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

Abstract 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.