DRUG INTERACTION BETWEEN ITRACONAZOLE AND ENZALUTAMIDE

Two phase 1 drug interaction studies performed in healthy volunteers.

24/12/2015 - A parallel-treatment design (n = 41) was used to evaluate the effects of itraconazole (200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). Coadministration of itraconazole increased the composite AUC(0-inf) by 1.3-fold. A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg). Enzalutamide reduced the AUC(0-inf) of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4. The authors recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.

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DRUG INTERACTION BETWEEN ISAVUCONAZOLE AND TACROLIMUS

A case report indicating the need for tacrolimus drug-level monitoring

15/09/2015 - This case reports describes a patient with a mediastinal Aspergillus fumigatus infection resistant to posaconazole who is successfully managed with tacrolimus therapeutic drug-level monitoring. It was concluded that when isavuconazole is given to patients on tacrolimus, the dose of the latter will need considerable reduction. An initial 50% reduction and close weekly monitoring of tacrolimus concentration is recommended. Further dose decreases of 25-50% may be required.

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DRUG-INTERACTIONS OF AZOLE ANTIFUNGALS WITH SELECTED IMMUNOSUPPRESSANTS IN TRANSPLANT PATIENTS

Strategies for optimal management in clinical practice

31/07/2015 - This article provides important tools for adequate assessment of the drug interactions that cause pharmacokinetic variability of immunosuppressants in transplant patients. A stepwise approach for the evaluation and subsequent management options, including a decision flow chart, are provided for optimal handling of these clinically relevant drug interactions

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ARTICLE - DRUG-DRUG INTERACTION BETWEEN ITRACONAZOLE AND RIFAMPICIN / RIFABUTIN

Significantly lower itraconazole plasma concentrations when coadministered with rifampicin / rifabutin

31/07/2015 - In patients with chronic pulmonary aspergillosis, serum itraconazole concentrations were found to be significantly lower when coadministered with rifampin (median, 0.1 μg/ml; P < 0.001) or rifabutin (median, 0.34 μg/ml; P < 0.001) than patients receiving itraconazole alone (median, 5.92 μg/ml). It was concluded that concomitant use of rifampin or rifabutin and itraconazole should be avoided in patients with chronic pulmonary aspergillosis and coexisting mycobacterial infections.

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ARTICLE - DRUG-DRUG INTERACTION BETWEEN EVEROLIMUS AND VORICONAZOLE

Case report in a renal transplant patient

31/07/2015 - Despite reduction of the dose of everolimus by a third, the blood trough concentration of everolimus increased considerably in a kidney transplant recipient upon oral administration of voriconazole. Everolimus was then discontinued. Pneumonia secondary to pulmonary aspergillosis worsened, possibly due to the excessive immunosuppression.
It was advised that a 80% decrease in dose or discontinuation of everolimus is required when concomitant voriconazole is introduced. Daily blood monitoring of everolimus is warranted until a steady state of concentrations is reached.

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ARTICLE - MANAGEMENT OF DRUG INTERACTION BETWEEN POSACONAZOLE AND SIROLIMUS

A study in Hematopoietic Stem Cell Transplant patients

15/06/2015 - This retrospective cohort study determined an appropriate empiric oral sirolimus dose adjustment when given concurrently with posaconazole oral suspension in 75 patients who undergo hematopoietic stem cell transplant (HSCT). It was determined that coadministration of posaconazole oral suspension with oral sirolimus increases the sirolimus C/D ratio by approximately 2.7-fold in HSCT patients. An initial empiric oral sirolimus dose reduction between 50% and 65% may be recommended for most clinically stable patients with close sirolimus concentration monitoring for at least 3 weeks following posaconazole initiation.

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ARTICLE - POSACONAZOLE LEVELS IN PATIENTS TAKING THE DELAYED-RELEASE TABLETS VERSUS THE ORAL SUSPENSION

A retrospective comparison

15/06/2015 - This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (> 700 ng/mL). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension (p = 0.003). Among patients with a steady state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension (p = 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/mL) was twice that of the suspension cohort (798 ng/mL) (P=0.004).

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ARTICLE - PHARMACOKINETICS OF ECHINOCANDINS IN SPECIAL PATIENT POPULATIONS

Pharmacokinetics of echinocandins in neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases

22/05/2015 - This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.

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ARTICLE - NO SIGNIFICANT INTERACTION BETWEEN ITRACONAZOLE AND TRAMADOL

A randomised placebo-controlled crossover study in 12 healthy subjects showed itraconazole has no meaningful interaction with tramadol in subjects who have functional CYP2D6 enzyme

22/05/2015 - A randomised placebo-controlled crossover study in 12 healthy subjects (8 extensive, 4 ultra-rapid CYP2D6 metabolisers) receiving itraconazole (200 mg/day for 5 days) described no significant change in the pharmacokinetics of tramadol (50 mg single, oral dose on day 4). This article confirmed earlier findings in literature.

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ARTICLE - INTERACTION BETWEEN VORICONAZOLE AND FLUCLOXACILLIN

A case report of undetectable voriconazole concentrations when flucloxacillin was administered concomitantly

07/04/2015 - A case report described undetectable voriconazole concentrations (400 mg daily) voriconazole after the start of therapy with 2 g flucloxacillin intravenously four times a day. Despite intravenous or increasingly higher oral dosing, voriconazole plasma concentrations remained undetectable until the flucloxacillin was ceased.

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ARTICLE - PHARMACOKINETICS OF FLUCONAZOLE, KETOCONAZOLE AND TOFACITINIB IN HEALTHY SUBJECTS

Co-administration of moderate to potent CYP3A4 inhibitors is likely to increase the systemic exposure of tofacitinib and thus may warrant dosage adjustments or restrictions

09/02/2015 - Coadministration of fluconazole (400 mg on day 1, 200 mg QD on days 2-7) and tofacitinib (30 mg, single dose on day 5) increased tofacitinib AUC and Cmax by 79% and 27%, respectively, in 12 healthy subjects. In addition, coadministration of ketoconazole (400 mg QD on days 1-3, a strong CYP3A4 inhibitor) and tofacitinib (10 mg, single dose on day 3) increased tofacitinib AUC and Cmax by 103% and 16%, respectively, in 12 healthy subjects. Tofacitinib half-life increased by 1h both with fluconazole and ketoconazole

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ARTICLE - Voriconazole and atazanavir: a CYP2C19-dependent manageable drug-drug interaction

Four HIV-positive patients with pulmonary aspergillosis treated with voriconazole and atazanavir-based regimens

27/10/2014 - Four HIV-positive patients with pulmonary aspergillosis treated with voriconazole and atazanavir-based regimens (with or without ritonavir) were studied. They were managed by assessing their CYP2C19 genotype (CYP2C19*2, rs4244285, G>A, real-time PCR) and therapeutic drug monitoring (HPLC-based validation methods).

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ARTICLE - Multiple drug interactions with voriconazole in a patient with an increased CYP2C19 activity

Significant interaction of voriconazole and esomperazole, but not ranitidine

27/10/2014 - A 35-year old African female patient with resistant HIV and a cerebral mass of unknown origin was treated with voriconazole for a suspicion of disseminated Aspergillosis infection. Voriconazole trough concentrations (C0) were within target range while the patient was under esomeprazole, a CYP2C19 inhibitor. Phenotyping showed decreased CYP2C19 activity, whereas genotyping showed a variant allele associated with increased enzyme activity. The patient was switched to ranitidine because of the introduction of atazanavir. CYP3A4 inhibition by atazanavir combined with uninhibited CYP2C19 activity resulted in subtherapeutic voriconazole C0. The reintroduction of esomeprazole allowed restoring voriconazole C0 back to target range.

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ARTICLE - Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis

08/09/2014 - Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterise the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics using a population pharmacokinetic approach.

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ARTICLE - Pharmacokinetics of caspofungin in ICU patients

19/08/2014 - Caspofungin is used for treatment of invasive fungal infections. As the pharmacokinetics (PK) of antimicrobial agents in critically ill patients can be highly variable, we set out to explore caspofungin PK in ICU patients.

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ARTICLE - FIVE YEAR RESULTS INTERNATIONAL PROFICIENCY TESTING PROGRAMME

Measurement of antifungal drug concentrations

15/07/2014 - Since 2007 the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring (KKGT) has organized an international interlaboratory proficiency testing (PT) programme for measurement of antifungal drugs in plasma. In this article, the 5 year results of the laboratories' performance are described.

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