• Respiratory medicine · Apr 2021

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

    • Ulrike Schmid, Benjamin Weber, Mats O Magnusson, and Matthias Freiwald.
    • Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany. Electronic address: ulrike_1.schmid@boehringer-ingelheim.com.
    • Respir Med. 2021 Apr 1; 180: 106369.

    BackgroundThe 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).MethodsData 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.ResultsUsing 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.ConclusionsFor 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.Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

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