Effects of oral posaconazole on the pharmacokinetics of sirolimus.
OBJECTIVE
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.


CONCLUSIONS
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.
Moton
Allen
A
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. Allen.Moton@spcorp.com
Ma
Lei
L
Krishna
Gopal
G
Martinho
Monika
M
Seiberling
Michael
M
McLeod
James
J
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D019540:Area Under Curve; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D020123:Sirolimus / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D055815:Young Adult
D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D014230:Triazoles; C101425:posaconazole; D020123:Sirolimus