Safety and Pharmacokinetic Data for Inhaled Administration of Nintedanib Dry Powder Inhalation for Treatment of Pulmonary Fibrotic Diseases

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable disease marked by irreversible fibrosis and declining respiratory function. Nintedanib inhalation powder is a novel dry powder inhalation formulation of nintedanib consisting of Technosphere® particles that deliver active drug directly to the lungs, aiming to reduce systemic effects associated with oral treatment. The objective of the present work was to assess whether nintedanib dry powder inhalation (DPI) has the potential to provide improved safety and thus effectiveness compared with that of currently available therapeutic options for IPF. METHODS: Three preclinical studies evaluated pharmacokinetic and toxicity outcomes associated with nintedanib inhalation powder. Two 28-day repeat-dose studies (one in rats and one in dogs), and a 6-month toxicity study in dogs assessed pulmonary and histological changes after inhaled nintedanib therapy. A phase 1, first-in-human, randomized, double-blind, placebo-controlled study evaluated the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of nintedanib DPI versus placebo in healthy adults. RESULTS: In the 28-day repeat-dose studies and the 6-month study, animals survived to scheduled necropsy without significant adverse findings, including no gastrointestinal adverse findings, and most achieved target pulmonary-deposited nintedanib concentrations. The phase 1 study demonstrated dose-proportional increases in nintedanib plasma concentrations after single doses and rapid absorption of nintedanib, with maximum concentrations within a few minutes of first dose at levels consistent with deep lung deposition. Nintedanib inhalation powder was considered safe and well tolerated throughout the study duration. CONCLUSION: Inhaled administration of nintedanib via DPI may offer advantages over oral therapies in patients with IPF, potentially reducing adverse effects associated with systemic exposure. Results of the preclinical and phase 1 studies support continued assessment of this formulation in patients with IPF and other pulmonary fibrotic diseases. CLINICAL TRIAL REGISTRATION NUMBER: NCT06532942.