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 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.ResultsExposure 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.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.
Nintedanib is an intracellular inhibitor of tyrosine kinases used in the treatment of non–small cell lung cancer and idiopathic pulmonary fibrosis (IPF). This phase 1 open‐label study investigated the influence of mild and moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of nintedanib following oral administration of a single 100‐mg dose. Subjects with hepatic impairment classified as Child‐Pugh A (mild hepatic impairment) or Child‐Pugh B (moderate hepatic impairment) were eligible. The control group comprised healthy matched subjects. Primary end points were Cmax and AUC0–∞ of nintedanib. Thirty‐three subjects received nintedanib (8 in each of the Child‐Pugh A and Child‐Pugh B groups and 17 controls). The shape of the plasma concentration–time curve for nintedanib was similar between Child‐Pugh A or B and healthy subjects. Nintedanib exposure was ∼2‐fold higher in Child‐Pugh A subjects and ∼8‐fold higher in Child‐Pugh B subjects than in healthy subjects. Adverse events were reported in 3 Child‐Pugh B subjects (37.5%), no Child‐Pugh A subjects, and 3 healthy subjects (17.6%). In conclusion, exposure to nintedanib was higher in Child‐Pugh A and B subjects than in matched healthy subjects. A single dose of nintedanib 100 mg had an acceptable safety and tolerability profile in subjects with hepatic impairment. Results of this dedicated phase 1 study are in line with exploratory investigations into the PK of nintedanib in patients with advanced solid tumors or IPF and hepatic impairment.
IntroductionBI 1015550 is a phosphodiesterase 4 (PDE4) inhibitor that has antifibrotic properties. Phase I and Ic studies were conducted to investigate the safety, tolerability and pharmacokinetics of BI 1015550 in healthy males and patients with idiopathic pulmonary fibrosis (IPF).MethodsIn the Phase I study, 42 subjects were partially randomised to receive placebo or BI 1015550 in single rising doses of 36 mg and 48 mg, or multiple rising doses of 6 mg and 12 mg twice daily over 14 days. In the Phase Ic study, 15 patients with IPF were randomised to receive 18 mg BI 1015550 or placebo twice daily for up to 12 weeks. For both studies, the primary endpoint was the number of subjects with drug-related adverse events (AEs).ResultsIn the Phase I study, drug-related AEs were reported for 50.0% of healthy males treated with a single dose of BI 1015550, compared with 16.7% receiving placebo. For those receiving multiple doses, drug-related AEs were reported for 37.5% of those treated with BI 1015550 and 12.5% receiving placebo. The most frequently reported AEs by organ class were nervous system disorders, which were largely driven by headache. In the Phase Ic study, drug-related AEs were reported in 90.0% of patients treated with BI 1015550, compared with 60.0% of those receiving placebo. The most frequent AEs by organ class were gastrointestinal AEs.ConclusionsBI 1015550 had an acceptable safety profile in healthy males and patients with IPF, supporting further development in larger trials.
PurposeIn two trials, the influences of hepatic and renal impairment on the pharmacokinetics of olodaterol, a novel long-acting inhaled β2-agonist for treatment of COPD, were investigated.Subjects and methodsThe first trial included eight subjects with mild hepatic function impairment (Child–Pugh A), eight subjects with moderate impairment (Child–Pugh B), and 16 matched healthy subjects with normal hepatic function. The second trial included eight subjects with severe renal impairment (creatinine clearance <30 mL·min−1) and 14 matched healthy subjects with normal renal function. Subjects received single doses of 20 or 30 μg olodaterol administered with the Respimat Soft Mist inhaler.ResultsOlodaterol was well tolerated in all subjects. The geometric mean ratios and 90% confidence intervals of dose-normalized area under the plasma concentration-time curve from time zero to 4 hours (AUC0–4) for subjects with mild and moderate hepatic impairment compared to healthy subjects were 97% (75%–125%) and 105% (79%–140%), respectively. Corresponding values for dose-normalized maximum concentration (Cmax) were 112% (84%–151%) (mild impairment) and 99% (73%–135%) (moderate impairment). The geometric mean ratio (90% confidence interval) of AUC0–4 for subjects with severe renal impairment compared to healthy subjects was 135% (94%–195%), and for Cmax was 137% (84%–222%). There was no significant relationship between creatinine clearance and AUC0–4 or Cmax. Renal clearance of olodaterol was reduced to 20% of normal in severe renal impairment.ConclusionMild to moderate hepatic function impairment or severe renal function impairment did not result in a clinically relevant increase of olodaterol systemic exposure after a single inhaled dose.
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