Nebulized nintedanib (AP02) for idiopathic pulmonary fibrosis demonstrates favorable safety and lung lining fluid exposures: results from two phase I safety, tolerability, and pharmacokinetics studies

Abstract Background Oral nintedanib has been associated with dose-limiting adverse events directly impacting tolerability and adherence. AP02 is a novel nintedanib solution for inhalation intended to minimize systemic exposure and thereby potentially improve tolerability. These studies assessed the safety, tolerability, and pharmacokinetics of AP02 in healthy volunteers and patients with idiopathic pulmonary fibrosis. Methods Data were generated in 2 randomized phase I clinical studies (AP02-001 and AP02-002). AP02-001 ( n = 38) evaluated AP02 in single ascending doses up to 2.0 mg in healthy volunteers ( n = 32) and patients with idiopathic pulmonary fibrosis ( n = 6). AP02-002 evaluated AP02 in single ( n = 36) and multiple ( n = 24) ascending doses up to 8.0 mg twice daily for 7 days in healthy volunteers. Safety, tolerability, and nintedanib plasma pharmacokinetics were evaluated. AP02 and oral nintedanib bronchoalveolar lavage pharmacokinetics were assessed. Results No serious adverse events were reported. The most common drug-related events were headache, nausea, and cough in AP02-001 and dizziness in AP02-002. Systemic exposure of the highest evaluated dose, 8.0 mg AP02 twice daily, was at a minimum 10-fold lower than the mean steady state exposure of the approved 150 mg oral nintedanib twice-daily dose. Nintedanib C max and AUC 0−12 in epithelial lining fluid following a 4.0 mg AP02 dose were predicted to exceed that of oral nintedanib by ~ 26-fold. Conclusions AP02 was well tolerated in single and multiple doses up to 8.0 mg twice daily. AP02 resulted in lower systemic and higher lung exposures than oral nintedanib. These findings suggest that nebulized delivery of nintedanib may be a promising treatment for idiopathic pulmonary fibrosis. Trial registration AP02-001 and AP02-002 were registered as ACTRN12620001141932 (November 2, 2020) and ACTRN12624000825550 (July 4, 2024), respectively, on ANZCT.