Relationship between nintedanib exposure and adverse events in patients with idiopathic pulmonary fibrosis

Background: In the TOMORROW and INPULSIS ® trials, nintedanib 150 mg twice daily (bid) reduced disease progression versus placebo in patients with idiopathic pulmonary fibrosis (IPF). Based on study protocol, adverse events were managed by treatment interruption and dose reduction. Aim: To explore the relationship between nintedanib exposure and adverse events of diarrhea and liver enzyme elevations. Methods: Data from 1403 patients with IPF who received nintedanib doses of 50-150 mg bid (N=895) or placebo (N=508) for up to 52 weeks in the TOMORROW trial (Phase II) or one of the two INPULSIS trials (Phase III) were analyzed. The relationship between exposure and the probability of experiencing diarrhea or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevation of ≥ 3x upper limit of normal (ULN) was investigated by parametric time-to-first event modeling. Observed and PK model predicted pre-dose plasma concentrations at steady-state were selected as exposure metrics. Results: A reliable association between nintedanib exposure and risk of diarrhea could not be established; results indicated that dose was a better predictor of diarrhea than exposure. A weak relationship between nintedanib exposure and ALT and/or AST elevations was found, with a trend towards increased risk with increasing exposure based on limited data (41 events). Conclusions: Together with the previously presented exposure-efficacy analyses, the current analyses provide a modelling framework for a quantitative benefit-risk assessment in patients with IPF with altered nintedanib exposure due to comedication or patient characteristics.