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

Abstract

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 (AUC0-∞) and maximum concentration (Cmax) 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 (AUC0-∞: geometric mean ratio, 160.5% [90% CI, 148.2-173.7]; Cmax: geometric mean ratio, 179.6% [90% CI, 157.6-204.8]) and decreased when it was administered following rifampicin versus alone (AUC0-∞: geometric mean ratio, 50.1% [90% CI, 47.2-53.3]; Cmax: geometric mean ratio, 59.8% [90% CI, 53.8-66.4]). The time to reach Cmax (tmax) and half-life (t½) 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.

Conflict of interest statement

Conflict of interest

All authors are employees of Boehringer Ingelheim.

Ethical Approval

All procedures in these studies were carried out in accordance with the Helsinki declaration and its amendments and the ethical committee or institutional review board which approved these studies.

Figures

Fig. 1

Patient disposition in (a) the study with ketoconazole and in (b) the study with rifampicin

Fig. 2

gMean plasma concentration–time profiles of a single dose of nintedanib 50 mg alone and after multiple doses of ketoconazole 400 mg (a) linear scale and b semi-log scale; and a single dose of nintedanib 150 mg alone and after multiple doses of rifampicin 600 mg (c) linear scale and d semi-log scale