Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Nintedanib in Healthy Subjects

BackgroundNintedanib is a substrate for p-glycoprotein which can impact bioavailability. We investigated the effects of ketoconazole, a p-glycoprotein inhibitor, and rifampicin, a p-glycoprotein inducer, on the pharmacokinetics of nintedanib.MethodsIn the ketoconazole study, 34 healthy subjects received nintedanib 50mg orally alone and 1h after the last dose of ketoconazole given orally at a dose of 400mg once daily for 3days in 1 of 2 randomized sequences. In the rifampicin study, 26 subjects received nintedanib 150mg orally alone and the morning after the last dose of rifampicin given orally at a dose of 600mg once daily for 7days. The primary objective was to determine the relative bioavailability of nintedanib administered following multiple doses of ketoconazole or rifampicin versus alone, based on AUC from time 0 extrapolated to infinity (AUC(0-)) and maximum concentration (C-max) calculated using an analysis of variance. Geometric mean ratios and 2-sided 90% CIs were calculated.ResultsExposure to nintedanib increased when it was administered following ketoconazole versus alone (AUC(0-): geometric mean ratio, 160.5% [90% CI, 148.2-173.7]; C-max: geometric mean ratio, 179.6% [90% CI, 157.6-204.8]) and decreased when it was administered following rifampicin versus alone (AUC(0-): geometric mean ratio, 50.1% [90% CI, 47.2-53.3]; C-max: geometric mean ratio, 59.8% [90% CI, 53.8-66.4]). The time to reach C-max (t(max)) and half-life (t(1/2)) of nintedanib were unaffected by co-administration of ketoconazole or rifampicin.ConclusionsExposure to nintedanib is increased by co-administration of ketoconazole and decreased by co-administration of rifampicin, likely due to effects on bioavailability of the absorbed fraction.ClinicalTrials.govidentifiers:NCT01679613, NCT01770392.