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Abstract
Background: Like itraconazole and ketoconazole, posaconazole, a broad-spectrum oral triazole
antifungal, inhibits the activity of the cytochrome P450 (CYP) isozyme 3A4. Midazolam,
a short-acting benzodiazepine, is metabolized by CYP3A4. Potential drug interactions
can be expected in patients who are concurrently receiving inhibitors and substrates
of CYP3A4 (eg, ketoconazole, posaconazole) and benzodiazepines (eg, midazolam). Because
of the potential for drug interactions, it is important to determine the effects of
posaconazole on the pharmacokinetic properties of midazolam.
Objective: The aim of this study was to compare the effects of oral administration of posaconazole
versus ketoconazole on the pharmacokinetic properties of orally and intravenously
administered midazolam.
Methods: This Phase I, randomized, open-label, crossover study was conducted at Swiss Pharma
Contract Ltd., Allschwil, Switzerland. Healthy volunteers were randomly assigned to
1 of 2 treatment arms. Arm 1 received posaconazole 200 mg BID for 7 days, posaconazole
400 mg BID for 7 days, no drugs during a 28-day washout, and ketoconazole 400 mg once
daily for 7 days. Arm 2 received posaconazole and ketoconazole in the reverse order,
with a 28-day washout between treatments. An oral/IV midazolam sequence (oral midazolam
2 mg and IV midazolam 0.4 mg) was administered on days -2/-1, 6/7, 13/14 (arm 1),
36/17 (arm 2), 43/44, and 50/51 in both treatment arms. Blood samples were collected
up to 24 hours after midazolam administration. Pharmacokinetic parameters, including
Cmax, Cmin (before azole administration), terminal-phase t1/2 (t1/2z), and AUC to final measurable sampling time (AUCtf), were calculated using noncompartmental methods, and drug interactions were evaluated
using analysis of variance. Adverse events were collected using physical examination,
including vital sign measurements; clinical laboratory analysis; electrocardiography;
and direct questioning at predefined time points throughout the study to assess tolerability.
Results: A total of 12 subjects were enrolled (11 men, 1 woman; all white; mean age, 42.8
years [range, 28-53 years]; mean weight, 80.6 kg; and mean body mass index, 25.6 kg/m2). All of the subjects completed the study. Based on point estimates of logarithm-transformed
data, posaconazole 200 and 400 mg BID were associated with significant increases in
midazolam Cmax (up to 1.3- and 2.4-fold) and AUCtf values (up to 4.6- and 6.2-fold), respectively. Ketoconazole 400 mg once daily was
associated with significantly increased midazolam Cmax and AUCtf (up to 2.8- and 8.2-fold, respectively). When midazolam was concurrently administered
with either azole, t1/2z was prolonged. Seven of 12 (58%) subjects reported ≥1 adverse event during the study
(5 with posaconazole alone and 4 with posaconazole + midazolam). The most common adverse
events were diarrhea (3 subjects [25%] with posaconazole alone, 2 [17%] with ketoconazole
alone, and 1 [8%] with posaconazole + midazolam) and flatulence (1 [8%] with posaconazole
alone and 1 [8%] with midazolam alone).
Conclusions: The results from this study in a small, all-white population of healthy volunteers
suggest that posaconazole was a potent inhibitor of CYP3A4, but to a lesser extent
than was ketoconazole. Monitoring patients for adverse events, the need for dose adjustments,
or both during coadministration with posaconazole may be warranted in patients being
treated with benzodiazepines that are predominantly metabolized through CYP3A4 (eg,
midazolam).
Key words:
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References
- Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease [published correction appears in N Engl J Med. 2007;357:428].N Engl J Med. 2007; 356: 335-347
- Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia.N Engl J Med. 2007; 356: 348-359
- Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions.Clin Infect Dis. 2006; 42: 1398-1403
- Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: An externally controlled trial.Clin Infect Dis. 2007; 44: 2-12
- Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection.Antimicrob Agents Chemother. 2006; 50: 658-666
- Posaconazole is effective as salvage therapy in zygomycosis: A retrospective summary of 91 cases [published correction appears in Clin Infect Dis. 2006;43:1376].Clin Infect Dis. 2006; 42: e61-e65
- In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts.Antimicrob Agents Chemother. 2006; 50: 2009-2015
- Posaconazole: Clinical pharmacology and potential for management of fungal infections.Expert Rev Anti Infect Ther. 2005; 3: 467-487
- Effect of posaconazole on cytochrome P450 enzymes: A randomized, open-label, two-way cross-over study.Eur J Pharm Sci. 2004; 21: 645-653
- Noxafil [package insert]. Schering Corporation, Kenil-worth, NJ2006
- Disposition of posaconazole following single-dose oral administration in healthy subjects.Antimicrob Agents Chemother. 2004; 48: 3543-3551
- Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4.Mol Pharmacol. 1989; 36: 89-96
- Midazolam kinetics.Clin Pharmacol Ther. 1981; 30: 653-661
- Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole.Clin Pharmacol Ther. 1994; 55: 481-485
- Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers.Br J Clin Pharmacol. 1995; 40: 270-272
- Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam.Clin Pharmacol Ther. 2006; 79: 362-370
- The effect of the systemic anti-mycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam.Anesth Analg. 1996; 82: 511-516
- Role of cytochrome P450 enzymes in drug-ddrug interactions.Adv Pharmacol. 1997; 43: 7-35
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(RR1). International Conference on Harmonisation Steering Committee. 1996: 11-53 (E6(RR1). Accessed September 19, 2008)
- A sensitive liquid chromatography and mass spectrometry method for the determination of posaconazole in human plasma.J Pharm Biomed Anal. 2007; 43: 228-236
National Cancer Institute.Common terminology criteria for adverse events v3.00 (CCTCAE). National Cancer Institute. 1-72
- (Accessed November 13, 2007)
- Pharmacokinetics. 2nd ed. Marcel Dekker, New York, NY1982
- First-pass metabolism of midazolam by the human intestine.Clin Pharmacol Ther. 1996; 60: 14-24
- Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-44 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes.Drug Metab Dispos. 1990; 18: 595-606
- Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes.Br J Clin Pharmacol. 1991; 32: 624-626
- Frequency of potential azole drug-drug interactions and consequences of potential fluconazole drug interactions.Pharmacoepidemiol Drug Saf. 2005; 14: 755-767
Article info
Publication history
Accepted:
December 10,
2008
Identification
Copyright
© 2009 Excerpta Medica Inc. All rights reserved. Published by Elsevier Inc.
