Exposure-safety analyses of nintedanib in patients with chronic fibrosing interstitial lung disease

Abstract

Background: Nintedanib reduces the rate of decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). The recommended dose of nintedanib is 150 mg twice daily (BID).

Methods: Data from Phase II and III trials in IPF and Phase III trials in SSc-ILD and progressive fibrosing ILDs other than IPF were analyzed to investigate the relationship between nintedanib plasma concentrations (exposure) and safety (liver enzyme elevations [defined as transaminase elevations equal or greater than 3 times the upper limit of normal] and diarrhea).

Results: Using data from 1403 subjects with IPF treated with 50-150 mg nintedanib BID, a parametric time-to-first-event model for liver enzyme elevations was established. Besides exposure, gender was a significant covariate, with a three-fourfold higher exposure-adjusted risk in females than males. Subsequent analysis of combined data from IPF, SSc-ILD (n = 576) and progressive fibrosing ILD (n = 663) studies suggested a consistent exposure-liver enzyme elevation relationship across studies. No exposure-diarrhea relationship was found using data from the various fibrosing ILDs, but diarrhea risk was dependent on dose administered.

Conclusions: The positive correlation between exposure and risk of liver enzyme elevations was consistent across nintedanib studies in IPF, SSc-ILD and progressing fibrosing ILDs other than IPF. The effect size does not warrant a priori dose adjustment in patients with altered plasma exposure (excluding hepatic impairment patients, where there are specific labelling recommendations). For diarrhea, dose administered was a better predictor than exposure.

Keywords: Exposure–safety relationship; Idiopathic pulmonary fibrosis; Liver enzyme elevation; Nintedanib; Progressive fibrosing ILDs; Systemic sclerosis-associated interstitial lung disease.

Fig. 1

Expected percentage of patients having a liver enzyme elevation for different nintedanib plasma exposure levels (C_pre,ss) after 1 year of treatment based on the final exposure–liver enzyme elevation model, using pooled data from trials in IPF, SSc-ILD and progressive fibrosing ILD other than IPF (TOMORROW, INPULSIS, SENSCIS and INBUILD). A, B Final liver enzyme elevation model based on 2014 references ranges of ALT and AST used for the INBUILD primary analysis. The figure is stratified by combined IPF and SSc-ILD trials (TOMORROW, INPULSIS, SENSCIS) versus the trial in progressive fibrosing ILDs other than IPF (INBUILD) C Sensitivity analysis with 2019 updated reference ranges of ALT and AST in the INBUILD trial (study effect removed). The solid lines represent the expected percentage of patients with liver enzyme elevations based on point estimates of the final liver enzyme elevation model. The shaded areas represent the 95% CI based on 2000 bootstrap replicates. The black-filled circle indicates the median C_pre,ss in patients receiving 150 mg nintedanib BID in TOMORROW, INPULSIS-1/2, SENSCIS and INBUILD. The dashed grey line indicates the 5th and 95th percentiles of C_pre,ss. A Final exposure–liver enzyme elevation model: IPF and SSc-ILD trials (TOMORROW, INPULSIS, SENSCIS), B Final exposure–liver enzyme elevation model: progressive fibrosing ILD trial (INBUILD). C Sensitivity analysis (use of 2019 updated reference ranges of ALT and AST for INBUILD and study effect removed): trials in IPF, SSc-ILD and progressive fibrosing ILD other than IPF (TOMORROW, INPULSIS, SENSCIS, INBUILD). AST aspartate transaminase, ALT alanine transaminase, BID twice daily, CI confidence interval, C_pre,ss pre-dose drug concentration in plasma at steady state, ILD interstitial lung disease, IPF idiopathic pulmonary fibrosis, SSc-ILD systemic sclerosis-associated interstitial lung disease