioavailability 87 +/-5% and  peritoneal clearance: 0.26 - 0.33 L/h. Volume of distribution was 40 - 60 L [5].

Noninfected patients (n=5) undergoing continuous cycling peritoneal dialysis (single intraperitoneal 200 mg dose): Cmax 3.46 +/- 0.86 mg/L after 12 hours; peritoneal absorption t1/2: 2.5 +/- 1.2 mg/L; peritoneal bioavailability: 96 +/- 2% after 12 hours;  serum elimination t1/2: 71.65 +/- 12.76 mg/L; peritoneal clearance: 5.96 +/- 0.93 mL/min and Vd: 0.66 +/- 0.13 L/kg (or 52.71 L) [22]

Hemofiltration: Dialyzable

Continuous hemodiafiltration decreased the average elimination half-life of fluconazole to 9 hours (approximately one-third of that in normal volunteers) in 4 critically ill patients, with an average total body clearance of 1 ml/kg/min [23].

Itraconazole

General pharmacokinetics

Itraconazole is available as oral capsules, oral solution and as an IV solution (not in the USA). The bioavailability of itraconazole is highly variable and bioavailability of the oral solution was 55% when administered under fed conditions and is known to increase under fasting conditions. The inverse is true for itraconazole capsules (enhanced absorption under fed conditions). In addition, decreased gastric pH leads to decreased absorption of itraconazole capsules (oral solution not affected) [1]. Time to maximum plasma concentration (Tmax) in steady state varies between 2-5 hours for both oral formulations. Without loading dose, oral itraconazole (capsules 50 - 400 mg/day) gives rise to steady state conditions within 15 days. The IV formulation is able to reach steady state concentrations within 2-3 days [1,2].
Itraconazole is lipophilic and has a high protein binding (>99%) and is widely distributed into tissue and limited into cerebrospinal and eye fluid. Volume of distribution is high with 796 L (~11 L/kg) [1].
Itraconazole is metabolized in the liver by cytochrome P450 (CYP) 3A4 enzymes and undergoes enterohepatic recirculation. This mechanism is saturable after multiple dosing. It is also a strong inhibitor of CYP3A4, and to a lesser extent CYP2C9. It is also an inhibitor of P-gp. Itraconazole has a major metabolite (hydroxyitraconazole), which is equally pharmacologically active.
Inactive metabolites are mainly excreted via bile (55%) and urine (40%); 3 - 18% is excreted in the feces as unchanged drug. Elimination half-life is 16-24 hours after a single 100 mg dose (capsules) and increases to >30 hours in steady state, indicating a saturable excretion mechanism [1]. Elimination half-life for multiple 200 mg doses of capsules, oral solution and intravenous formulation is 36-64 hours.

General recommendation: Administer oral capsules with food and oral solution in fasting state to increase bioavailability. Itraconazole capsules and oral solution should not be used interchangeably. The use of itraconazole oral solution is preferred over itraconazole capsules.

References

[1] Product Information: Sporanox(R) itraconazole capsules / oral solution / injection

[2] Zhou H, Goldman M, Wu J, Woestenborghs R, Hassell AE, Lee P, Baruch A, Pesco-Koplowitz L, Borum J, Wheat LJ. A pharmacokinetic study of intravenous itraconazole followed by oral administration of itraconazole capsules in patients with advanced human immunodeficiency virus infection. J Clin Pharmacol. 1998 Jul;38(7):593-602

[3] Willems L, van der Geest R, de Beule K. Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics.Clin Pharm Ther. 2001 Jun;26(3):159-69.

[4] Poirier JM, Cheymol G. Optimisation of itraconazole therapy using target drug concentrations. Clin pharmacokinet 1998;35:461-73.

[5] Tucker RM, Denning DW, Dupont B, Stevens DA. Itraconazole therapy for chronic coccidioidal meningitis. Ann Intern Med. 1990 Jan 15;112(2):108-12.

[6] Grant SM,  Clissold SP. Itraconazole. Drugs March 1989, 37(3), 310-344

[7] Matthieu L, De Doncker P, Cauwenbergh G, Woestenborghs R, van de Velde V, Janssen PA, et al. Itraconazole penetrates the nail via the nail matrix and the nail bed--an investigation in onychomycosis. Clin Exp Dermatol. 1991 Sep;16(5):374-6.

[8] Watkins DN, Badcock NR, Thompson PJ. Itraconazole concentrations in airway fluid and tissue. Br J Clin Pharmacol. 1992 Feb;33(2):206-7.

[9] Van Peer A, Woestenborghs R, Heykants J, Gasparini R, Gauwenbergh G. The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects. Eur J Clin Pharmacol.  1989;36(4):423-6.

[10] Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC,Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers. Antimicrob Agents Chemother. 1993 Apr;37(4):778-84.

[11] J Boelaert, M Schurgers, E Matthys, R Daneels, A van Peer, K De Beule,  et al. Itraconazole pharmacokinetics in patients with renal dysfunction. Antimicrob Agents Chemother. Oct 1988; 32(10): 1595–1597.

Absorption

BIOAVAILABILITY

Bioavailability of itraconazole is highly variable and depends on the formulation, fasting/fed conditions and is influenced by gastric pH.
Bioavailability was 55% after dosing of oral solution in 6 healthy male volunteers when administered under fed conditions (although not ideal for oral solution, see food effects) [1].

FOOD EFFECTS

Capsules: food enhances absorption. Itraconazole capsules are adviced to be administered with a full meal. Absorption reduces with increased gastric acidity for instance with concomitant use of gastric acid secretion suppressors or antacids [1].

Oral solution: food decreases bioavailability. Bioavailability and Tmax increases during fasting conditions. Do not administer the oral solution with food.
AUC(0-24) of itraconazole oral solution under fasted conditions was 131 ± 30% of that obtained under fed conditions. Unlike itraconazole capsules, itraconazole oral solution should be administered without food [1].

PLASMA CONCENTRATIONS

Capsules: The pharmacokinetics of itraconazole capsules were also studied in a crossover design in 6 healthy volunteers who received single 100 mg doses of itraconazole capsules (fed and fasted state). Also, a single dose of 50 mg and 200 mg was studied in the fed state, see Table 1 [1].

Table 1.

  50 mg (fed) 100 mg (fed) 100 mg (fasted) 200 mg (fed)
Cmax (mg/L) 0.045 ± 0.016* 0.132 ± 0.067 0.038 ± 0.020 0.289 ± 0.100
Tmax (hours) 3.2 ± 1.3 4.0 ± 1.1 3.3 ± 1.0 4.7 ± 1.4
AUC0-inf (mg*h/L) 0.567 ± 0.264 1.899 ± 0.838 0.722 ± 0.289 5.211 ± 2.116

 *mean ± standard deviation

Table 2 shows the Cmax, Tmax, AUC and T1/2 of itraconazole (200 mg b.i.d. oral dose with a full meal) and its active metabolite hydroxyitraconazole after administration in steady-state conditions (day 15) in 27 healthy volunteers [1].

Table 2.

  Itraconazole Hydroxyitraconazole
Cmax (mg/L) 2.282 ± 0.514* 3.488 ± 0.742
Cmin (mg/L) 1.855 ± 0.535 3.349 ± 0.761
Tmax (hours) 4.6 ± 1.8 3.4 ± 3.4
AUC0-12 (mg*h/L) 22.569 ± 5.375 38.572 ± 8,450
T1/2 (hours) 64 ± 32 56 ± 24

*mean ± standard deviation

Oral solution: Table 3 shows the Cmax, Tmax, AUC and T1/2 of itraconazole (200 mg b.i.d. oral dose) and its active metabolite hydroxyitraconazole after administration in steady-state conditions (day 15) in 27 healthy volunteers [1].

Table 3.

   Itraconazole                                    Hydroxyitraconazole                                
   Fasted  Fed  Fasted  Fed
Cmax (mg/L)       1.963 ± 0.601*  1.435 ± 0.477  2.055 ± 0.487  1.781 ± 0.397
Tmax (hours)  2.5 ± 0.8  4.4 ± 0.7  5.3 ± 4.3  4.3 ± 1.2
AUC0-24h (mg*h/L)  29.271 ± 10.285  22.815 ± 7.098  45.184 ± 10.981  38.823  ± 8.907    
T1/2  39.7 ± 13  37.4 ± 13  27.3 ± 13  26.1 ± 10

*mean ± standard deviation

Pharmacokinetics of single 200 mg doses of itraconazole oral solution (n = 27) and capsules (n = 30) administered to healthy volunteers in the fasted and fed state are represented in Table 4 [1].

Table 4.

  Itraconazole Hydroxyitraconazole
Oral solution fasted Capsules fed Oral solution fasted Capsules fed
Cmax (mg/L) 0.544 ± 0.213* 0.302 ± 0.119 0.622 ± 0.116 0.504 ± 0.132
Tmax (hours) 2.2 ± 0.8 5 ± 0.8 3.5 ± 1.2 5 ± 1
AUC0-24 (mg*h/L) 4.505 ± 1.670 2.682 ± 1.084 9.552 ± 1.835 7.293 ± 2.144

*mean ± standard deviation

The AUC0-inf for itraconazole oral solution was 149 ± 68% of that obtained from itraconazole capsules (similar for hydroxyitraconazole). Therefore, itraconazole capsules and oral solution should not be used interchangeably.

Peak plasma concentrations (Cmax)
  • Oral capsules: Cmax was 2.282 mg/L for itraconazole and 3.488 mg/L for hydroxyitraconazole in steady state conditions after twice daily itraconazole 200 mg dosing with a full meal (Table 2) [1].
  • Oral solution: Cmax was 1.963 mg/L for itraconazole and 2.055 mg/L for hydroxyitraconazole in steady state conditions after itraconazole 200 mg/day dosing in the fasted state (Table 3) [1].
  • Intravenous: Cmax was 2.856 mg/L for itraconazole and 1.906 mg/L for hydroxyitraconazole after one week of therapy with 200 mg over 1 hour IV [1,2]
Time to peak plasma concentrations (Tmax)

• Oral capsules: Tmax was 4.6 hours for itraconazole and 3.4 hours for hydroxyitraconazole in steady state conditions after twice daily itraconazole 200 mg dosing with a full meal (Table 2) [1].
• Oral solution: Tmax was 2.5 hours for itraconazole and 5.3 hours for hydroxyitraconazole in steady state conditions after itraconazole 200 mg/day dosing in the fasted state (Table 3) [1].
• Intravenous administration: about 1 hour post-infusion for itraconazole, 8.3 hours for hydroxyitraconazole. [1,2]

Time to steady state

Without loading dose, oral itraconazole (capsules 50 - 400 mg/day) gives rise to steady state conditions within 15 days. The IV formulation is able to reach steady state concentrations within 2-3 days. [1,3]

Area under the curve (AUC)

• Oral capsules: AUC0-12 was 22.569 mg*h/L for itraconazole and 38.572 mg*h/L for hydroxyitraconazole in steady state conditions after twice daily itraconazole 200 mg dosing with a full meal (Table 2) [1].
• Oral solution: AUC0-24 was 29.271 mg*h/L for itraconazole and 45.184 mg*h/L for hydroxyitraconazole in steady state conditions after itraconazole 200 mg/day dosing in the fasted state (Table 3) [1].

LINEARITY

The pharmacokinetics of itraconazole are non-linear, although this is relatively poorly characterized [4].

Recommendation

Administer oral capsules with food and oral solution in fasting state to increase bioavailability. Itraconazole capsules and oral solution should not be used interchangeably. The use of itraconazole oral solution is preferred over itraconazole capsules.

Distribution

VOLUME OF DISTRIBUTION

Volume of distribution is 796 ± 185 L (approximately 11L/kg) [1].

PROTEIN BINDING

Protein binding is 99.8% for itraconazole and 99.5% for hydroxyitraconazole [1].

DISTRIBUTION SITES

Cerebrospinal fluid

Itraconazole shows limited penetration in cerebrospinal fluid, although efficacy has been demonstrated in the treatment of cryptococcal and coccidioidal meningitis. It appears that CSF concentrations are not mandatory for efficacy [5].

Tissue

Itraconazole is extensively distributed into human tissues due to highly liphophilic properties. High levels have been found in skin, liver, adipose tissue, bone, endometrium, cervical mucus, pus and the vagina [6].

Nail

Itraconazole penetrates extensively in the nails via the nail matrix as well as via other routes such as the nail bed. In a group of patients with onychomycosis and inea coporis (n=21) receiving itraconazole 100 mg for up to 7 months, concentrations of 160 ng/g in fingernail clippings and 197 ng/g in toenails were reached within 1 month of therapy [7].

Bronchial fluid

In one case bronchial washings and bronchoalveolar lavage contained high concentrations of itraconazole (5-14 nmol/L and 13-25 nmol/L, respectively) after longterm treatment with 100 mg itraconazole on alternate days [8].

Metabolism

METABOLISM SITES

Itraconazole is extensively metabolized in the liver. Itraconazole shows saturable metabolism with multiple dosing and may undergo the hepatic recirculation [1,5].

METABOLITES

Metabolism of itraconazole results in the formation of more than 30 metabolites. Hydroxyitraconazole is the major metabolite, which is pharmacologically active and comparable to its parent compound [1,5].

BIOTRANSFORMATION

Itraconazole is extensively metabolized in the liver, predominantly by cytochrome P450 (CYP) 3A4 isoenzymes. It is also a strong inhibitor of CYP3A4, and to a lesser extent CYP2C9. It is also an inhibitor of P-glycoprotein [1].

Excretion

CLEARANCE

Renal excretion

Excretion of the parent drug is negligible (0.03%), but about 40% of the dose is excreted as inactive metabolites in the urine (no single excreted metabolite represents more than 5% of a dose) [1].

Bile

About 3-18% of the parent drug is excreted via bile. 55% of the metabolites are excreted via bile within 7 days [1,6].

TOTAL BODY CLEARANCE

Plasma clearance averages 381 ± 95 mL/min following intravenous administration [1].

ELIMINATION HALF-LIFE

Elimination half-life is different after single dosing than after repeated dosing suggesting a saturable excretion mechanism.

• Oral capsules: T1/2 was 16-24 hours after single oral dosing of 100 mg in healthy subjects and >30 hours after repeated daily dosing of 100 mg (2-4 weeks of treatment) [1,6,9]. T1/2 of hydroxyitraconazole was about 12-14 hours after single oral dose of 100 mg itraconazole [10].

• Oral capsules: T1/2 was 64 hours for itraconazole and 56 hours for hydroxyitraconazole in steady state conditions after twice daily itraconazole 200 mg dosing with a full meal (Table 2) [1].
• Oral solution: T1/2 was 39.7 hours for itraconazole and 27.3 hours for hydroxyitraconazole in steady state conditions after itraconazole 200 mg/day dosing in the fasted state (Table 3) [1].
• Intravenous: T1/2 was 35 hours for itraconazole after one week of therapy with 200 mg over 1 hour IV (hydroxyitraconazole not determined) [1,2]

Cirrhotic subjects

•T1/2 of itraconazole increased from 16 to 37 hours in cirrhotic subjects after dosing of 100 mg itraconazole, compared to healthy individuals [1]

EXTRACORPOREAL EXCRETION

In a study in subjects with renal impairment (n=19), hemodialysis and peritoneal dialysis did not significantly influence AUC or Cmax. Therefore, itraconazole is thought to be non-dialyzable [11].

Posaconazole

General pharmacokinetics

Posaconazole is currently available as oral suspension and tablet formulation. Bioavailability of posaconazole oral suspension is highly variable. Posaconazole tablet formulation showed improved (3-fold) exposure compared to oral suspension. Posaconazole oral suspension exerts linear pharmacokinetics if administered as 50 - 800 mg doses to healthy volunteers; doses >800 mg did not increase the total exposure. Dividing one daily dose of posaconazole oral suspension into 2 or 4 daily doses, increased exposure 2-fold or 3-fold, respectively. Administration during and immediately after consumption of a high fat meal significantly increased absorption of posaconazole oral suspension. Exposure of posaconazole as oral tablet formulation is not markedly affected by food. A high-fat meal can moderately increase the mean exposure (AUC) ~1.5 fold. Time to maximum plasma concentration is approximately 3 - 5 hours for posaconazole oral suspension and steady state concentrations are reached within 7 - 10 days of multiple dosage. Plasma half-life of posaconazole oral suspension is relatively long with approximately 35 hours (range 20 - 66 hours). Plasma half-life of the tablet formulation was similar compared to oral suspension.
Posaconazole is highly protein-bound (>98%) and has a large apparent volume of distribution (5 - 25 L/kg) after oral administration (Vd/F), suggesting extensive distribution and penetrations into extravascular spaces. Posaconazole penetrates well into the lungs.
Metabolism of posaconazole is limited, with about 20 – 30% being metabolized by a phase II reaction (UDP-glucoronosyl-transferrase enzymsystem) to inactive metabolites. Plasma concentrations are unlikely to be altered by inhibitors of CYP-enzymes. Posaconazole is a substrate for and inhibitor of P-gP in vitro.
The major elimination route is via the feces (77%), with 66% excreted as unchanged drug. Renal clearance is a minor elimination pathway, with 14% of the dose is excreted in urine (< 0.2% parent compound). Posaconazole is not removed by dialysis.

References

[1] Summary of Product Characterisitcs, Noxafil 40 mg/ml Oral suspension. (SPC)

[2] Courtney R, Wexler D, Radwanski E, Lim J, Laughlin M. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol. 2004 Feb;57(2):218-22.

[3] Krishna G, Ma L, Martinho M, O'Mara E A single dose phase I study to evaluate the pharmacokinetics of posaconazole new tablet and capsule formulations relative to oral suspension. Antimicrob. Agents Chemother. 2012; 56:4196–4201.

[4] Krishna G, Moton A, Ma L, Medlock MM, McLeod J. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother. 2009 Mar;53(3):958-66.

[5] Noxafil (Full prescribing information). Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2014.

[6] Conte JE , DeVoe C, Little E, Golden JA. Steady-state intrapulmonary pharmacokinetics and pharmacodynamics of posaconazole in lung transplant recipients. Antimicrob Agents Chemother. 2010 Sep;54(9):3609-13

[7] Conte JE, Golden JA, Krishna G, McIver M, Little E, Zurlinden E. Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole at Steady State in Healthy Subjects. Antimicrob Agents Chemother. 2009 Feb;53(2):703-7

[8] Herbrecht R. Posaconazole: a potent, extended-spectrum triazole anti-fungal for the treatment of serious fungal infections. Int J Clin Prac 2004; 58(6):612-624.

[9] Kersemaekers WM, Dogterom D, Xu J, Marcantonio EE, de Greef R, Waskin H, van Iersel MLPS. Effect of a High-Fat Meal on the Pharmacokinetics of 300-Milligram Posaconazole in a Solid Oral Tablet Formulation. Antimicrob. Agents Chemother. 2015; 59(6): 3385-3389.

Absorption

BIOAVAILABILITY

Posaconazole oral suspension has a very variable bioavailability making sufficient exposure sometimes difficult. Bioavailability of the oral suspension can further be increased by administration in the fed state (high-fat meal). Another option to increase exposure is by dividing the daily dose into four instead of two dosing moments [1,2]
Posaconazole oral tablet formulation consists a pH-sensitive polymer (hypromellose acetate succinate), which limits release of posaconazole at low gastric pH and releases posaconazole at elevated pH of the intestine, resulting in substantially improved (>3-fold) exposure compared to posaconazole oral suspension (in healthy adults, fasting state) [3]

FOOD EFFECTS

As mentioned above, food has a considerable influence on absorption of posaconazole oral suspension. Its absorption is higher in the fed state: non-fat meals or administration with nutritional supplement (14 grams of fat) increase AUC 2.6 fold while high-fat meals increase AUC 4 fold [1,2]. An acidic carbonated beverage increased AUC by 70% [4].
Exposure of posaconazole as oral tablet formulation is not markedly affected by food [3]. A high-fat meal can only moderately increase the mean posaconazole exposure [9].

PLASMA CONCENTRATIONS

Peak plasma concentrations (Cmax)

Oral suspension:
• 2.3 mg/L with 200 mg QID multiple dosed in healthy volunteers (fasting conditions; n=12)
• 0.982 mg/L with 400 mg BID multiple dosed in healthy volunteers (fasting conditions; n=11)
• 0.84 mg/L with 100 mg single dose in healthy volunteers (fasting conditions; n=16) [3]
• 0.243 mg/L with 100 mg single dose in healthy volunteers (fed conditions; n=16) [3]

Cmax of the oral suspension was similar in patients with mild hepatic impairment (Child-Pugh A, n=6), increased by 40% in patient with moderate hepatic impairment (Child-Pugh B, n=6) and was 34% lower in patients with severe hepatic impairment (Child-Pugh C, n=6) [1].

Oral tablet formulation:
• 0.358 - 0.385 mg/L with 100 mg single dose in healthy volunteers (fasting conditions; n=16) [3]
• 0.327 - 0.348 mg/L with 100 mg single dose in healthy volunteers (fed conditions; n=16) [3]
• 0.731 - 1.090 mg/L with 300 mg single dose in healthy volunteers (fasting conditions; n=14 [9]
• 0.915 - 1.190 mg/L with 300 mg single dose in healthy volunteers (high-fat meal; n=16) [9]

Time to peak plasma concentrations (Tmax)

Oral suspension:
• 3 - 5 hours, in healthy volunteers. Tmax depended on the dose and fed/fasted state [1]
• 4 hours with 200 mg QID for 7 days (fasting conditions; n=12) [4]
• 6 hours with 400 mg BID for 7 days (fasting conditions; n=11) [4]
• 4 hours with 100 mg single dose in healthy volunteers (fasting conditions; n=16) [3]
• 6 hours with 100 mg single dose in healthy volunteers (fed conditions; n=16) [3]

Oral tablet formulation:
• 5 hours with 100 mg single dose in healthy volunteers (fasting conditions; n=16) [3]
• 6 - 8 hours with 100 mg single dose in healthy volunteers (fed conditions; n=16) [3]
• 5 hours with 300 mg single dose in healthy volunteers (fasting conditions; n=14) [9]
• 6 hours with 300 mg single dose in healthy volunteers (high-fat meal; n=16) [9]

Area under the Curve (AUC)

Oral suspension:
• AUC(0-24): 15.9 mg*h/L in neutropenic patients receiving 200 mg TID (n=215) [1]
• AUC(0-24): 132 mg*h/L in neutropenic patients receiving 200 mg QID for 7 days (fasting conditions, n=12) [4]
• AUC(0-24): 52.3 mg*h/L in neutropenic patients receiving 400 mg BID for 7 days (fasting conditions, n=11) [4]
• AUC(0-12): 9.1 mg*h/L in neutropenic patients or patients refractory to first line therapy (n=23) receiving 400 mg BID [1]
• AUC(0-inf): 3.42 mg*h/L with 100 mg single dose in healthy volunteers (fasting conditions; n=16) [3]
• AUC(0-inf): 8.75 mg*h/L with 100 mg single dose in healthy volunteers (fed conditions; n=16) [3]

AUC increased in patients with mild, moderate and severe hepatic impairment (all groups n=6) by 43%, 27% and 21% compared to individuals with normal hepatic function (n=18) after single dose of 400 mg posaconazole [1].

AUC of the oral solution was highly variable in patients with severe renal impairment (CrCl<20 ml/min) but not significantly increased. Covariation was 96% compared to 40% in subjects with a normal renal function. [1]

Oral tablet formulation:
• AUC(0-inf): 11.3 - 11.7 mg*h/L with 100 mg single dose in healthy volunteers (fasting conditions; n=16) [3]
• AUC(0-inf): 11.9 - 12.4 mg*h/L with 100 mg single dose in healthy volunteers (fed conditions; n=16) [3]
• AUC(0-72h): 21.5 - 30.4 mg*h/L with 300 mg single dose in healthy volunteers (fasting conditions; n=14) [9]
• AUC(0-72h): 35.0 - 42.7 mg*h/L with 300 mg single dose in healthy volunteers (high-fat meal; n=16) [9]

STEADY STATE PLASMA CONCENTRATIONS

Steady state concentrations are achieved by day 6 in healthy volunteers dosed with 300 mg delayed-release tablets once daily after a loading dose of 300 mg twice daily on day 1 [5].
With oral suspension, steady state attained after 7 - 10 days following multiple-dose administration [1,5].

Distribution

VOLUME OF DISTRIBUTION

• 1744 L (range 774 - 5845 L) in healthy volunteers (n=24), indicating high tissue penetration [5]
• 2425 L in neutropenic patients on chemotherapy for acute myelodysplastic syndrome receiving 200 mg TID (n=215) [5]
• 3088 L in neutropenic patients with refractory fungal infections receiving multiple doses of 400 mg BID (n=23) [5]

PROTEIN BINDING

Protein binding of posaconaozole is greater than 98% (mostly to albumin) [1]

DISTRIBUTION SITES 

• Intrapulmonal concentrations were 1.3 mg/L in pulmonary epithelial fluid and 55.4 mg/L in alveolar cells of lung transplant recipients (n=20) in steady state after receiving 400 mg oral suspension BID [6]
• Intrapulmonal concentrations were 1.8 mcg/mL in pulmonary epithelial lining fluid and 60.7 (87.6) mcg/mL in alveolar cells in healthy volunteers (n=25) receiving 400mg oral suspension BID [7]

Metabolism

METABOLISM SITES

Posaconazole is primarily metabolized in the liver [1]. 

METABOLITES

Posaconazole glucoronide conjugates are formed by UDP glucoronidation (UDP-G: phase-2 enzymes). No major ciruclating oxidative (CYP450-mediated) metabolites are formed. 

BIOTRANSFORMATION

Posaconazole is primarily metabolized in the liver trough glucuronidation by uridine diphosphate (UDP) to a monoglucoronide of posaconazole (18 - 28% of profiled radioactive dose). Only minor metabolites are formed by CYP450-mediated pathways [1] Posaconazole is substrate and inhibitor for P-gp efflux pumps and is a strong inhibitor of CYP3A4 [1]

Excretion

CLEARANCE

Renal excretion

• 13% of the dose was eliminated via the kidneys (up to 120 hours) in which less than <0.2% is parent compound [1]
• Approximately 14% of the dose was eliminated via the kidneys as multiple glucoronidated deriates (minor amounts as parent derivates) [8]

Faecal excretion

• 71% of the dose was eliminated in the faeces (up to 120 hours) in which 66% is parent compound [1]
• 77% of the dose was eliminated in the faeces as parent compound [8]

TOTAL BODY CLEARANCE

• Mean total body clearance: 32 L/h [1]
• Mean total body clearance: 21.2 L/h in neutropenic patients receiving 200 mg QID for 7 days (fasting conditions, n=12) [4]
• Mean total body clearance: 54.6 L/h in neutropenic patients receiving 400 mg BID for 7 days (fasting conditions, n=11) [4]
• 51.2 L/h (CV 54%, range 10.7 - 146 L/h) in patients (n=215) receiving 200 mg oral suspension TID [5]
• 76.1L/h in neutropenic patients or patients refractory to first line therapy (n=23) receiving 400 mg BID [1]

Mean apparent total body clearance decreased in patients with mild, moderate and severe hepatic impairment (all groups n=6) by 18%, 36% and 28% compared to individuals with normal hepatic function (n=18) after single dose of 400 mg posaconazole [1].

ELIMINATION HALF-LIFE

Oral suspension:
• 35 hours (range 20-66 hours) [1]
• 34.7 hours in neutropenic patients receiving 200 mg QID for 7 days (fasting conditions, n=12) [4]
• 25.7 hours in neutropenic patients receiving 400 mg BID for 7 days (fasting conditions, n=11) [4]
• 37.2 h (range 19.1-148) after 200 mg oral suspension TID in steady state conditions (n=215) [1]
• 31.7 h (range 12.4-67.3) after 400 mg oral suspension BID in steady state conditions (n=23) [5]
• 29.2 hours with 100 mg single dose in healthy volunteers (fasting conditions; n=16) [3]
• 25.1 hours with 100 mg single dose in healthy volunteers (fed conditions; n=16) [3]

Half-life increased in patients with mild, moderate and severe hepatic impairment (all groups n=6) from 27 hours (normal hepatic function) to 39, 27 and 43 hours, respectively.

Although Cmax and AUC of posaconazole oral suspension are highly affected by the presence of (high-fat) food, elimination half-life is not [4]

Oral tablet formulation:
• 25.0 - 26.1 hours with 100 mg single dose in healthy volunteers (fasting conditions; n=16) [3]
• 23.7 - 25.3 hours with 100 mg single dose in healthy volunteers (fed conditions; n=16) [3]

EXTRACORPOREAL ELIMINATION

Posaconazole is not removed by haemodalysis [5]

Voriconazole

General pharmacokinetics

Available in both oral (tablet and oral suspension) and intravenous preparations, oral voriconazole is rapidly and almost completely absorbed (bioavailability ~96% in fasting state). Bioequivalence is established between tablets and suspension (200 mg dose). Absorption of voriconazole is decreased by food, in particular high fat meals (Cmax and AUC of the tablet formulation reduced by 34% and 24%, respectively. This effect was more pronounced for the suspension). Absorption is not impacted by gastric pH. Time to maximum plasma concentration is 1 - 2 hours after dosing  in fasting state. Steady state concentrations are reached after 5 - 7 days of multiple dosing in healthy volunteers, but can be reached after 24 hours by administering a loading dose. Voriconazole exerts non-linear PK in adult patients due to saturable metabolism, resulting in Cmax and AUC increasing more than proportionally with an increase in dose (both time and dose dependent). Apparent plasma half-life is approximately 6 hours and increases when voriconazole concentration increases. Pediatric and adolescent patients have different PK compared to adults (pseudo linear PK).
The volume of distribution of steady state voriconazole is estimated to be 4.6 L/kg, with a plasma protein binding of ~58%.  It is extensively distributed into human tissue and penetrates well into the CSF, vitreous and aqueous humors.
CYP2C19 is the key isoenzyme of voriconazole metabolism (exhibiting genetic polymorphism: 20-30% of the Asian population is expected to be poor metabolizers), with CYP2C9 and CYP3A4 being involved to a much lesser extent. Voriconazole is also an inhibitor of CYP2C9, CYP2C19 and CYP3A4. The major metabolite of voriconazole (voriconazole-N-oxide) lacks considerable antifungal activity.
Due to extensive metabolism, the parent compound is not recovered in urine or feces (metabolites are primarily excreted into urine). Voriconazole is hemodialysed with a clearance of 121 ml/min. Whilst a 4 hour hemodialysis session does not remove a sufficient amount of voriconazole, dose adjustments are not warranted.

References

[1] Product Information: VFEND(R) IV injection, oral tablets, suspension, voriconazole IV injection, oral tablets, solution. Roerig, New York, NY, 2008.

[2] Walsh TJ, Driscoll T, Milligan PA, Wood ND, Schlamm H, Groll AH, et al. Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children. Antimicrob Agents Chemother 2010; 54(10):4116-4123.

[3] Michael C, Bierbach U, Frenzel K, Lange T, Basara N, Niederwieser D, et al. Voriconazole pharmacokinetics and safety in immunocompromised children compared to adult patients. Antimicrob Agents Chemother 2010; 54(8):3225-3232.

[4] Pai MP and Lodise TP. Steady-state plasma pharmacokinetics of oral voriconazole in obese adults. Antimicrob Agents Chemother 2011; 55(6):2601-2605.

[5] Abel S, Allan R, Gandelman K, Tomaszewski K, Webb DJ, Wood ND. Pharmacokinetics, safety and tolerance of voriconazole in renally impaired subjects: two prospective, multicentre, open-label, parallel-group volunteer studies. Clin Drug Investig. 2008;28(7):409-20.

[6] Radford SA, Johnson EM, Warnock DW. In vitro studies of activity of voriconazole (UK-109,496), a new triazole antifungal agent, against emerging and less-common mold pathogens. Antimicrob Agents Chemother. 1997 April; 41(4): 841–843.

[7] Michael C, Bierbach U, Frenzel K, Lange T, Basara N, Niederwieser D, et al. Voriconazole pharmacokinetics and safety in immunocompromised children compared to adult patients. Antimicrob Agents Chemother 2010; 54(8):3225-3232.

[8] Schwartz S, Milatovic D,  Thiel E. Successful treatment of cerebral aspergillosis with a novel triazole (voriconazole) in a patient with acute leukaemia. Br J Haematol 1997; 97:663-665.

[9] Stern JB, Girard P, Caliandro R. Pleural diffusion of voriconazole in a patient with Aspergillus fumigatus empyema thoracis (letter). Antimicrob Agents Chemother 2004; 48(3):1065.

[10] Lau D, Leung L, Ferdinands M, Allen PJ, Fullinfaw RO, Davies GE et al. Penetration of 1% voriconazole eye drops into human vitreous humour: a prospective, open-label study. Clin Experiment Ophthalmol 2009; 37(2):197-200.

Absorption

BIOAVAILABILITY

  • Adults: 96%. Voriconazole is rapidly and almost completely absorbed after oral administration in a group of healthy subject (n=207). Similar results were obtained in a group of patients at risk of aspergillosis [1]
  • Pediatrics: 65 - 66% in a group of pediatric patients aged between 2 and 12 (n=18). The authors  suggested a difference in the development of the activity of intestinal metabolizing enzymes and efflux transporters as a cause for this difference between adults and children [1,2]
  • Influence pH: Absorption not affected by gastric pH [1]

FOOD EFFECTS

With high fat meals, voriconazole Cmax and AUC are reduced by 34% and 24%, respectively, when voriconazole is given as tablet and 58% and 37% when given as oral suspension [1]

BIOEQUIVALENCE

Bioequivalence is proven between the 200 mg oral tablet and the 40mg/mL oral suspension administered as a 400 mg twice daily loading dose followed by 200 mg twice daily maintenance dose [1]

PLASMA CONCENTRATIONS

Peak plasma concentrations (Cmax)

Adults:

• Oral: 2.08 mg/L on day 10 with 400 mg oral every 12 hours on day 1 followed by 200 mg every 12 hours on days 2 - 10 (n=17 healthy volunteers) [1]
• Intravenous: 3.06 mg/L on day 10 with voriconazole i.v. 6 mg/kg every 12 hours on day 1, followed by 3 mg/kg intravenously on days 2 - 10 (n=9 healthy volunteers) [1]

Pediatric:

Children (2 - 12 yrs):

• Oral:
4 mg/kg multiple dosing: 1.2 mg/L (n = 21 patients) [2]
6 mg/kg multiple dosing: 1.8 mg/L (n = 19 patients) [2]

• Intravenous: 
4 mg/kg every 12 hours: 3.2 mg/L (n = 23 patients) [2]
6 mg/kg every 12 hours: 4.3 mg/L (n = 41 patients) [2]
7 mg/kg every 12 hours: 11.4 mg/L (2.4 - 19.2 mg/L; n=9 patients) [3]
8 mg/kg every 12 hours: 5.8 mg/L (n = 20 patients) [2]

Adolescents (12 - 18 yrs):

• Oral:
200 mg every 12 hours: 1.16 mg/L (interquartile range 0.85 - 2.14 mg/L; n = 17 patients) [1]

• Intravenous
4 mg/kg every 12 hours: 1.6 mg/L (interquartile range 0.28 - 2.73 mg/L; n = 11 patients) [1]

Gender

83% increase in Cmax in healthy young females (18 - 45 yrs) compared with healthy young males in a multiple dose study with voriconazole (oral tablet). No differences were obseved when the oral suspension was used. Safety profiles and plasma concentrations between the two groups were similar. Hence, no dosing adjustment is required on the basis of gender [1] 
No differences between gender in the population over 65 years were observed [1]

Geriatric

61% increase in Cmax was observed comparing elderly males (≥65 years) to young males (18 - 45 years) in an oral multiple dose study. Those differences were not observed among women [1]
Safety profiles and plasma concentrations between the two groups were similar. Hence, no dosing adjustment is required on the basis of age [1]

Obesity

• 2.36 mg/L (n=8 obese patients with BMI ≥35 kg/m2) versus 1.89 mg/L in controls (n=14) with multiple dose of 200 mg oral every 12 hours [4]
• 4.16 mg/L (n=8 obese patients with BMI ≥35 kg/m2) versus 4.83 mg/L in controls (n=7) with multiple dose of 200 mg oral every 12 hours [4] 

Hepatic impairment

• No difference in Cmax after oral single dose of 200 mg in patients with Child-Pugh Class A to Class B (mild to moderate) hepatic impairment (n=12) [1]
• 20% lower Cmax in patients with Child-Pugh Class B given a lower maintenance dose of 100 mg oral twice daily (n=6) compared to subjects with normal hepatic function receiving 200 mg twice daily (n=6) [1]
It is recommended to keep loading dose equal for patients with hepatic impairment but to decrease the maintenance dose [1]

Renal impairment

• Oral
Cmax was not significantly affected in subjects with mild (CrCL 41 - 60 ml/min) to severe (CrCL <20 ml/min) renal impairment (28 - 68 years), compared to subjects with normal renal function after administration of a single oral dose of 200 mg voriconazole:

Normal renal function 972 ng/mL (n=6)
Mild renal impairment 1057 ng/mL (n=6)
Moderate renal impairment 967 ng/mL (n=6)
Severe renal impairment 692 ng/mL (n=6) [5]

• Intravenous:
No change in Cmax was observed in patients with different grades of renal impairment following intravenous multiple dosing. In a group of subjects with moderate renal impairment (n=7), intravenous voriconazole resulted in elevated sulfobutyl ether beta-cyclodextrin sodium (SBECD, excipient of intravenous voriconazole) levels but not in worsening of their creantinineclearance [1,5]

Time to peak plasma concentration (Tmax)

Adults: 1 - 2 hours [1,6]

Children (2 - 12 yrs):

• Intravenous:
4 mg/kg every 12 hours: 1 - 2 hours [2]
6 mg/kg every 12 hours: 1 - 2 hours [2]
7 mg/kg every 12 hours: 1.1 hours post-dose [7]
8 mg/kg every 12 hours: 2.84 hours [2]

Area Under the Curve (AUC)

Aduts:

• Oral: 19.86 mcg*h/mL (200 mg twice daily) to 50.32 mcg*h/mL (300 mg twice daily) [1]

• Intravenous: 21.81 mcg*h/mL (3 mg/kg twice daily) to 50.40 mcg*h/mL (4 mg/kg twice daily) [1]

Pediatric:

Children (2 - 12 yrs):

• Oral:
4 mg/kg multiple dosing: 5.2 mg*h/L (n = 19 patients) [2]
6 mg/kg multiple dosing: 8.4 mg*h/L (n = 18 patients) [2]

• Intravenous:
4 mg/kg every 12 hours: 11.8 mg*h/L (n = 22 patients) [2]
6 mg/kg every 12 hours: 17.2 - 22.9 mg*h/L (n = 21 - 19 patients) [2]
7 mg/kg every 12 hours: 49.3 mg*h/L (4.7 - 106.6 mg*h/L; n = 9 patients) [3]
8 mg/kg every 12 hours: 29.8 mg*h/L (n = 20 patients) [2]

Gender

In a multiple dose study with oral voriconazole in healthy young females, the AUC was reported to be 113% higher compared to younger males (18-45 years). In the same study, no differences between gender in the population over 65 years were observed. The oral tablet gives a 45% increase in AUC for healthy young females compared to healthy young males. Safety profiles and plasma concentrations between the two groups were similar. Hence, no dosing adjustment is required on the basis of gender [1]

Geriatric

An increase in AUC (86%) was observed in an oral multiple dose study in elderly males (≥65 years) compared to young males (18 - 45 years) [1]

Data from 10 clinical trials showed an increase in AUC of 80% to 90% in elderly (aged >65) compared to younger patients (≤ 65 years). Safety profiles and plasma concentrations between the two groups were similar. Hence, no dosing adjustment is required on the basis of age [1]

Obesity

14.6 mg*h/L (200 mg oral every 12 hours; n = 8) - 29.2 mg*h/L (300 mg oral every 12 hours; n = 8) [4]

Hepatic impairment

• 3.2-fold higher after oral single dose of 200 mg in patients with Child-Pugh Class A to Class B (mild to moderate) hepatic impairment (n=12) [1]
• 2.3-fold higher in patients with Chil-dPugh Class A (mild hepatic impairment)
• No data avilable on patients with Child-Pugh Class C (severe hepatic impairment)
It is recommended to decrease the maintenance dose for patients with hepatic impairment [1]

Renal impairment

• Intravenous: No change in AUC was observed in patients with different grades of renal impairment following intravenous multiple dosing.  In a group of subjects with moderate renal impairment (n=7), intravenous voriconazole resulted in elevated sulfobutyl ether beta-cyclodextrin sodium (SBECD, excipient of intravenous voriconazole) concentrations, but not in worsening of their creantinineclearance [1,5]
• Oral:No change in AUC was observed in patients with mild (CrCL 41 - 60 mL/min, n = 6) to severe renal dysfunction (CrCL <20 mL/min, n = 6) after a single dose of 200mg when compared to patients with normal renal function (CrCL 80 mL/min, n = 6) [1,5]

Steady state plasma concentrations

Steady state concentrations are achieved within 24 hours after administering the recommended intravenous or oral loading dose. Without the loading dose, steady state peak plasma concentrations are achieved by day 6 (using a twice daily regime) [1]

LINEARITY

Voriconazole displays non-linear kinetics. A greater than proportional increase in exposure is seen with increasing doses. Following intravenous dosing, increasing the dose from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours resulted in a 2.3-fold increase in AUC. Following oral dosing, increasing the dose from 200 mg every 12 hours to 300 mg every 12 hours resulted in a 2.5-fold increase in AUC [1]

Distribution

VOLUME OF DISTRIBUTION

• Adults: 4.6 L/kg (extensively distributed into tissues) [1]

• Children (age 2 - 1 yrs): 1.852 L/kg (7 mg/kg every 12 hours, n=9) [7]

• Obesity: No change in volume of distribution was observed in obese patients (mean weight 133.4 +/- 16.8 kg) when compared to patients with normal weight [4]

PROTEIN BINDING

Protein binding is approximately 58%, achieved following single or multiple doses of 200 or 300 mg oral voriconazole, independent of plasma concentration. Protein binding does not seem to be influenced by the degree of hepatic and renal insufficiency.

DISTRIBUTION SITES

Cerebrospinal fluid

42 - 67% of corresponding plasma concentrations in one case of cerebral aspergillosis in a patient with acute leukaemia [8]

Pleural fluid

• 200 mg every 12 hours (2 hours post-dose): 0.8 mg/L (plasma concentrations 1.24 mg/L) [9]

• 300 mg every 12 hours (2 hours post-dose): 1.4 mg/L (plasma concentrations 3.1 mg/L) [9]

Vitreous Humor

A median vitreous humor voriconazole concentration of 0.3 mg/L (range: 0.1 and 1.1 mcg/mL; n=5) was  achieved after hourly ocular dosing of a 1% voriconazole solution during the four hours prior to vitrectomy surgery [10]

Metabolism

METABOLISM SITES

Voriconazol is extensively metabolised in the liver [1]

METABOLITES

Voriconazole is mainly metabolised to its inactive N-oxide form, which accounts for 72% of circulating plasma metabolites [1]

BIOTRANSFORMATION

Voriconazole is mainly metabolised via the cytochrome P450 enzymes CYP2C19, and less significant via CYP2C9 and CYP3A4. CYP2C19 exhibits polymorphisms and the homozygote poor metabolizers (Caucasian and Japanese) demonstrated a 4-fold increase in their AUC while the heterozygote extensive metabolizers showed a 2-fold increase in their AUC, both compared to the homozygote extensive metabolizers.
Voriconazole also is an inhibitor of CYP2C19, CYP2C9 and CYP3A4.
The metabolism of voriconazole is saturable, leading to non-linear pharmacokinetics. Increase in dose leads to a more than proportional increase in Cmax and AUC [1]

Excretion

CLEARANCE

Renal excretion

Less than 2% is excreted as unchanged drug via the kidneys. After administration of multiple doses of either oral or intravenous voriconazole, 80 - 83% of voriconazole in its metabolite form was recovered in the urine [1,6]

Bile

An unknown part is excreted with the bile, primarily as metabolites [6] 

TOTAL BODY CLEARANCE

20.0 L/h (n=14) and 8.36 L/h (n=7) following multiple dosing of 200 mg or 300 mg every 12 hours respectively [4]

Obesity

13.4 L/h and 10.1 L/h for multiple dosing of 200 mg or 300 mg every 12 hours, respectively, in obese patients (mean weight 133.4 +/- 16.8 kg) [4]

Renal impairment

• Intravenous: No change in clearance was observed in patients with renal impairment compared with healthy volunteers. Clearance was 11.3 L/h for subjects with moderate renal impairment (CrCL 30 - 50 mL/min; n=7) and 7.4 L/h for subjects with normal renal function (n=6), both with a maintenance dose of 3mg/kg every 12 hours. In contrast, the clearance of SBECD was decreased in patients with moderate renal impairment compared to subjects with a normal renal function: 1.8 L/hour (n=7) versus 8.5 L/hour (n=6) respectively, although this did not worsen the CrCL [1,5]

• Oral: No change in clearance was observed in patients with mild (CrCL 41 - 60 mL/min), moderate (CrCL 20- 40 mL/min) or severe renal impairment (CrCL >20 mL/min; all groups n=6) compared with healthy volunteers (CrCL >80 mL/min) after a single dose of voriconazole 200 mg [5]

Pediatric

Clearance may be more rapid in children. Multiple dosing of 7 mg/kg every 12 hours in children aged 2 - 11 years resulted in a clearance of 141.0 mL/h/kg (range 65.7 - 1.483 mL/h/kg; n=9).
High inter- and  intra- variability was reported [7]

ELIMINATION HALF-LIFE

Terminal half life of voriconazole is 6 hours following a 200 mg oral dose. Because of the non-linear pharmacokinetics of voriconazole, this half-life is not useful as a predictor of the accumulation or elimination of voriconazole [1,6]

Renal impairment

Renal impairment does not influence terminal half-life of oral voriconazole. The intravenous formulation contains sulfobutylether-beta-cyclodextrin (SBECD), which does show prolonged terminal half-life in patients with moderate renal impairment [5]

Pediatrics

Mean elimination half-life was 10.9 hours in children aged 2 - 11 years receiving intravenous voriconazole 7 mg/kg every 12 hours (n=9) and 7.7 hours in the same age group receiving 5 mg/kg every 12 hours (n=3). There is a large degree of variability, as half-life varied between 3.1 and 29.2 hours [7]

EXTRACORPOREAL ELIMINATION

Voriconazole is dialyzable. Hemodialysis clearance is 121 ml/min for voriconazole and 55 ml/min for sulfobutyl ether beta-cyclodextrin sodium (SBECD, the solubilizing agent).
A four hour session of hemodialysis does not remove sufficient voriconazole to require dose adjustment of voriconazole. In an overdose setting, hemodialysis may assist in removal of voriconazole and SBECD from the body [1]

Isavuconazole

General pharmacokinetics

Isavuconazole is available in both oral and intravenous formulations. Oral isavuconazonium is rapidly and almost completely absorbed (bioavailability 98%) and quickly hydrolised by plasma esterases to isavuconazole [1-3]. Bioequivalence is established between the oral and intravenous formulation [2,3]. Absorption is not impacted by food or gastric pH [1]. Time to maximum plasma concentrations is reached 2-3 hours after oral administration [1-3]. Isavuconazole plasma and peak concentrations are proportional to dose [1]. Due to the long elimination half-life of 130 hours, steady state concentrations are reached after 4 weeks [3]. The long half-life allows isavuconazole to be administered once daily.
Isavuconazole is highly protein bound (>99%) and is widely distributed in the body (apparent volume of distribution: 450 L) [1].
Isavuconazole is metabolized by CYP3A4, CYP3A5 and uridine diphosphate-glucuronosyltransferases (UGT) [1]. It is a mild inhibitor of drug transporters P-glycoprotein (P-gp) and organic cation transporter 2 (OCT2) and possibly breast cancer resistance protein (BCRP) [1,8-10]. Only a few minor metabolites of isavuconazole were detected, with no individual metabolite observed with an AUC greater than 10% of drug related material [1].
Renal excretion of isavuconazole is <1% of the administered dose. Isavuconazole is not readily dialyzable [1].

References

[1] US Food and Drug Administration. Cresemba (isavuconazonium sulfate): US prescribing information. 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207500Orig1s000lbl.pdf.

[2] Schmitt-Hoffmann A, Roos B, Heep M, et al. Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and
400 milligrams) of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother 2006;50(1):279-85

[3] Schmitt-Hoffmann A, Roos B, Maares J, et al. Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother 2006;50(1):286-93

[4] Cornely OA, Bohme A, Reichert D, et al. Pharmacokinetics, safety and tolerability results from a dose escalation study of isavuconazole in neutropenic patients [M-2137]. In: 48th annual international interscience conference on antimicrobial agents and chemotherapy (ICAAC). American Society for Microbiology;Washington; 2008

[5] Schmitt-Hoffmann A, Roos B, Spickermann J, et al. No relevant food effects in man on isavuconazole oral pharmacokinetics preliminary data (abstract no. A-008). In: 48th interscience conference on antimicrobial agents and chemotherapy/Infectious Diseases Society of America 46th annual meeting. 2008.

[6] Schmitt-Hoffmann A, Roos B, Spickermann J, et al. Effect of mild and moderate liver disease on the pharmacokinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557. Antimicrob Agents Chemother. 2009;53(11):4885–90.

[7] Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, p. 445–449, 2nd ed. Marcel Dekker, Inc., New York, N.Y.

[8] Desai A, Zadeikis N, Breese N, et al. Isavuconazole does not significantly affect the pharmacokinetics of p-glycoprotein substrate digoxin in healthy subjects. Clin Pharmacol Ther.
2013;93:S40.

[9] Desai A, Yamazaki T, Kowalski D, et al. Effect of multiple doses of isavuconazole on the pharmacokinetics of metformin in healthy subjects (abstract no. PI-072). Clin Pharmacol Ther.
2014;95(Suupl 1):S41.

[10] Yamazaki T, Desai A, Kowalski D, et al. Effect of multiple doses of isavuconazole on the pharmacokinetics of methotrexate in healthy subjects (abstract no. PII-095). Clin Pharmacol Ther.
2014;95(Suppl 1):S93.

Absorption

BIOAVAILABILITY

Isavuconazole is administered as the prodrug isavuconazolnium sulphate (BAL8557) and almost completely absorbed  after oral administration, with a bioavailability of 98% in healthy subjects [1-3]. Isavuconazonium is rapidly hydrolysed by estrases into the active moiety isavuconazol and an inactive cleavage component (BAL 8728) both after oral and IV administration. In neutropenic patients, the bioavailability also appeared to be excellent [4].

Absorption not affected by gastric pH [1].

FOOD EFFECTS

With high fat meals, isavuconazole 400 mg oral dose increased Cmax by 9% and reduced AUC by 9%. Isavuconazole can be administered with or without food [5].

Bioequivalence
There is bioequivalence between oral tablet and the IV formulation[2,3]. A loading dose is not required when switching between formulations [1].

PLASMA CONCENTRATIONS

Peak plasma concentrations (Cmax)

Single dose:

Oral; healthy subjects [2]
• 1.45 mg/L (± 0.177) with 100 mg (n=6)
• 2.59 mg/L (± 0.449) with 200 mg (n=6)
• 5.57 mg/L (± 0.212) with 400 mg (n=3)

Intravenous; healthy subjects [2]
• 0.446 mg/L (± 0.076) with 50 mg (n=6)
• 1.03 mg/L (± 0.184) with 100 mg (n=6)
• 2.47 mg/L (± 0.374) with 200 mg (n=6)

Multiple dose:

Oral; healthy subjects [1]
• 7.5 mg/L (± 1.89) with 200 mg at steady state (n=37)
• 20.0 mg/L (± 3.58) with 600 mg at steady state (n=32)

Oral: 100 mg loading dose, 50 mg/day maintenance dose; healthy subjects (n=6) [3]
• Day 1: 1.10 mg/L (± 0.173)
• Day 8: 1.20 mg/L (± 0.215)
• Day 14: 1.40 mg/L (± 0.178)
• Day 21: 1.37 mg/L (± 0.230)

Oral: 200 mg loading dose, 100 mg/day maintenance dose; healthy subjects (n=6) [3]
• Day 1: 1.85 mg/L (± 0.326)
• Day 8: 2.33 mg/L (± 0.472)
• Day 14: 2.61 mg/L (± 0.365)
• Day 21: 2.56 mg/L (± 0.434)

Intravenous: 100 mg loading dose, 50 mg/day maintenance dose (1 h constant infusion); healthy subjects [3]
• Day 1: 1.28 mg/L (± 0.122; n=6)
• Day 8: 0.987 mg/L (± 0.180; n=6)
• Day 14: 1.17 mg/L (± 0.237, n=5)

Intravenous: 200 mg loading dose, 100 mg/day maintenance dose (1 h constant infusion); healthy subjects (n=6) [3]
• Day 1: 2.32 mg/L (± 0.445)
• Day 8: 2.52 mg/L (± 1.05)
• Day 14: 2.55 mg/L (± 0.883)

Hepatic impairment

Cmax after single dose of 100 mg decreased by 2% and 30% in patients with mild (Child-Pugh Class A) hepatic impairment (n=32; 16 oral, 16 IV) and moderate (Child-Pugh class B) hepatic impairment (n=32; 16 oral, 16 IV) respectively, compared to 32 age and weight-matched healthy subjects with normal hepatic function.
Pharmacokinetic properties of isavuconazole have not been studied in patients with severe (Child-Pugh Class C) hepatic disease [1,6].
No dose adjustment is required in patients with mild to moderate hepatic disease [1].

Renal impairment

No change in AUC and Cmax was observed for patients with different grades (mild, moderate, severe) of renal impairment when compared to healthy subjects [1].
No dose adjustment is required in patients with renal impairment.

Time to peak plasma concentration (Tmax)

Tmax is generally reached within 2-3 hours after single and multiple oral doses [1].

Single dose:

Oral; healthy subjects [2]
• 2.0 h (1.6 – 2.0) with 100 mg (n=6)
• 1.8 h (1.5 – 3.0) with 200 mg (n=6)
• 3.0 h (2.1 – 3.0) with 400 mg (n=3)

Multiple dose:

Oral; healthy subjects [1]
• 3.0 h (2.0 – 4.0) with 200 mg at steady state (n=37)
• 4.0 h (2.0 – 4.0) with 600 mg at steady state (n=32)

Oral: 100 mg loading dose, 50 mg/day maintenance dose; healthy subjects (n=6) [3]
• Day 1: 2.0 h (2.0 – 3.0)
• Day 8: 2.0 h (1.5 – 3.0)
• Day 14: 3.0 h (1.25 – 4.0)
• Day 21: 2.25 h (1.5 – 3.0)

Oral: 200 mg loading dose, 100 mg/day maintenance dose; healthy subjects (n=6) [3]
• Day 1: 2.0 h (1.25 – 3.07)
• Day 8: 3.0 h (2.0 – 12.0)
• Day 14: 2.25 h (1.5 – 4.0)
• Day 21: 3.5 h (2.0 – 4.0)

Area Under the Curve (AUC)

Single dose (AUC0-inf):

Oral; healthy subjects [2]
• 37.0 mg*h/L (± 6.75) with 100 mg (n=6)
• 78.5 mg*h/L (± 10.8) with 200 mg (n=6)
• 215 mg*h/L (± 42.0) with 400 mg (n=3)

Intravenous; healthy subjects [2]
• 11.3 mg*h/L (± 4.43) with 50 mg (n=6)
• 26.6 mg*h/L (± 6.25) with 100 mg (n=6)
• 73.2 mg*h/L (± 12.4) with 200 mg (n=6)

Multiple dose:

Oral; healthy subjects [1]
• 121.40 mg*h/L (± 35.77) with 200 mg at steady state (AUC0-inf ; n=37)
• 352.81 mg*h/L (± 72.02) with 600 mg at steady state (AUC0-inf ; n=32)

Oral: 100 mg loading dose, 50 mg/day maintenance dose; healthy subjects (AUC0-24 ; n=6) [3]
• Day 1: 8.75 mg*h/L (± 1.26)
• Day 8: 18.1 mg*h/L (± 4.45)
• Day 14: 22.1 mg*h/L (± 4.92)
• Day 21: 21.6 mg*h/L (± 4.30)

• AUC0-inf on day 21: 130 mg*h/L (± 26.5)

Oral: 200 mg loading dose, 100 mg/day maintenance dose; healthy subjects (AUC0-24 ; n=6) [3]
• Day 1: 18.5 mg*h/L (± 3.11)
• Day 8: 34.0 mg*h/L (± 5.70)
• Day 14: 41.5 mg*h/L (± 6.02)
• Day 21: 40.3 mg*h/L (± 4.28)

• AUC0-inf on day 21: 255 mg*h/L (± 80.5)

Intravenous: 100 mg loading dose, 50 mg/day maintenance dose (1 h constant infusion); healthy subjects (AUC0-24) [3]
• Day 1: 7.32 mg*h/L (± 1.09; n=6)
• Day 8: 12.4 mg*h/L (± 3.77; n=6)
• Day 14: 14.3 mg*h/L (± 5.33, n=5)

• AUC0-inf on day 14: 90.2 mg*h/L (± 52.2)

Intravenous: 200 mg loading dose, 100 mg/day maintenance dose (1 h constant infusion); healthy subjects (AUC0-24 ; n=6) [3]
• Day 1: 12.9 mg*h/L (± 1.93)
• Day 8: 24.3 mg*h/L (± 5.79)
• Day 14: 33.6 mg*h/L (± 9.67)

• AUC0-inf on day 14: 236 mg*h/L (± 31.5, n=4)

Gender

AUC estimates were similar between healthy young females (18-45 years) and healthy young males. However, a difference in AUC in elderly females (65 years and older) was observed ‘see Geriatric’ [1].
No dose adjustment is required based on gender [1].

Geriatric

Following a single oral dose of 200 mg, AUC estimates in elderly females (65 years and older) were 38% and 47% greater compared to healthy elderly males (65 years and older) and young females (18-45 years), respectively. This pharmacokinetic difference is considered not to be of clinical significance. Therefore, no dose adjustment is required based on age and gender [1].

Race

Healthy Chinese subjects were found to have on average a 40% lower CL compared to Western subjects (1.6 L/hr and 2.6 L/hr, respectively). Hence, the AUC was 50% higher in Chinese subjects.
No dose adjustment is required based on race [1].

Hepatic impairment

AUC0-24 after single dose of 100 mg increased by 64% and 84% in patients with mild (Child-Pugh Class A) hepatic impairment (n=32; 16 oral, 16 IV) and moderate (Child-Pugh class B) hepatic impairment (n=32; 16 oral, 16 IV) respectively, compared to 32 age and weight-matched healthy subjects with normal hepatic function.
Pharmacokinetic properties of isavuconazole have not been studied in patients with severe (Child-Pugh Class C) hepatic disease [1,6].
No dose adjustment is required in patients with mild to moderate hepatic disease [1].

Renal impairment

No change in AUC and Cmax was observed for patients with different grades (mild, moderate, severe) of renal impairment when compared to healthy subjects [1].
No dose adjustment is required in patients with renal impairment.

Steady state plasma concentration

In a study with multiple-dose oral and intravenous doses, it is reported that 90% of steady-state concentrations is theoretically reached after 332 h (2 weeks) and 99% of the steady state after 664 h (4 weeks) [3].

LINEARITY

Isavuconazole displays linear pharmacokinetics in doses up to 600 mg once daily [1].

Distribution

VOLUME OF DISTRIUTION

Extensive distribution with a mean steady state volume of distribution of approximately 450 L (following intravenous infusion) [1].

Single dose:

Oral; healthy subjects [2]
• 248 L (± 80.4) with 100 mg (n=6)
• 292 L (± 80.8) with 200 mg (n=6)
• 155 L (± 39.2) with 400 mg (n=3)

Intravenous; healthy subjects [2]
• 444 L (± 175) with 50 mg (n=6)
• 494 L (± 280) with 100 mg (n=6)
• 304 L (± 86.6) with 200 mg (n=6)

Multiple dose:

Oral: 100 mg loading dose, 50 mg/day maintenance dose; healthy subjects (n=6) [3]
• Day 21: 346 L (± 112)

Oral: 200 mg loading dose, 100 mg/day maintenance dose; healthy subjects (n=6) [3]
• Day 21: 308 L (± 118)

Intravenous: 100 mg loading dose, 50 mg/day maintenance dose (1 h constant infusion); healthy subjects [3]
• Day 14: 470 L (± 162, n=5)

Intravenous: 200 mg loading dose, 100 mg/day maintenance dose (1 h constant infusion); healthy subjects [3]
• Day 14: 542 L (± 229, n=4)

PROTEIN BINDING

Highly protein bound (>99%), predominantly to albumin [1].

Metabolism

METABOLITES

In vitro studies show that the prodrug isavuconazonium sulfate is rapidly and almost completely hydrolyzed in blood to isavuconazole by esterases (maily butylcholinesterase) [1]. Following oral administration, the prodrug and inactive cleavage product were not detected in plasma in significant concentrations. Following IV administration, the prodrug was undetectable in plasma by 1.25 h from the start of a 1 h infusion (AUC of the prodrug was <1% of isavuconazole) [1].
Besides isavuconazole and the inactive cleavage product, a number of minor metabolites were identified after single doses of [cyano14C]isavuconazonium and [pyridinylmethyl14C]isavuconazonium. No individual metabolite was observed with an AUC greater than 10% of drug related material [1].

BIOTRANSFORMATION

In vivo studies show that CYP3A4, CYP3A5 and uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole [1].
Isavuconazole is a mild inhibitor of drug transporters P-glycoprotein (P-gp) and organic cation transporter 2 (OCT2) since it showed a weak inhibitory effect on digoxin (a P-gp substrate) [8] and metformin (an OCT2 substrate) in healthy subjects [9].
Preclinical studies showed that isavuconazole may inhibit breast cancer resistance protein (BCRP), although isavuconazole did not significantly alter the pharmacokinetics of methotrexate (a BCRP substrate) in healthy subjects [10].

Excretion

CLEARANCE

Renal excretion

After administration of a single-dose of radio-labeled isavuconazonium sulfate to healthy volunteers, a mean of 45.5% of the radioactive dose was recovered in urine [1].
Renal excretion of isavuconazole itself was <1% of the dose administered.

Faecal excretion

After administration of a single-dose of radio-labeled isavuconazonium sulfate to healthy volunteers, a mean of 46.1% of the radioactive dose was recovered in feces [1].

Total body clearance

Single dose:

Oral; healthy subjects [2]
• 2.80 L/h (± 0.548) with 100 mg (n=6)
• 2.59 L/h (± 0.363) with 200 mg (n=6)
• 1.91 L/h (± 0.418) with 400 mg (n=3)

Intravenous; healthy subjects [2]
• 5.03 L/h (± 1.99) with 50 mg (n=6)
• 3.96 L/h (± 1.04) with 100 mg (n=6)
• 2.80 L/h (± 0.519) with 200 mg (n=6)

Multiple dose:

Oral: 100 mg loading dose, 50 mg/day maintenance dose; healthy subjects (n=6) [3]
• Day 14: 2.36 L/h (± 0.479)
• Day 21: 2.39 L/h (± 0.430)

Oral: 200 mg loading dose, 100 mg/day maintenance dose; healthy subjects (n=6) [3]
• Day 14: 2.45 L/h (± 0.356)
• Day 21: 2.51 L/h (± 0.275)

Intravenous: 100 mg loading dose, 50 mg/day maintenance dose (1 h constant infusion); healthy subjects [3]
• Day 14: 4.06 L/h (± 1.97, n=5)

Intravenous: 200 mg loading dose, 100 mg/day maintenance dose (1 h constant infusion); healthy subjects (n=6) [3]
• Day 14: 3.19 L/h (± 0.901)

Hepatic impairment

Population pharmacokinetic evaluation indicated that isavuconazole CL decreased by 40% and 48%, respectively, in patients with mild (Child-Pugh Class A) hepatic impairment (n=32; 16 oral, 16 IV) and moderate (Child-Pugh class B) hepatic impairment (n=32; 16 oral, 16 IV) compared to 32 age and weight-matched healthy subjects with normal hepatic function.
Pharmacokinetic properties of isavuconazole have not been studied in patients with severe (Child-Pugh Class C) hepatic disease [1,6].
No dose adjustment is required in patients with mild to moderate hepatic disease [1].

Race

Healthy Chinese subjects were found to have on average a 40% lower CL compared to Western subjects (1.6 L/hr and 2.6 L/hr, respectively). Hence, the AUC was 50% higher in Western subjects.
However, no dose adjustment is required based on race [1].

ELIMINATION HALF-LIFE

Long plasma half-life of mean 130 hours [1].

Single dose:

Oral; healthy subjects [2]
• 63.1 h (± 21.7) with 100 mg (n=6)
• 77.1 h (± 12.8) with 200 mg (n=6)
• 56.0 h (± 2.49) with 400 mg (n=3)

Intravenous; healthy subjects [2]
• 76.2 h (± 32.0) with 50 mg (n=6)
• 104 h (± 56.7) with 100 mg (n=6)
• 80.4 h (± 33.0) with 200 mg (n=6)

Multiple dose:

Oral: 100 mg loading dose, 50 mg/day maintenance dose; healthy subjects (n=6) [3]
• Day 21: 98.4 h (± 21.3)

Oral: 200 mg loading dose, 100 mg/day maintenance dose; healthy subjects (n=6) [3]
• Day 21: 84.5 h (± 28.3)

Intravenous: 100 mg loading dose, 50 mg/day maintenance dose (1 h constant infusion); healthy subjects [3]
• Day 14: 93.0 h (± 40.1, n=5)

Intravenous: 200 mg loading dose, 100 mg/day maintenance dose (1 h constant infusion); healthy subjects (n=6) [3]
• Day 14: 117 h (± 17.6, n=4)

EXTRACORPOREAL ELIMINATION

Renal replacement therapy

Isavuconazole is not readily dialyzable. No dose adjustments are required in patients with ESRD [1].

Anidulafungin

General pharmacokinetics

Anidulafungin absorption is very low after oral administration (bioavailability 2 – 7%) and therefore an intravenous formulation has been developed. Hence, absolute bioavailability is considered to be 100%.
Linear pharmacokinetics were seen after once daily dosing (15 – 130 mg).
The volume of distribution of anidulafungin is comparable to body fluid (0.6 L/kg), with a rapid distribution half-life of 0.5 – 1 hour. It is extensively bound to human plasma proteins (>99%). Data derived from animal studies indicate accumulation of anidulafungin in several organs (liver, spleen, kidney and lung), crossing of placenta and excretion into mother milk. Due to a lack of distribution studies of anidulafungin, no information is available about penetration of anidulafungin into the CSF and/or across the blood brain barrier. Steady state plasma concentrations were achieved on the first day after a loading dose (twice the daily maintenance dose).
Anidulafungin undergoes slow chemical degradation (non-enzymatic) at physiologic temperature and pH to an inactive ring-opened peptide and ultimately to inactive peptide degradants. These degradants are mainly  eliminated through biliary excretion. It is not a clinically relevant substrate, inducer or inhibitor of cytochrome P450 isoenzymes.
Total body clearance of anidulafungin is 1 L/h, independent of dose and not affected by repeated administration. Approximately 29% is recovered in feces over 9 days, of which less than 10% parent compound. Renal clearance is negligible, with less than 1% of the drug recovered in urine. Elimination half-life is 24 hours, characterizing the majority of the plasma concentration-time profile (terminal half-life of 40 – 50 hours). Anidulafungin is not dialyzable.

References

[1] ECALTA: EPAR, Scientific Discussion 2007: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000788/WC500020676.pdf

[2] Product Information: ERAXIS(TM) IV injection, anidulafungin IV injection. Roerig, New York, NY, 2010.

[3] Benjamin DK Jr, Driscoll T, Seibel NL, et al: Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother 2006; 50(2):632-638.

[4] Cohen-Wolkowiez M, Benjamin DK Jr, Piper L, et al: Safety and pharmacokinetics of multiple-dose anidulafungin in infants and neonates. Clin Pharmacol Ther 2011; 89(5):702-707.

Absorption

BIOAVAILABILITY

Oral bioavailability of anidulafungin is low (2 - 7%) [1]

PLASMA CONCENTRATIONS

Peak plasma concentrations (Cmax)

Adults:
• 4.2 mg/L, after a loading dose of 100 mg and multiple daily doses of 50 mg [2]
• 7.2 mg/L, after a loading dose of 200 mg and multiple daily doses of 100 mg [2]

Note: Cmax is similar between healthy adults and adult patients with fungal infections (4 phase 2/3 clinical trials, n=225) [2]

Children (2 - 17 yrs):
• 3.32 - 4.35 mg/L, after a loading dose of 1.5 mg/kg and multiple daily doses of 0.75 mg/kg [2]
• 6.88 - 7.57 mg/L, after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [2]

Note: Cmax is similar between children (2 - 17 yrs) and adults (open-label dose-escalation study, n=24) [2,3]

Infants (30d - 2 yrs):
• 5.2 mg/L, after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [4]

Neonates and infants (<3 months)
• 3.9 mg/L, after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [4]

Area under the curve (AUC0-24h)

Adults:
• 55.2 mg*h/L, after a loading dose of 100 mg and multiple daily doses of 50 mg [2]
• 110.3 mg*h/L, after a loading dose of 200 mg and multiple daily doses of 100 mg [2]

Note: AUC is similar between healthy adults and adult patients with fungal infections (4 phase 2/3 clinical trials, n=225) [2]

Children (2 - 17 yrs):
• 41.1 - 57.8 mg*h/L, after a loading dose of 1.5 mg/kg and multiple daily doses of 0.75 mg/kg [2]
• 96.1 - 102.9 mg*h/L, after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [2]

Note: Cmax is similar between children (2 - 17 yrs.) and adults (open-label dose-escalation study, n=24) [2,3]

Infants (30d - 2 yrs):
• 97.7 mg*h/L, after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [4]

Neonates and infants (<3 months)
• 74.9 mg*h/L, after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [4]

Renal impairment:
Dose adjustment is not needed in patients with any degree of renal insufficiency [1]

Hepatic imparment:
Dose adjustment is not needed in patients with mild, moderate or severe hepatic impairment [1]

Steady state plasma concentrations

Steady state concentrations are reached on the first day after a loading dose (twice the daily maintenance dose) [1]

LINEARITY

Anidulafungin displays linear pharmacokinetics across the dose range of 15 - 130 mg once daily [2]

Distribution

VOLUME OF DISTRIBUTION

Adults:
Volume of distribution of anidulafungin in adults is 0.6 L/kg (30 - 50L), comparable to total body fluid [1]

Children (2 - 17 yrs):
• 0.434 L/kg, after a loading dose of 3.0 mg/kg and multiple daily doses of 1.5 mg/kg [3]
• 0.537 L/kg, after a loading dose of 1.5 mg/kg and multiple daily doses of 0.75 mg/kg [3]

Infants (30d - 2 yrs):
• 0.9 L/kg, after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [4]

Neonates and infants (<3 months):
• 1.7 L/kg, after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [4]

PROTEIN BINDING

Anidulafungin is highly bound to human plasma proteins (~99%) and does not accumulate in erythrocytes [1]

DISTRIBUTION SITES

Data derived from animal studies indicate accumulation of anidulafungin in several organs (liver, spleen, kidney and lung), crossing of placenta and excretion into mother milk [1]

Due to a lack of distribution studies of anidulafungin, no information is available about penetration of anidulafungin into the CSF and/or across the blood brain barrier [2]

DISTRIBUTION HALF LIFE

0.5 - 1 hour [2]

TISSUE CONCENTRATIONS

No specific tissue distribution studies of anidulafungin have been performed in humans. Therefore, it is unclear whether anidulafungin penetrates into the cerebrospinal fluid (CSF) and/or across the blood-brain barrier [1]

Metabolism

METABOLISM SITES

Liver/none: Hepatic metabolism has not been observed for anidulafungin [1] 

METABOLITES

At physiologic temperature and pH, anidulafungin undergoes slow chemical non-enzymatic degradation to an open-ring peptide. This metabolite is further metabolised by non specific peptidases into small peptides; none of the metabolites are considered to have antifungal activity [1]

BIOTRANSFORMATION

Anidulafungin is not considered to be a substrate, inhibitor or inducer of CYP P450 isoenzymes. At clinically relevant concentrations, anidulafungin did not significantly inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A in vitro [2] 

Excretion

CLEARANCE

Renal excretion

Renal clearance is negligible: after administration of a single-dose of radioactive anidulafungin, approximately 0.56% (± 0.12%) was excreted in urine [1,2]

Faecal excretion

After administration of a single-dose of radioactive anidulafungin, approximately 29% (±13%) of the dose was recovered in faeces over 9 days; <10% was recovered as intact anidulafungin [1,2]

Total body clearance

Adults:
• 1 L/h [1,2]

Note: Clearance is similar between healthy adults and adult patients with fungal infections (4 phase 2/3 clinical trials, n=225) [2]

Children (2 - 17 yrs):
• 0.0175 L/kg/h after a loading dose of 1.5 mg/kg and multiple daily doses of 0.75 mg/kg [3]
• 0.0159 L/kg/h after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [3]

Infants (33d - 2 yrs):
• 0.015 L/kg/h after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [4]

Neonates and infants (<3 months):
• 0.02 L/kg/h after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [4]

ELIMINATION HALF LIFE

Approximately 24 hours

Adults:
• 26.5 hours [1,2]

Children (2 - 17 yrs):
• 23.1 hours after a loading dose of 1.5 mg/kg and multiple daily doses of 0.75 mg/kg [3]
• 19.9 hours after a loading dose of 3 mg/kg and multiple daily doses of 1.5 mg/kg [3]

TERMINAL ELIMINATION HALF LIFE

40 - 50 hours [1,2]

EXTRACORPOREAL ELIMINATION

Renal replacement therapy

Anidulafungin is not removed by hemodialysis [2]

Caspofungin

General pharmacokinetics

Caspofungin is not absorbed after oral administration and therefore an intravenous formulation has been developed. Hence, absolute bioavailability is considered to be 100%. Linear pharmacokinetics were seen after once daily dosing (5 – 100 mg). However, caspofungin exerted moderate non-linear pharmacokinetics after multiple dosing, with increased accumulation as the dose increased. Time to reach steady state was dose dependent.
Caspofungin plasma concentration-time profile is triphasic, with a short alpha-phase, dominant beta-phase (6 - 48 h after infusion) and long gamma-phase. Caspofungin shows marked inter-subject variability in systemic exposure (coefficient of variation ~30%). Caspofungin is extensively bound to albumin (97%), with a varying unbound fraction of 3.5% in healthy volunteers and 7.6% in patients with invasive candidiasis. Distribution is the rate-controlling step in both alpha and beta-phases, with peaking distribution into tissues at 1.5 – 2 days when 92% of the dose was distributed into tissues. Because elimination occurs without a distribution equilibrium, the volume of distribution of caspofungin can currently not be estimated.
Caspofungin undergoes spontaneous degradation to an open ring compound, and is further metabolized via hydrolysis and N-acetylation into two inactive metabolites. In vitro studies have shown that caspofungin does not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6 and 3A4. Clinical studies showed that caspofungin does not inhibit CYP3A4. It is not a substrate for P-gp and is a poor substrate of cytochrome P450 enzymes.
Total body clearance of caspofungin from plasma is 10 - 12 ml/min, primarily influenced by distribution (rather than excretion or biotransformation). Approximately 75% of the dose (caspofungin + metabolites) is recovered over 27 days (41% urine and 34% feces). Renal clearance is negligible, with ~1.4% of the drug excreted in urine. Caspofungin is not dialyzable, it can be administered without regard to hemodialysis.

References

[1] Cancidas: EPAR, Scientific Discussion 2005: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000379/WC500057186.pdf

[2] Product Information: CANCIDAS(R) IV infusion, caspofungin acetate IV infusion. Merck & Co,Inc, Whitehouse Station, NJ, 2008.

[3] Walsh TJ, Adamson PC, Seibel NL, et al: Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother 2005; 49(11):4536-4545.

[4] Saez-Llorens X, Macias M, Maiya P, et al: Pharmacokinetics and Safety of Caspofungin in Neonates and Infants Less than 3 Months of Age. Antimicrobial agents and chemotherapy 2009; 53(3):869-875.

[5] Balani SK, Xu X, Arison BH, et al: Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. Drug Metab Dispos 2000; 28(11):1274-1278.

Absorption

BIOAVAILABILITY

Oral bioavailability of caspofungin is not determined as it is developed for parenteral use only [1]. Oral bioavailability of anidulafungin (another echinocandin antifungal) is proven to be low (2 - 7%).

PLASMA CONCENTRATIONS

Peak plasma concentrations (Cmax)

Adults:
• 8.7 ± 2.1 mg/L after multiple daily doses of 50 mg [2]
• 9.39 mg/L (mean end-of-infusion-concentration) after multiple daily doses of 50 mg. Mean trough (C24) was 2.01 mg/L [3]
• 13.3 mg/L after multiple daily doses of 70 mg. Mean trough (C24) was 3.33 mg/L [3]

Adolescents (12 - 17 yr):
• 14 ± 6.9 mg/L after multiple daily doses of 50 mg/m2/day [2]
• 12.9 mg/L (mean end-of-infusion-concentration) after multiple daily doses of 50 mg/m2/day. Mean trough was 2.15 mg/L [3]

Children (2 - 11 yr):
• 16.1 ± 4.2 mcg/mL after multiple daily doses of 50 mg/m2/day [2]
• 15.6 mg/L (mean end-of-infusion-concentration) after multiple daily doses of 50 mg/m2/day. Mean trough (C24) was 1.46 mg/L [3]
• 20.9 mg/L after multiple daily doses of 50 mg/m2/day. Mean trough (C24) was 2.47 mg/L [3]

Children (3 - 23 months):
• 17.6 ± 3.9 mg/L after multiple daily doses of 50 mg/m2/day [2]

Neonates and infants (<3 months)
• 8.2 mg/L after single dose of 25mg/m2. Mean trough (C24) was 1.8 mg/L [4]
• 10.9 mg/L after single dose of 25mg/m2. Mean trough (C24) was 2.3 mg/L [4]

Area under the curve (AUC0-24h)

Adults:
• 87.3 ± 30 mg*h/L after multiple daily doses of 50 mg/day [2]
• 103 mg*h/L after multiple daily doses of 50 mg/day [3]
• 154 mg*h/L after multiple daily doses of 70 mg/day [3]

Adolescents (12 - 17 yr):
• 124.9 ± 50.4 mg*h/L after multiple daily doses of 50 mg/m2/day [2]
• 117 mg*h/L after multiple daily doses of 50 mg/m2/day [3]

Children (2 - 11 yr):
• 120 ± 33.4 mg*h/L after multiple daily doses of 50 mg/m2/day [2]
• 115 mg*h/L after multiple daily doses of 50 mg/m2/day [3]
• 161 mg*h/L in children treated with 70 mg/m2/day [3]

Children (3 - 23 months):
• 131.2 ± 17.7 mg*h/L after multiple daily doses of 50 mg/m2/day [2]

Renal impairment:
• Mild renal insufficiency (CrCL 50 - 80 mL/min): no significant change in plasma concentration [1,2]
• Moderate (CrCL 31 - 49 mL/min), severe (CrCL 5 - 30 mL/min) and end stage (CrCL <10 mL/min and dialysis dependent) renal insufficiency after single dose of 70mg: increase in AUC of 31%, 49% and 30%, respectively [1]
• Moderate, severe and end stage renal insufficiency after 50mg/day: no significant change in plasma concentration [1,2]

Hepatic impairment:
• Mild hepatic impairment (Child-Pugh score 5 - 6) after a single dose of 70mg: increase in AUC of 55% compared to healthy subjects [2]
• Mild hepatic impairment after multiple daily doses of 50 mg: increase in AUC of 19% (day 7) and 25% (day 14) compared to healthy subjects [2]
• Moderate hepatic impairment (Child-Pugh score 7-9) after a single dose of 70mg: increase in AUC of 76% compared to healthy subjects [2]

Steady state plasma concentrations

Steady state concentrations appear to be reached within 10 days. Time to reach steady state was dose dependent [1,2]

LINEARITY

Linear pharmacokinetics were seen after once daily dosing (5 – 100 mg) [1]. However, caspofungin exerted moderate non-linear pharmacokinetics after multiple dosing, with increased accumulation as the dose increased.

Distribution

VOLUME OF DISTRIBUTION

Caspofungin shows polyphasic, log linear distributional behaviour. A short alpha phase occurs immediately after infusion. A log linear beta phase follows between 6 - 48 hours after infusion (plasma concentrations decline 10-fold), followed by a gamma phase [2] Because elimination occurs without a distribution equilibrium, the volume of distribution of caspofungin can currently not be estimated [2]

PROTEIN BINDING

Caspofungin is highly bound to albumin (97%) and is minimally distributed to erythrocytes [1] Caspofungin exhibits a varying unbound fraction of 3.5% in healthy volunteers and 7.6% in patients with invasive candidiasis [2].

DISTRIBUTION SITES

Slow but extensive distribution into tissues (approximately 92% is distributed into tissues within 36 - 48h) [2]

DISTRIBUTION HALF LIFE

Distribution is the primary factor influencing plasma clearance, rather than excretion [2]

Adults:
• Beta phase distribution half life: 9 - 11 h after a single dose [2]
• Beta phase distribution half life: 13 ± 1.9 h after multiple doses of daily 50 mg/day [3]
• Beta phase distribution half life: 16.5 ± 7 h in patients treated with 70mg/day [3]
• Gamma phase distribution half life: 40 - 50 h after a single dose [2]

Adolescents (12 - 17 yr):
• Beta phase distribution half life 11.2 ± 1.7 h after multiple doses of daily 50 mg/m2/day [3]

Children (2 - 11 yr):
• Beta phase distribution half life 8.2 ± 2.4 h after multiple doses of daily 50 mg/m2/day [3]
• Beta phase distribution half life 9.7 ± 2 h after multiple doses of daily 70 mg/m2/day [3]

Metabolism

METABOLISM SITES

Liver and plasma, to an unknown extent [5]

METABOLITES

Primary metabolism is slow, with minimal biotransformation occuring during the first 24 hours after administration of an IV dose [5]:

• Spontaneous degradation to an open-ring peptidecompound (L-747969, activity not specified) [2]

• Constitutive aminoacids and degradates (including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine) through N-acetylation and hydrolysis (activity not specified) [1,2]

Five days of more after dosing, ≤ 1,3% of the administered dose is found in plasma [2,5]

BIOTRANSFORMATION

In vitro studies suggest that caspofungin did not inhibit any enzyme in the cytochrome P450 system. Clinical studies confirmed that caspofungin did not induce CYP3A4. It is a poor substrate for CYP450 enzymes, but not for P-glycoprotein [2].

Excretion

CLEARANCE

Renal excretion

41% of the administered dose (caspofungin and metabolites) was recovered in urine during 27 days [1] There is little excretion of intact caspofungin during the first 30 hours after administration [1]

Only 1 - 9% of the administered dose has been recovered as unchanged drug [1,5]

Faecal excretion

35% of the administered dose (caspofungin and metabolites) was recovered in faeces during 27 days [1]

Total body clearance

Adults:
• 10.6 ± 3.8 mL/min after multiple doses of 50 mg/day [2]

Adolescents:
• 12.6 ± 5.5 mL/min after multiple doses of 50 mg/m2/day [2]

Children (2 - 11 yr):
• 6.4 ± 2.6 mL/min after multiple doses of 50mg/m2/day [2]

Children (3 - 23 months):
• 3.2 ± 0.4 mL/min after multiple doses of 50 mg/m2/day [2]

ELIMINATION HALF LIFE

Elimination half life of the parent compound was similar to distribution half life:

• Adults: 13 ± 1.9 h after multiple doses of 50 mg/day [2]

• Adolescents: 11.2 ± 1.7 h after multiple doses of daily 50 mg/m2/day [2]

• Children (2 - 11 yr): 8.2 ± 2.4 h after multiple doses of daily 50 mg/m2/day [2]

• Children (3 - 23 months): 8.8 ± 2.1 h after multiple doses of daily 50 mg/m2/day [2]

TERMINAL ELIMINATION HALF LIFE

12 - 15 days [1]

EXTRACORPOREAL ELIMINATION

Renal replacement therapy

Caspofungin is not cleared by dialysis [2] 

Micafungin

General pharmacokinetics

Micafungin is not absorbed after oral administration and therefore an intravenous formulation has been developed. Hence, absolute bioavailability is considered to be 100%. Linear pharmacokinetics were seen after once daily dosing (12.5 - 200 mg and 3 mg/kg to 8 mg/kg). Steady state plasma concentrations were generally achieved after 4 – 5 days.
Micafungin is extensively bound to plasma proteins (>99%, primarily albumin) and independent of concentration (10 – 100 µg/ml). The drug is rapidly and extensively distributed into tissues: micafungin concentrations decline biexponential after intravenous administration. Apparent volume of distribution is 0.2 l/kg (approximately 18 - 19 L) and does not increase when going from steady state to pseudodistribution equilibrium (indicating a rapid equilibrium between plasma and issue).
Micafungin is metabolized by arylsulfatase to its catechol form (M-1) and further metabolized to the methoxy form (M-2) by cathechol-O-methyltransferase. Metabolite M-5 is thought to be formed via hydroxylation at the side chain by cytochrome P450 isoenzymes. However, these metabolites are inactive and exposure is considered low. Although in vitro studies show micafungin is a substrate of CYP3A, hydroxylation by CYP3A has not been shown to be a major pathway for micafungin metabolism in vivo.
Total body clearance of micafungin is 0.15 – 0.3 ml/min/kg in healthy subjects and adult patients and is irrespective of single or multiple dosing. Approximately 82.6% of a 25 mg dose is recovered over 28 days (11.6% urine and 71.0% feces), indicating that elimination of micafungin is primarily non-renal. Terminal half life is approximately 14 – 15 hours (mean 14.7 hours) and is dose-independent up to 150 mg.
Micafungin is not dialyzable, it may be administered without regard to hemodialysis.

References

[1] Product Information: MYCAMINE(R) lyophilized powder for IV injection, micafungin sodium lyophilized powder for IV injection. Astellas Pharma US, Inc. (per manufacturer), Northbrook, IL, 2011/2013

[2] Mukai T, Ohkuma T, Nakahara K et al: Pharmacokinetics of FK463, a novel echinocandin analogue, In elderly and non-elderly subjects (abstract A-30). Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, IL, p. 5, December 16-19, 2001.

[3] Hunter P: Micafungin: a novel antifungal agent for invasive infections. Inpharma August 11 2001; 1300:7-8.

[4] Sasaki J , Yamanouchi S , Kudo D , et al: Micafungin concentrations in the plasma and burn eschar of severely burned patients. Antimicrob Agents Chemother 2012; 56(2):1113-1115.

[5] Walsh TJ, Goutelle S, Jelliffe RW, et al: Intrapulmonary pharmacokinetics and pharmacodynamics of micafungin in adult lung transplant patients. Antimicrob Agents Chemother 2010; 54(8):3451-3459.

[6] Undre NA, Stevenson P, Freire A, et al: Pharmacokinetics of micafungin in pediatric patients with invasive candidiasis and candidemia. Pediatr Infect Dis J 2012; 31(6):630-632.

[7] Benjamin DK Jr, Smith PB, Arrieta A, et al: Safety and pharmacokinetics of repeat-dose micafungin in young infants. Clin Pharmacol Ther 2010; 87(1):93-99.

[8] Heresi GP, Gerstmann DR, Reed MD, et al: The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants. Pediatr Infect Dis J 2006; 25(12):1110-1115.

[9] Kawada M, Fukuoka N, Kondo M, et al: Pharmacokinetics of Prophylactic Micafungin in Very-Low-Birth-Weight Infants. Pediatr Infect Dis J 2009; Epub:Epub.Yamada N, Kumada K, Kishino S, et al: Distribution of micafungin in the tissue fluids of patients with invasive fungal infections. J Infect Chemother 2011; 17(5):731-734.

[10] Yamada N, Kumada K, Kishino S, et al: Distribution of micafungin in the tissue fluids of patients with invasive fungal infections. J Infect Chemother 2011; 17(5):731-734.

[11] Fromtling RA: Micafungin sodium (FK-463). Drugs Today 2002; 38(4):245-257.

[12] Seibel N, Schwartz C, Arrieta A et al: A phase 1 study to determine the safety and pharmacokinetics (PK) of FK 463 (echinocandin) in febrile neutropenic pediatric patients. Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Ontario, Canada, p. 1, September 17-20, 2000.

[13] Hiemenz J, Cagnoni P, Simpson D et al: Maximum tolerated dose and pharmacokinetics of FK463 in combination with fluconazole for the prophylaxis of fungal infections in adult bone marrow or peripheral stem cell transplant patients (abstract 1648). Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, California, p. 576, September 26-29, 1999.

Absorption

BIOAVAILABILITY

Oral bioavailability of micafungin is not determined as it is developed for parenteral use only [1]. Oral bioavailability of anidulafungin (another echinocandin antifungal) is proven to be low (2 - 7%).

PLASMA CONCENTRATIONS

Peak plasma concentrations (Cmax)

Adults (Healthy subjects, single dose, 1 h infusion) [2,3]:
• 4.9 mg/L after single dose of 50 mg
• 8.2 mg/L after single dose of 100 mg

Adults (HIV-positive patients with esophageal candidiasis, steady state)[1]:
• 5.1 mg/L after multiple doses of 50 mg/day
• 10.1 mg/L after multiple doses of 100 mg/day
• 16.4 mg/L after multiple doses of 150 mg/day

Adults (Hematopoietic stem cell transplant recipients, steady state)[1]:
• 21.1mg/L after multiple doses of 3 mg/kg/day
• 29.2 mg/L after multiple doses of 4 mg/kg/day
• 38.4 mg/L after multiple doses of 6 mg/kg/day
• 60.8 mg/L after multiple doses of 8 mg/kg/day

Renal impairment:
Patients with severe renal impairment (creatinine clearance <30 mL/min) receiving micafungin 100 mg, single dose showed no significant alterations in AUC and Cmax compared to age-, gender-, and weight-matched patients with normal renal function (creatinine clearance >80 mL/min). Dose adjustment is not needed in patients with renal impairment [1]

Hepatic impairment:
Patients with moderate (Child Pugh score 7 - 9) and severe (Child Pugh score 10 - 12) hepatic impairment receiving micafungin 100 mg, single dose showed reduction in AUC and Cmax of 22% and 30% respectively, compared to age-, gender-, and weight-matched patients [1]
Patients with severe hepatic impairment showed an approximately 2.3-fold higher Cmax and AUC value of the M-5 metabolite. Dose adjustment is not needed in patients with hepatic impairment. [1]

Area under the curve (AUC0-24h)

Adults (HIV-positive patients with esophageal candidiasis, steady state)[1]:
• 54 mg*h/L after multiple dose of 50 mg/day
• 115 mg*h/L after multiple dose of 100 mg/day
• 167 mg*h/L after multiple dose of 150 mg/day

Adults (Hematopoietic stem cell transplant recipients, steady state)[1]:
• 234 mg*h/L after multiple dose of 3 mg/kg/day
• 339 mg*h/L after multiple dose of 4 mg/kg/day
• 479 mg*h/L after multiple dose of 6 mg/kg/day
• 663 mg*h/L after multiple dose of 8 mg/kg/day

Children (4m – 16y, ≤ 30kg), multiple dose [1]:
• 55 ± 16 mg*h/L after multiple dose of 1 mg/kg/day
• 109 ± 31 mg*h/L after multiple dose of 2 mg/kg/day
• 164 ± 47 mg*h/L after multiple dose of 3 mg/kg/day

Children (4m – 16y, > 30kg), multiple dose [1]:
• 67 ± 17 mg*h/L after multiple dose of 1 mg/kg/day
• 134 ± 33 mg*h/L after multiple dose of 2 mg/kg/day
• 176 ± 42 mg*h/L after multiple dose of 2.5 mg/kg/day

Children, multiple dose, <40kg: 2mg/kg; >40kg: 100mg [6]:
• 72.19 - 90.43 mg*h/L

Infants (3 - 119 d), multiple dose [7]:
• 307.6 ± 173.7 mg*h/L after multiple dose of 7 mg/kg/day (bodyweight >1 kg)
• 308 ± 100.6 mg*h/L after multiple dose of 10 mg/kg/day (bodyweight <1 kg)

Premature neonates, single dose [8]:
• 19  ± 7.3 mcg*h/mL in patients treated with 0 .75 mg/kg/day
• 34.5 ± 5.6 mcg*h/mL in patients treated with 1.5 mg/kg/day
• 69 ± 19.2 mcg*h/mL in patients treated with 3 mg/kg/day

Renal impairment:
Patients with severe renal impairment (creatinine clearance <30 mL/min) receiving micafungin 100 mg, single dose showed no significant alterations in AUC and Cmax compared to age-, gender-, and weight-matched patients with normal renal function (creatinine clearance >80 mL/min). Dose adjustment is not needed in patients with renal impairment [1]

Hepatic impairment:
Patients with moderate (Child Pugh score 7 - 9) and severe (Child Pugh score 10 - 12) hepatic impairment receiving micafungin 100 mg, single dose showed reduction in AUC and Cmax of 22% and 30% respectively, compared to age-, gender-, and weight-matched patients [1]
Patients with severe hepatic impairment showed an approximately 2.3-fold higher Cmax and AUC value of the M-5 metabolite. Dose adjustment is not needed in patients with hepatic impairment [1]

Time to peak plasma concentrations (Tmax)

Adults (lung transplant patients), single dose:
• 4.0 ± 0.5 h after single dose of 150 mg/day [5]

Children, multiple dose, <40kg: 2mg/kg; >40kg: 100 mg [6]
• 0.84 ± 0.31 - 2.01 ±2.23 h

Infants (3 - 119 d), multiple dose [7]:
• 1.2 ± 0.4 h after multiple dose of 7 mg/kg/day (bodyweight >1 kg)
• 1.1 ± 0.04 h after multiple dose of 10 mg/kg/day (bodyweight <1 kg)

Steady state plasma concentrations

Steady state concentrations are reached within approximately 4 - 5 days [1].

LINEARITY

Pharmacokinetics are linear over dose ranges of 12.5 - 200mg/day and 3 - 8 mg/kg/day. Repeated administration of micafungin does not lead to systemic accumulation [1]

Distribution

VOLUME OF DISTRIBUTION

Micafungin is rapidly distributed into tissues [1].
Volume of distribution at steady state in adult patients with esophageal candidiasis (50 - 150 mg): approximately 18 - 19L or 0.39 L/kg [1].

Volume of distribution in neonates differs from that in adults:

Infants (3 - 119 d), multiple dose:
• 0.76 ± 0.28 L/kg after multiple dose of 1 mg/kg/day [9]
• 0.39 ± 0.13 L/kg after multiple dose of 7 mg/kg/day (bodyweight >1 kg) [7]
• 0.51 ± 0.08 L/kg after multiple dose of 10 mg/kg/day (bodyweight <1 kg) [7]

Premature neonates, single dose [8]:
• 0.4 ± 0.12 L/kg after single dose of 0.75 mg/kg/day
• 0.44 ± 0.06 L/kg after single dose of 1.5 mg/kg/day
• 0.47 ± 0.15 L/kg after single dose of 3 mg/kg/day

PROTEIN BINDING

Micafungin is highly bound to plasma protein (>99%), primarily to albumin and, to a lesser extent, to alpha 1-acid-glycoprotein. Distribution into erythrocytes is approximately 35%. Concentration does not influence protein binding (within a range of 10 - 100 mg/L) [1]

DISTRIBUTION SITES

Radid, extensive distribution into tissues [1]

TISSUE CONCENTRATIONS

• Burn escar: 4 mg/L (initial dosis) and 14.8 mg/L (repeated doses) of 200mg/day (2.2-6.4 times higher than found in relating plasma samples) [4]
• Cerebrospinal fluid: 1.94 mg/L after repeated doses of 150 mg/day 2 patients [10]
• Pleural effusion: 0.68 mg/L after repeated doses of 150 mg/day in 2 patients [10]
• Ascites: 1.02 mg/ml after repeated doses of 150 mg/day in 1 patient [10]
• Wound tissue fluid: 4.42 mg/L after repeated doses of 150 mg/day in 1 patient [10]
• Pulmonary epithelial lining fluid: 1.38 ± 1.93 mg/L after repeated doses of 150mg in 20 patients [5]
• Alveolar cell: 17.41 ± 24.25 mg/L after repeated doses of 150 mg in 20 patients [5]

Metabolism

METABOLISM SITES

Liver, to an unknown extent [11]

METABOLITES

Metabolites do not contribute to the overall efficacy of micafungin [1]:

• M-1 (catechol form) by arylsulfatase, further metabolised to M-2
• M-2 (methoxy form) by metabolism of the metabolite M-1 by catechol-O-methyltransferase
• M-5 by hydroxylation at the omega-1 position side chain of micafungin (by cytochrome P-450 enzymes)

Metabolite to parent drug exposure after micafungin 150 mg/day [1]:
• M-1: 6% (healthy volunteers), 11% (patients with esophageal candidiasis)
• M-2: 1% (healthy volunteers), 2% (patients with esophageal candidiasis)
• M-5: 6% (healthy volunteers), 12% (patients with esophageal candidiasis)

BIOTRANSFORMATION

Even though micafungin is a substrate for CYP3A in vitro, hydroxylation by CYP3A is not a major
pathway for micafungin metabolism in vivo. Micafungin is not an inhibitor of P-glycoprotein [1]

Excretion

CLEARANCE

Renal excretion

15 % or less is excreted unchanged by the kidneys [3,11]

Faecal excretion

71% is excreted via faeces, the major route of micafungin excretion [1]

Biliary excretion

40% of the total amount of micafungin and metabolites is excreted via bile [11]

Total body clearance

Adults (Healthy subjects, single dose, 1 h infusion) [2]:
• 11 mL/h/kg after single dose of 50 mg

Adults (HIV-positive patients with esophageal candidiasis, steady state) [1]:
• 0.3 mL/min/kg after multiple doses of 50 mg/day
• 0.301 mL/min/kg after multiple doses of 100 mg/day
• 0.297 mL/min/kg after multiple doses of 150 mg/day

Adults (Hematopoietic stem cell transplant recipients, steady state)[1]:
• 0.214 mL/min/kg after multiple doses of 3 mg/kg/day
• 0.204 mL/min/kg after multiple doses of 4 mg/kg/day
• 0.224 mL/min/kg after multiple doses of 6 mg/kg/day
• 0.223 mL/min/kg after multiple doses of 8 mg/kg/day

Children (4m – 16y, ≤ 30kg): 0.328 ± 0.091 mL/min/kg [1]

Children (4m – 16y, > 30kg): 0.241 ± 0.061 mL/min/kg [1]

Children, multiple dose, <40kg: 2mg/kg; >40kg: 100 mg [6]
• 42.72 ± 18.78 mL/h/kg  
• 28.52 ± 8.1 mL/h/kg

Infants (3 - 119 d), multiple dose:
• 89 ± 47 mL/hr/kg after multiple dose of 1 mg/kg/day [9]
• 0.4 mL/min/kg after multiple dose of 7 mg/kg/day (bodyweight >1 kg) [7]
• 0.6 mL/min/kg after multiple dose of 10 mg/kg/day (bodyweight <1 kg) [7]

Premature neonates, single dose [8]:
• 39  ± 18 mL/h/kg after single dose of 0.75 mg/kg/day
• 38.6 ± 8.9 mL/h/kg after single dose of 1.5 mg/kg/day
• 39.1 ± 10.6 mL/h/kg after single dose of 3 mg/kg/day

ELIMINATION HALF LIFE

Adults (HIV-positive patients with esophageal candidiasis, steady state) [1]:
• 15.6 h after multiple doses of 50 mg/day
• 16.9 h after multiple doses of 100 mg/day
• 15.2 h after multiple doses of 150 mg/day

Adults (Hematopoietic stem cell transplant recipients, steady state)[1]:
• 14 h after multiple doses of 3 mg/kg/day
• 14.2 h after multiple doses of 4 mg/kg/day
• 14.9 h after multiple doses of 6 mg/kg/day
• 17.2 h after multiple doses of 8 mg/kg/day

Adults (lung transplant patients), single dose[5]:
• 12.1 h after single dose of 150 mg/day

Adults (adults receiving bone marrow or peripheral stem cell transplantation)[13]:
• 10.7 - 13.9 h

Children (4m – 16y, ≤ 30kg) :12.5 h ± 4.6 [1]

Children (4m – 16y, > 30kg): 13.6 h ± 8.8 [1]

Children, multiple dose, <40kg: 2mg/kg; >40kg: 100 mg [6]
• 10.13 ± 1.76 h 
• 13.81 ± 4.38 h

Premature neonates, single dose [8]:
• 8.0 (5.6 - 10.3) h after single dose of 0.75 mg/kg/day
• 7.8 (6 - 11) h after single dose of 1.5 mg/kg/day
• 8.2 (6.2 - 10.5) h after single dose of 3 mg/kg/day

Infants (3 - 119 d), multiple dose [7]:
• 11 ± 3 h

Children (2 - 17 yrs): 12-21h [12]

TERMINAL HALF LIFE

Approximately 14 – 15 hours (mean 14.7 hours), dose-independent up to 150 mg [1]

EXTRACORPOREAL ELIMINATION

Renal replacement therapy

Micafungin is not cleared by dialysis [1].

Amphotericin B

General pharmacokinetics

Although amphotericin B has been clinically used for over 40 years, relatively little is known of its pharmacokinetics. Due to (nephro)toxicity seen with conventional amphotericin B deoxycholate (AmB), lipid-based amphotericin B formulations have been developed in an attempt to reduce toxicity: amphotericin B lipid complex (ABLC), amphotericin B cholesteryl sulfate complex (ABCD) and liposomal amphotericin B (L-AmB). In vivo studies show that kidney concentrations are several times lower after administration of lipid formulations compared to AmB.
The pharmacologic profiles of these lipid-based formulations differ considerably from AMB and from each other.
Oral AmB is poorly absorbed (<5%), requiring intravenous administration for treatment of invasive mucosis. After dosing 30 -50 mg of AmB, serum concentrations ranged from 1 – 2 mg/L. Systemic absorption following aerosol administration is also thought to be minimal.
AmB has a large volume of distribution of approximately 4 L/kg and is highly protein bound (up to 95%, primarily lipoproteins). It is distributed into various tissues and fluids, but passes into the CSF <2.5% of serum concentrations.
No circulating metabolites of AmB have been identified. Metabolism sites of AmB are unknown.
Elimination pathways of AmB remain largely unknown, with urine and biliary excretion accounting for only >5% of parent compound. Plasma half-life of AmB is about 24 hours. With long term use, the terminal half-life is estimated to be 15 days (biphasic elimination). Hepatic and renal function do not influence serum levels. Amphotericin B is not removed by hemodialysis.

References

[1] Janknegt R, de Marie S, Bakker-Woudenberg IA, Crommelin DJ.Liposomal and lipid formulations of amphotericin B. Clinical pharmacokinetics. Clin Pharmacokinet. 1992 Oct;23(4):279-91.

[2] Ching MS, Raymond K, Bury RW, et al: Absorption of orally administered amphotericin B lozenges. Br J Clin Pharmacol 1983; 16:106-108.

[3] Kan VL, Bennett JE, Amantea MA, Smolskis MC, McManus E, Grasela DM et al. Comparative safety, tolerance, and pharmacokinetics of amphotericin B lipid complex and amphotericin B desoxycholate in healthy male volunteers. J Infect Dis. 1991 Aug;164(2):418-21.

[4] Prescribers Information Abelcet. From Aspen Australia, Orphan Australia. Last modification: 26th of June 2012.

[5] Product Information AmBisome intravenous injection, amphotericin b liposome intravenous injection. Astellas Pharma US, Inc., Deerfield, IL, 2012.

[6] Daneshmend TK, Warnock DW. 1983. Clinical pharmacokinetics of systemic antifungal drugs. Clin Pharmacokinet 8:17–42.

[7] Product Information: Fungizone, amphotericin injection, suspension. Apothecon, Princeton, NJ, 1999.

[8] Bekersky I, Fielding RM, Dressler DE et al. Plas,a protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate. Antimicrob Agents Chemother 2002 46: 834-840

[9] Ostrosky-Zeichner L, Marr KA, Rex JH, Cohen SH. 2003. Amphotericin B: Time for a new ‘‘gold
standard’’. Clin Infect Dis 37:415–425.

[10] Atkinson AJ Jr, Bennett JE. Amphotericin B pharmacokinetics in humans. Antimicrob Agents Chemother. 1978 Feb;13(2):271-6.

[11] Block ER, Bennett JE, Livoti LG, et al: Flucytosine and amphotericin B: hemodialysis effects on the plasma concentrations and clearance. Studies in man. Ann Intern Med 1974; 80:613.

[12] Muther RS & Bennett WM: Peritoneal clearance of amphotericin B and 5-fluorocytosine. West J Med 1980; 133:157-160.

Absorption

BIOAVAILABILITY

Due to a poor oral bioavailability, Amphotericin B is usually administered as IV formulation. After oral administration of amphotericin B (decontamination of digestive tract) in dosages of 2 - 5 g, serum concentrations remained below 0.5 mg/L [1]
The oral formulation of Amphotericin B (Fungilin) has a bioavailability of ~10% or less [2]
Systemic absorption following aerosol administration is also thought to be minimal.

PLASMA CONCENTRATIONS

Plasma concentrations vary considerably with every formulation of amphotericin B:

Peak plasma concentrations (Cmax)

Fungizone (ampothericin B deoxycholate)

  • 0.54 mg/L in healthy volunteers administered 0.10 mg/kg/day [3]
  • 0.99 mg/L in healthy volunteers administered 0.25 mg/kg/day [3]
  • 1.1 ± 0.2 mg/L in patients treated with 0.6 mg/kg/day [4]

Ambisome (liposomal amphotericin B)

  • 7.3 ± 3.8 mg/L in patients treated with 1 mg/kg/day (day 1) [5]
  • 12.2 ± 4.9 mg/L in patients treated with 1 mg/kg/day (steady state) [5]
  • 17.2 ± 7.1 mg/L in patients treated with 2.5 mg/kg/day (day 1) [5]
  • 31.4 ± 17.8 mg/L in patients treated with 2.5 mg/kg/day (steady state) [5]
  • 10 - 35 mg/L in patients treated with 3 mg/kg [1]
  • 11 - 35 mg/L in patients treated with 4 mg/kg [1]
  • 25 - 59 mg/L in patients treated with 5 mg/kg [1]
  • 57.6 ± 21 mg/L with 5 mg/kg/day (day 1) [5]
  • 83 ± 35.2 mg/L with 5 mg/kg/day (steady state) [5]

Abelcet (amphotericin B lipid complex)

  • 0.12 mg/L in healthy volunteers administered 0.10 mg/kg/day [3]
  • 0.21 mg/L in healthy volunteers administered 0.25 mg/kg/day [3]
  • 0.26 mg/L in healthy volunteers administered 0.50 mg/kg/day [3]
  • 1.7 ± 0.8 mg/L in patients treated with 5mg/kg/day [4]
Area under the curve (AUC0-24h)

Fungizone (ampothericin B deoxycholate)

  • 8.1 mg*h/L in healthy volunteers administered 0.10 mg/kg/day [3]
  • 21 mg*h/L in healthy volunteers administered 0.25 mg/kg/day [3]
  • 17.1 ± 5 mg*h/L in patients treated with 0.6 mg/kg/day [4]

Ambisome (liposomal amphotericin B)

  • 27 ± 14 mg*h/L in patients treated with 1 mg/kg/day (day 1) [5]
  • 60 ± 20 mg*h/L in patients treated with 1 mg/kg/day (steady state) [5]
  • 65 ± 33 mg*h/L in patients treated with 2.5 mg/kg/day (day 1) [5]
  • 197 ± 183 mg*h/L in patients treated with 2.5 mg/kg/day (steady state) [5]
  • 211 mg*h/L in patients treated with 3 mg/kg [1]
  • 419 mg*h/L in patients treated with 4 mg/kg [1]
  • 523 mg*h/L in patients treated with 5 mg/kg [1]
  • 269 ± 96 mg*h/L in patients treated with 5 mg/kg/day (day 1) [5]
  • 555 ± 311 mg*h/L in patients treated with 5 mg/kg/day (steady state) [5]

Abelcet (amphotericin B lipid complex)

  • 1.4 mg/L in healthy volunteers administered 0.10 mg/kg/day [3]
  • 4.3 mg/L in healthy volunteers administered 0.25 mg/kg/day [3]
  • 7.0 mg/L in healthy volunteers administered 0.50 mg/kg/day [3]
  • 14 ± 7 mg*h/L in patients treated with 5 mg/kg/day [4]

Renal impairment:
The effect of renal impairment on the pharmacokinetics of Ambisome (liposomal aphotericin B) has not been studied. However, it has been reported that AmBisome was successfully administered to patients with pre-existing renal impairment [5]

Hepatic impairment:
The effect of hepatic impairment on the pharmacokinetics of Ambisome (liposomal aphotericin B) has not been studied [5]

Steady state plasma concentrations

Ambisome (liposomal amphotericin B): within 4 days [5]

LINEARITY

At dosages >50 mg, dose proportionality of amphotericin B is lost and serum concentrations are lower than those predicted on the basis of linearity [1]
Mean trough concentrations of AmBisome remained relatively constant over a dose range of 1 - 5 mg/L (repeated administration), although inter-patient variability was high [5]

Distribution

VOLUME OF DISTRIBUTION

Amphotericin B is widely disitributed with a Vd of approximately 4 L/kg [6]

Fungizone (amphotericin B deoxycholate)

  • 0.5 L/kg in healthy volunteers administered 0.10 mg/kg/day [3]
  • 0.74 L/kg in healthy volunteers administered 0.25 mg/kg/day [3]
  • 5 ± 2.8 L/kg in patients treated with 0.6 mg/kg/day [4]

Ambisome (liposomal amphotericin B) [5]

  • 0.44 ± 0.27 L/kg in patients treated with 1 mg/kg/day (day 1)
  • 0.14 ± 0.05 L/kg in patients treated with 1 mg/kg/day (steady state)
  • 0.40 ± 0.37 L/kg in patients treated with 2.5 mg/kg/day (day 1)
  • 0.16 ± 0.09 L/kg in patients treated with 2.5 mg/kg/day (steady state)
  • 0.16 ± 0.10 L/kg in patients treated with 5 mg/kg/day (day 1)
  • 0.10 ± 0.07 L/kg in patients treated with 5 mg/kg/day (steady state)

Abelcet (amphotericin B lipid complex)

  • 1.7 L/kg in healthy volunteers administered with 0.10 mg/kg/day [3]
  • 2.6 L/kg in healthy volunteers administered 0.25 mg/kg/day [3]
  • 3.9 L/kg in healthy volunteers administered 0.50 mg/kg/day [3]
  • 131 ± 57.7 L/kg in patients treated with 5 mg/kg/day [4]

DISTRIBUTION HALF LIFE

Amphotericin B: 15 days [6,7]

PROTEIN BINDING

Amphotericin B: more than 95%, by Beta-lipoprotein, albumin and alpha1-acid glycoprotein [8]

TISSUE CONCENTRATIONS

Fungizone (ampothericin B deoxycholate)

  • < 2.5% of serum concentrations were found in CSF [7]
  • ~ 67% of serum concentrations were found in the eye, pleural fluid, peritoneal fluid and synovial fluid [7]

Ambisome (liposomal amphotericin B)

Human autopsy studies have shown the following [1]:

  • 14 - 22% of the dose is found in the liver
  • 6% of the dose is found in the spleen
  • Less than 1% of the dose is found in the heart, kidney and lung

Abelcet (amphotericin B lipid complex)

Human autopsy studies have shown the following (after administration abelcet at a dose  of 5.3 mg/kg/day for 3 days) [4]:

  • 290 mcg/g is found in the spleen
  • 222 mcg/g is found in the lung
  • 196 mcg/g is found in the liver
  • 7.6 mcg/g is found in the lymph node
  • 6.9 mcg/g is found in the kidney
  • 5.0 mcg/g is found in the heart
  • 1.6 mcg/g is found in the brain

The relationship between these concentrations and the clinical activity remains unknown.

Important differences in amphotericin B distribution are found, depending on the drug carier. The table below shows the effect of formulation on in vivo distribution of amphotericin B [9]:

Organ            Abelcet    AmBisome
Liver 2 x 0.5 - 1 x
Spleen 5 x 3 x
Lung 2 x 0.2 x
Kidney 0.2 x 0.2 x
Brain 0.2 x 1.2 x

 

Metabolism

METABOLISM SITES

The metabolism pathways of amphotericin B are unknown [4,5,7]

METABOLITES

No metabolites have been identified in either human or animal studies [4,5,7]

Excretion

CLEARANCE

Renal excretion

Fungizone (amphotericin B desoxycholate)

About 40% of the dose is excreted via the kidneys. Only 2 - 5% of the unchanged form of amphotericin B is found in the urine within 24 hours, but this concentration increases with prolonged monitoring of urine concentrations [10]. Amphotericin B can appear in urine for up to 8 weeks [7]

• 0.17 mL/min/kg in healthy volunteers administered 0.10 mg/kg/day [3]
• 0.17 mL/min/kg in healthy volunteers administered 0.25 mg/kg/day [3]
• 38 ± 15 mL/h*kg in patients treated with 0.6 mg/kg/day [4]

Ambisome (liposomal amphotericin B)

Excretion mechanisms are largely unknown.

• 39 ± 22 mL/h/kg in patients treated with 1 mg/kg/day (day 1) [5]
• 17 ± 6 mL/h/kg in patients treated with 1 mg/kg/day (steady state) [5]
• 51 ± 44 mL/h/kg in patients treated with 2.5 mg/kg/day (day 1) [5]
• 22 ± 15 mL/h/kg in patients treated with 2.5 mg/kg/day (steady state) [5]
• 21 mL/min in patients treated with 3 mg/kg [1]
• 21 mL/min in patients treated with 4 mg/kg [1]
• 16 mL/min in patients treated with 5 mg/kg [1]
• 21 ± 14 mL/h/kg in patients treated with 5 mg/kg/day (day 1) [5]
• 11 ± 6 mL/h/kg in patients treated with 5 mg/kg/day (steady state) [5]

Abelcet (liposomal amphotericin B)

• 1.5 mL/min/kg in healthy volunteers administered 0.10 mg/kg/day [3]
• 1.2 mL/min/kg in healthy volunteers administered 0.25 mg/kg/day [3]
• 1.3 mL/min/kg in healthy volunteers administered 0.50 mg/kg/day [3]
• 436 ± 188.5 mL/h*kg in patients treated with 5mg/kg/day [4]

ELIMINATION HALF LIFE

After intravenous administration of amphotericin B, a triexponential decay is observed in serum concentrations, with second and third-phase elimination half-lives.

Fungizone (amphotericin B deoxycholate)
• 31 h in healthy volunteers administered 0.10 mg/kg/day [3]
• 50 h in healthy volunteers administered 0.25 mg/kg/day [3]

• 24 and 28 h for the second phase half-life
• 15 days for third phase half-life in two patients treated for 50 and 136 days [7,10]

Ambisome (liposomal amphotericin B) [5]
• 10.7 ± 6.4 h in patients treated with 1 mg/kg/day (day 1)
• 7 ± 2.1 h in patients treated with 1 mg/kg/day (steady state)
• 8.1 ± 2.3 h in patients treated with 2.5 mg/kg/day (day 1)
• 6.3  ± 2 h in patients treated with 2.5 mg/kg/day (steady state)
• 6.4 ± 2.1 h in patients treated with 5 mg/kg/day (day 1)
• 6.8 ± 2.1 h in patients treated with 5 mg/kg/day (steady state)

Total amphotericin B concentrations within 24 hours after administration indicated a half life of 7 - 10 hours. This was prolonged to 100 - 153 hours after 49 days, probably due to slow redistribution from tissues [5]

• 0.40 h (first phase) and 26 h (second phase) in patients treated with 3 mg/kg [1]
• 0.62 h (first phase) and 38 h (second phase) in patients treated with 4 mg/kg [1]
• 0.83 h (first phase) and 32 h (second phase) in patients treated with 5 mg/kg [1]

Abelcet (amphotericin B lipid complex)
• 19 h in healthy volunteers administered 0.10 mg/kg/day [3]
• 27 h in healthy volunteers administered 0.25 mg/kg/day [3]
• 45 h in healthy volunteers administered 0.50 mg/kg/day [3]

TERMINAL ELIMINATION HALF LIFE

Fungizone (amphotericin B deoxycholate)
• 91.1 ± 40.9 h in patient treated with 5 mg/kg/day [4]

Abelcet (amphotericin B lipid complex)
• 173 ± 78 h in patients treated with 5 mg/kg/day [4]

EXTRACORPOREAL ELIMINATION

Renal replacement therapy

Serum levels of amphotericin B / AmBisome are not aleterd by hemodialysis or peritoneal dialysis [7, 11, 12]

Flucytosine

General pharmacokinetics

Flucytosine (5-FC) is available as oral capsules, whereas the intravenous formulation is only available in some countries. 5-FC is rapidly and almost completely absorbed, with a bioavailability of approximately 78 – 89%.
Time to maximum plasma concentrations occur within 2 hours after a 6-week regimen of flucytosine (150 mg/kg/day given in divided doses every 6 hours) resulting in peak plasma concentrations of 70 - 80 mg/L Similar concentrations (but more rapid) occur after intravenous dosing. Plasma half-life of 5-FC  ranges from 2 – 5 hours in patients with normal renal function, but may extend for up to 250 hours in patients with end-stage renal disease.
Plasma protein binding of 5-FC is minimal (approximately 2.9 - 4%), contributing to a volume of distribution almost equal to total body water (0.6 – 0.9 L/kg). It is widely distributed into body tissues and fluids and penetrates well into CSF (65 – 90 % of plasma concentrations).
5-FC is for a small amount metabolized to 5-fluorouracil.
Of the total dose, up to 96% is excreted as unchanged drug in the urine, primarily by glomerular filtration. The small fraction of 5-FC not absorbed from the gastrointestinal tract is eliminated unchanged in the faeces. 5-FC can be removed by haemodialysis.

References

[1] Daneshmend TK & Warnock DW: Clinical pharmacokinetics of systemic antifungal drugs. Clin Pharmacokin 1983; 8:17-42.

[2] Ancobon (flucytosine) [prescribing information]. Costa Mesa, CA: ICN Pharmaceuticals; March 2003.

[3] Polak A: Pharmacokinetics of amphotericin B and flucytosine. Postgrad Med J 1979; 55:667-670.

[4] Vermes A, Guchelaar HJ and Dankert J: Flucytosine, a review of its pharmacology, clinical implications, pharmacokinetics, toxicity and drug interactions. J of Antimicrobiol Chemother 2000; 46: 171-179.

[5] O'Day DM, Head WS, Robinson RD, et al: Intraocular penetration of systemically administered antifungal agents. Curr Eye Res 1985; 4:131-134.

[6] Block ER, Bennett JE, Livoti LG, et al: Flucytosine and amphotericin B: hemodialysis effects on the plasma concentrations and clearance studies in man. Ann Intern Med 1974; 80(5):613-617.

Absorption

Bioavailability

Bioavailability: 78 - 89% (oral administration compared with intravenous administration in healthy volunteers). [1,2]

Plasma concentrations

Peak plasma concentrations (Cmax)

Patients with normal renal function: 30 - 40 mg/L following a 2 g single dose. [1,2]
Patients with normal renal function: 70 - 80 mg/L following a 6-week regimen of flucytosine (150 mg/kg/day given in divided doses every 6 hours) in combination with amphotericin B. [2]

Time to peak plasma concentrations (Tmax)

Patients with normal renal function: 2 hours (serum) following a 2 g single dose. [1,2]
Patients with normal renal function: ~1 - 2 hours (serum) following a 6-week regimen of flucytosine (150 mg/kg/day given in divided doses every 6 hours) in combination with amphotericin B. [2]

Plasma elimination half life (t1/2)

Healthy subjects: 2.4 - 4.8 hours [2]

Patients with normal renal function: 2 - 5 hours. [2,4]

Nephrectomized / Anuric patients: 85 hours (range: 29.9 - 250 hours). [2]

Patients with end stage renal disease: 75 - 200 hours. [2,4]

The elimination rate constant of flucytosine and creatinine clearance showed a linear correlation. [2]

Distribution

Volume of distribution

Close to total body water with a Vd of 0.6 - 0.9 L/kg. [3,4]

Protein binding

In vitro studies show that 2.9 - 4% of flucytosine is protein bound over a range of therapeutic concentrations in blood. [2]

Distribution sites

Widely distributed through the body tissues and fluids, not alteredby renal failure. Drug levels in the spleen, heart, liver, kidney and lung are similar to serum concentrations. [1,3,4]

Cerebrospinal fluid (CSF)

Flucytosine readily penetrates the blood-brain barrier, with concentrations about 65 - 90% of those in serum [2]

Ocular

High concentrations are found in the vitreous humour.

Metabolism

Metabolism sites

Minimally hepatic: flucytosine is deaminated (both in yeasts and possibly via gut bacteria) to 5-fluorouracil.  A small fraction of the dose is excreted in the feces. [1 - 4]

Metabolites

5-fluorouracil (5-FU). The AUC-ratio of 5-FU to flucytosine is 4%.

Excretion

Clearance

Renal Clearance

Flucytosine is excreted via the kidneys by means of glomerular filtration: no tubular resorption or secretion takes place [4]

Renal Excretion

More than 90% of the total radioactivity after oral administration was recovered in the urine as intact drug. [2]

Approximately 1% of the dose is present in the urine as the α-fluoro-β-ureido-propionic acid metabolite. [2]

Extracorporeal Elimination

Hemodialysis

Removed by dialysis [2].

Clearances of flucytosine and creatinine by hemodialysis were similar, with both increasing linearly with increasing blood flow through the dialyzer. [6]

Peritoneal

Removed by dialysis [2]