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

Background: The tyrosine kinase inhibitor nintedanib reduces the rate of decline in forced vital capacity (FVC) 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, SSc-ILD and progressive fibrosing ILDs other than IPF were analyzed to investigate the relationship between nintedanib plasma concentrations (exposure) and efficacy. Results: Using data from 1403 patients with IPF treated with 50-150 mg nintedanib BID in Phase II and III studies, a linear disease progression model with a maximum drug effect on the rate of decline in FVC was established. Age, height and gender were pre-specified covariates on baseline FVC. Stepwise analysis revealed no other covariates with a distinct effect on the exposure-efficacy relationship. The estimated plasma concentration producing 80% of the maximum drug effect was 10-13 ng/mL, close to the median exposure at 150 mg BID (10 ng/mL). The model in IPF was adapted using Phase III data from 575 patients with SSc-ILD and 663 patients with progressive fibrosing ILDs other than IPF. Besides differences in the natural decline in FVC without treatment, data were consistent with the exposure-efficacy relationship in IPF. Conclusions: For most patients with chronic fibrosing ILDs, the 150 mg nintedanib BID dose provides exposure levels associated with a therapeutic effect close to the maximum nintedanib effect independent of disease condition or baseline demographics.