A PHASE 1/1B STUDY OF AN INHALED FORMULATION OF ITRACONAZOLE IN HEALTHY VOLUNTEERS AND ASTHMATICS

Abstract

Introduction Oral itraconazole has variable pharmacokinetics and risks of significant adverse events (AEs) associated with high plasma exposure. A dry powder inhalation formulation of itraconazole (ITRA) is being developed to treat Allergic Bronchopulmonary Aspergillosis (ABPA). This study was conducted to evaluate safety, tolerability and pharmacokinetics of ITRA in healthy volunteers and asthmatics. Methods The study was a 3-part, multi-center, open-label study. Healthy volunteers (n=5-6/cohort) received either single (Part 1 - 5mg, 10mg, 25mg, 35mg) or multiple doses of ITRA (Part 2 -10mg, 20mg, 35mg) over 14d. In Part 3 stable, adult asthmatics received a single dose of 20mg ITRA or 200mg of oral itraconazole in a 2-period cross-over design. Itraconazole plasma (Parts 1-3) and sputum (Part 3) concentrations were evaluated. Results All study drug-related AEs were mild, and no moderate, severe or serious study drug-related AEs were reported. The most common drug-related AE was the infrequent occurrence of mild cough. At steady-state, ITRA resulted in plasma exposure (AUC0-24h) that was 100-400 fold lower across doses tested than reported for oral itraconazole. In asthmatics, ITRA achieved Cmax sputum concentrations 45-fold higher and plasma AUC0-24h concentrations 85-fold lower than oral itraconazole. Conclusions ITRA was safe and well-tolerated under the study conditions tested, and achieved significantly higher lung and lower plasma exposure compared to oral itraconazole, supporting the potential of ITRA to improve upon both the efficacy and safety profile observed with oral itraconazole in patients with ABPA.