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

BACKGROUND: Nintedanib 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. METHODS: In the ketoconazole study, 34 healthy subjects received nintedanib 50 mg orally alone and 1 h after the last dose of ketoconazole given orally at a dose of 400 mg once daily for 3 days in 1 of 2 randomized sequences. In the rifampicin study, 26 subjects received nintedanib 150 mg orally alone and the morning after the last dose of rifampicin given orally at a dose of 600 mg once daily for 7 days. 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. RESULTS: Exposure 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(½)) of nintedanib were unaffected by co-administration of ketoconazole or rifampicin. CONCLUSIONS: Exposure 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.