title: The effect of rifampin on the pharmacokinetics of sirolimus in healthy volunteers.
abstract: Sirolimus, metabolized primarily by intestinal and hepatic CYP3A4, is a substrate for P-glycoprotein. CYP3A4 inducers would be expected to decrease sirolimus exposure. This open-label, nonrandomized study investigated effects of CYP3A4 induction, by rifampin, on sirolimus pharmacokinetics. Healthy volunteers received sirolimus 20 mg on day 1. After washout period, multiple 600-mg rifampin doses were administered daily for 14 days. On day 9, one 20-mg sirolimus dose was administered after an overnight fast (≥10 hours). Whole blood samples for sirolimus collected for 144 hours after each dose were analyzed by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters, assessed using noncompartmental methods, were compared using analysis of variance. Geometric mean ratios of Cmax and AUCinf were 29% (90% CI: 26, 32%) and 18% (90% CI: 16, 21%), respectively, with rifampin co-administration versus sirolimus alone. Corresponding decreases in Cmax and AUC were 71% and 82%, respectively, which would likely cause trough concentrations to fall below the recommended therapeutic range. Mean CL/F increased approximately fivefold with rifampin versus sirolimus alone. Co-administering sirolimus and potent CYP3A inducers is not recommended. If co-administration is necessary, dose adjustment and concentration monitoring should be conducted.
authors.affiliation: Associate Director, Clinical Pharmacology, Specialty Care Business Unit, Pfizer Inc, Collegeville, PA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tortorici
authors.affiliation: Pharmacometrician, Statistics, Primary Care Business Unit, Pfizer Inc, Collegeville, PA, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Matschke
authors.affiliation: Senior Director, Clinical Pharmacology, Specialty Care Business Unit, Pfizer Inc, Collegeville, PA, USA.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Korth-Bradley
authors.affiliation: Wyeth Research, Collegeville, PA, USA.
authors.forename: Cliff
authors.initials: C
authors.lastname: DiLea
authors.affiliation: Clinical Pharmacology of Miami, Miami, FL, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Lasseter
keywords: drug interaction; healthy volunteers; rifampin; sirolimus