Dry powder inhaled ribavirin in healthy volunteers: safety, tolerability, lung and systemic pharmacokinetics

Inhaled Ribavirin is used to treat respiratory syncytial virus infection in infants and could be used to treat respiratory viral infections in COPD patients, if effective levels could be conveniently delivered to the lung. An inhalable ribavirin was manufactured using Liquidia’s PRINT® (Particle Replication In Non-wetting Templates) technology producing 1 µm uniformly shaped particles, which improves delivery to the lung compared to conventional formulations. Modelling predicts that bronchoalveolar epithelial lining fluid (ELF) Cmax levels u003e 200 µM could be achieved, which is above EC50 of ribavirin against respiratory viruses involved in COPD. This was a double-blind, randomized, placebo-controlled, single dose escalating study in healthy volunteers, investigating doses of 7.5, 15, 30, and 60 mg inhaled ribavirin PRINT compared to placebo. Lung function and vital signs were monitored during and after the inhalation. Ribavirin levels in the ELF were assessed by bronchoalveolar lavage within 1 h after dosing (after the predicted lung Tmax). Serial blood samples were taken for systemic PK analysis. No clinically significant changes in vital signs, ECGs, or spirometry were observed and no serious adverse events (SAE) reported. 33 non-severe AEs were reported by 25 subjects (16 possibly drug-related). Model-based extrapolation of the observed ELF ribavirin levels predicts that bronchoalveolar Cmax exceeded 200 μM following both 30 and 60 mg doses. Liquidia PRINT technology allows effective delivery of ribavirin to the lung. Inhaled ribavirin formulated using Liquidia PRINT technology was well-tolerated with no withdrawals due to AEs and no SAEs.