Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis

Abstract

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis.50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo.Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone.In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone. @ERSpublications Nintedanib had acceptable safety and tolerability in Japanese patients with IPF

Successful Concomitant Therapy with Pirfenidone and Nintedanib in Idiopathic Pulmonary Fibrosis: A Case Report

“…The safety, tolerability and pharmacokinetics of concomitant therapy with pirfenidone and nintedanib have previously been evaluated in Japanese patients with IPF in a randomised, double-blind phase II study in which 21 of 50 randomised patients were treated with concomitant therapy [16]; only 9 patients receiving pirfenidone and nintedanib at the full recommended dosage. The follow-up periods were 14 days in two cohorts and 28 days in one cohort.…”

Combination therapy in idiopathic pulmonary fibrosis: the way ahead will be hard

“…Finally, the pharmacokinetic data may have been heavily influenced by outliers, always a risk when studies are seriously under-powered. The value of the study of OGURA et al [7] seems to lie primarily in its unanswered questions, which, it can be hoped, will give structure to future work. Also in the current issue of the ERJ, LEY et al [8] have attempted to improve mortality prediction in IPF.…”

“…The rate of FVC decline of approximately 110 mL·year −1 in patients receiving either pirfenidone or nintedanib will pose major challenges with regard to powering future trials [6]. The current issue of the European Respiratory Journal (ERJ) features two studies that are highly relevant to tolerability and study design issues.OGURA et al [7] report a randomised, double-blind, phase II, dose escalation trial in 50 Japanese IPF patients, in which the safety, tolerability and pharmacokinetics of nintedanib were assessed, alone and when added to pirfenidone. Studied interventions consisted of placebo (n=12), nintedanib 50 mg twice daily for 14 days (n=6), nintedanib 100 mg twice daily for 14 days (n=8) or nintedanib 150 mg twice daily for 28 days (n=24).…”

“…OGURA et al [7] report a randomised, double-blind, phase II, dose escalation trial in 50 Japanese IPF patients, in which the safety, tolerability and pharmacokinetics of nintedanib were assessed, alone and when added to pirfenidone. Studied interventions consisted of placebo (n=12), nintedanib 50 mg twice daily for 14 days (n=6), nintedanib 100 mg twice daily for 14 days (n=8) or nintedanib 150 mg twice daily for 28 days (n=24).…”

Switching to nintedanib after discontinuation of pirfenidone due to adverse events in IPF

“…Hence, no conclusions can be drawn regarding the comparison of efficacy and tolerability between the two drugs in less selected and patients who did not undergo pretreatment. Recently, safety and pharmacokinetics of nintedanib when added to pirfenidone were evaluated [14]. In patients who display a good tolerability of one treatment, such combination therapy may be the next step in IPF treatment.…”