title: Effects of oral posaconazole on the pharmacokinetics of sirolimus.
abstract: 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.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. Allen.Moton@spcorp.com
authors.forename: Allen
authors.initials: A
authors.lastname: Moton
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.forename: Gopal
authors.initials: G
authors.lastname: Krishna
authors.forename: Monika
authors.initials: M
authors.lastname: Martinho
authors.forename: Michael
authors.initials: M
authors.lastname: Seiberling
authors.forename: James
authors.initials: J
authors.lastname: McLeod
mesh_terms: 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
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D014230:Triazoles; C101425:posaconazole; D020123:Sirolimus