Abstract
BackgroundNintedanib 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).MethodsData 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).ResultsUsing 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.ConclusionsThe 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.
Highlights
Nintedanib is a tyrosine kinase inhibitor that inhibits key pathways involved in lung fibrosis in interstitial lung diseases (ILDs) and is approved for the treatment of idiopathic pulmonary fibrosis (IPF), other chronicSchmid et al BMC Pulm Med (2021) 21:244 dose has been shown in randomized trials in Systemic sclerosis (SSc)-Interstitial lung disease (ILD) [7] and progressive fibrosing ILDs other than IPF [8]
Description of data set A total of 2642 patients with IPF, sclerosis-associated ILD (SSc-ILD) or chronic fibrosing ILDs with a progressive phenotype other than IPF from the TOMORROW, INPULSIS, SENSCIS and INBUILD trials were considered for exposure–safety analyses; 1403 patients with IPF who received 50–150 mg nintedanib Twice daily (BID) (n = 895) or placebo (n = 508) in TOMORROW and INPULSIS were used for initial model development
A higher frequency of liver enzyme elevations was observed in patients in both arms of the INBUILD trial (2% placebo, 13% nintedanib) compared with the TOMORROW, INPULSIS and SENSCIS studies (1% placebo, 5% nintedanib), the INBUILD rate was substantially lowered by using the 2019 updated reference ranges for alanine transaminase (ALT) and aspartate transaminase (AST) measurements as evaluated in the sensitivity analysis (1% placebo, 8% nintedanib)
Summary
Nintedanib is a tyrosine kinase inhibitor that inhibits key pathways involved in lung fibrosis in interstitial lung diseases (ILDs) and is approved for the treatment of idiopathic pulmonary fibrosis (IPF), other chronicSchmid et al BMC Pulm Med (2021) 21:244 dose has been shown in randomized trials in SSc-ILD [7] and progressive fibrosing ILDs other than IPF [8]. For patients with mild and moderate hepatic impairment, an approximately twofold and eightfold increase in nintedanib exposure has been shown respectively [12]. In this analysis, we explore the association between nintedanib plasma exposure and safety— diarrhea and liver enzyme elevations—and evaluate the impact of selected intrinsic and extrinsic factors on these outcomes. 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)
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