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Effects of oral posaconazole on the pharmacokinetics of sirolimus.

Abstract：

OBJECTIVES:Azole antifungal agents are often coadministered with immunosuppressants to recipients of solid organ and hematopoietic stem cell transplants. Posaconazole, an extended-spectrum triazole, is an inhibitor of the cytochrome P450 (CYP) isoenzyme CYP3A4, and sirolimus, an immunosuppressant, is a substrate of the enzyme. We evaluated the effects of posaconazole on sirolimus pharmacokinetics in an open-label, multiperiod, drug-interaction study. METHODS:Twelve healthy subjects received one dose of sirolimus 2 mg on day 1. After a 28-day washout period, subjects received posaconazole 400 mg bid for 16 days (to day 45). On day 36, sirolimus 2 mg and posaconazole 400 mg were coadministered. Blood samples to determine sirolimus plasma concentrations were collected up to 216 hours post dose on days 1 and 36 and plasma pharmacokinetic parameters were calculated. Drug interactions were evaluated using one-way analysis of variance. Mean (% coefficient of variation) maximum plasma concentration (C(max)) and area under the curve (AUC) of sirolimus at day 1 were 4.9 ng/mL (38) and 145 h x ng/mL (45), respectively. RESULTS:Coadministration with posaconazole increased sirolimus C(max) and AUC by 6.7- and 8.9-fold, respectively. These increases are consistent with CYP3A4 inhibition by posaconazole. Adverse events were reported by five subjects (42%) receiving posaconazole and sirolimus and by three (25%) and eight (67%) subjects receiving posaconazole only on days 30 to 35 (presirolimus) and days 37 to 45 (postsirolimus), respectively. CONCLUSION:Because posaconazole has a clinically relevant effect on sirolimus exposure, the agents should probably not be coadministered. Although this was a descriptive study, one potential limitation was the small sample size. The conclusion could have been made stronger if the number of people enrolled in the study had been greater.

journal_name

Curr Med Res Opin

journal_title

Current medical research and opinion

authors

Moton A,Ma L,Krishna G,Martinho M,Seiberling M,McLeod J

doi

10.1185/03007990802644209

subject

Has Abstract

pub_date

2009-03-01 00:00:00

pages

701-7

issue

eissn

0300-7995

issn

1473-4877

pii

10.1185/03007990802644209

journal_volume

pub_type

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Effects of oral posaconazole on the pharmacokinetics of sirolimus.