Inhalation: A means to explore and optimize nintedanib's pharmacokinetic/pharmacodynamic relationship

Area of Science:

• Pulmonary Medicine
• Pharmacology
• Drug Delivery Systems

Background:

• Oral nintedanib is approved for idiopathic pulmonary fibrosis (IPF) but has limitations.
• Reformulating nintedanib for nebulization and inhalation aims to improve efficacy and reduce side effects.
• Understanding the pharmacokinetic/pharmacodynamic relationship is crucial for optimizing nintedanib delivery in IPF.

Purpose of the Study:

• To investigate the pharmacokinetic properties of inhaled versus oral nintedanib.
• To evaluate the efficacy of inhaled nintedanib in a preclinical model of pulmonary fibrosis.
• To determine if short-duration inhaled exposure can achieve equivalent or superior lung activity compared to continuous oral dosing.

Main Methods:

• Pharmacokinetic analysis of oral nintedanib in plasma and lung tissue.
• In vitro studies using human fibroblasts exposed to IPF-cellular matrix.
• In vivo studies using a silica-induced pulmonary fibrosis model in rodents, comparing intranasal (inhaled) and oral nintedanib administration.

Main Results:

• Oral nintedanib showed non-proportional exposure and partitioning into lung tissue, with limited availability in epithelial lining fluid.
• In vitro, nintedanib reversed IPF-cellular matrix-induced fibroblast changes.
• In vivo, once-daily inhaled nintedanib demonstrated equivalent-to-superior efficacy in reducing fibrotic markers compared to twice-daily oral dosing at equivalent lung exposure.

Conclusions:

• Pharmacokinetic analysis suggests short-duration lung exposure to nintedanib is sufficient for IPF efficacy.
• Infrequent, low-dose inhaled nintedanib can achieve significant pulmonary activity.
• Inhaled nintedanib offers a promising alternative for IPF treatment, potentially enhancing efficacy and reducing systemic side effects.