A Novel Inhaled Dry-Powder Formulation of Ribavirin Allows for Efficient Lung Delivery in Healthy Participants and Those with Chronic Obstructive Pulmonary Disease in a Phase 1 Study

Abstract

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition, causing progressive decline in lung function leading to premature death. Acute exacerbations in COPD patients are predominantly associated with respiratory viruses. Ribavirin is a generic broad-spectrum antiviral agent that could be used for treatment of viral respiratory infections in COPD. Using the Particle Replication In Nonwetting Templates (PRINT) technology, which produces dry-powder particles of uniform shape and size, two new inhaled formulations of ribavirin (ribavirin-PRINT-CFI and ribavirin-PRINT-IP) were developed for efficient delivery to the lung and to minimize bystander exposure. Ribavirin-PRINT-CFI was well tolerated in healthy participants after single dosing and ribavirin-PRINT-IP was well tolerated in healthy and COPD participants after single and repeat dosing. Ribavirin-PRINT-CFI was replaced with ribavirin-PRINT-IP since the latter formulation was found to have improved physicochemical properties and it had a higher ratio of active drug to excipient per unit dose. Ribavirin concentrations were measured in lung epithelial lining fluid in both healthy and COPD participants and achieved target concentrations. Both formulations were rapidly absorbed with approximately dose proportional pharmacokinetics in plasma. Exposure to bystanders was negligible based on both the plasma and airborne ribavirin concentrations with the ribavirin-PRINT-IP formulation. Thus, ribavirin-PRINT-IP allowed for an efficient and convenient delivery of ribavirin to the lungs while minimizing systemic exposure. Further clinical investigations would be required to demonstrate ribavirin-PRINT-IP antiviral characteristics and impact on COPD viral-induced exacerbations. (The clinical trials discussed in this study have been registered at ClinicalTrials.gov under identifiers NCT03243760 and NCT03235726.).

Keywords: COPD; antiviral; exacerbations; novel inhalation powder; respiratory viruses; ribavirin.

Copyright © 2020 Dumont et al.

Figures

FIG 1

Mean Plasma Concentrations versus Time for Ribavirin-PRINT-CFI in Healthy Participants. Dashed line represents the lower limit of quantification of 2.0 ng/ml.

FIG 2

Lung ELF drug concentration versus time of dosing with ribavirin-PRINT-CFI. The lower limit of quantification (LLQ) is 2.0 μg/liter (2.0 ng/ml).

FIG 3

Study design with crystalline ribavirin-PRINT-IP (cohort B, multiple dose; 8 participants [6 active; 2 placebo]).

FIG 4

Mean plasma concentrations versus time with ribavirin-PRINT-IP in healthy participants. The dashed line represents the lower limit of quantification of 0.25 ng/ml.

FIG 5

Scatter plot of ELF drug concentration versus plasma drug concentration with ribavirin-PRINT-IP. The dashed line represents the lower limit of quantification of 0.25 ng/ml.