ABSTRACT
RATIONALE: Ribavirin is an inosine monophosphate dehydrogenase inhibitor. Studies suggest ribavirin aerosol could be a safe and efficacious treatment option in the fight against coronaviruses. It is currently approved for treatment of lower respiratory tract infections due to respiratory syncytial virus in pediatrics. However, treatment is long and continuous (12-18 hours per day, 3-7 days) limiting wider clinical utility. A reduction in treatment time would mean ribavirin could become a practical treatment option for SARS-CoV-2. The primary objective of this study was to evaluate the safety and pharmacokinetics (PK) of four, single-dose regimens of ribavirin aerosol in healthy volunteers. METHODS : Thirty-two subjects entered this phase Ia, randomized, doubleblinded, placebo-controlled, study. Four successive cohorts received ribavirin (active) or placebo. Cohort 1 received 50 mg/mL ribavirin/placebo (10 ml total volume);2 - 50 mg/mL ribavirin/placebo (20 ml total volume);3 - 100 mg/mL ribavirin/placebo (10 ml total volume);4 - 100 mg/mL ribavirin/placebo (20 ml total volume). All treatments were aerosolized and administered over 20 or 40 min for the 10ml and 20 ml volumes respectively. Randomization to cohorts took place on day 1, followed by intense safety monitoring and PK sampling on days 1, 2, 3 and 40. Treatment-emergent adverse events (TEAEs) were summarized by cohort and treatment group. PK parameters were analyzed using non-compartmental methods for maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), area under the curve (AUC), and elimination half life (t1/2). RESULTS : Subjects were (mean ± SD, active vs placebo) aged 57 ± 4.5 vs 60 ± 2.5 years;83% vs 88% were female;and 75% vs 50% were Caucasian. 12.5% (3/24) and 25% (2/8) of subjects experienced at least one TEAE (2 moderate;5 mild) in active and placebo groups respectively. TEAEs were unrelated to study treatment. No clinically significant safety concerns were reported. Table I provides a summary of PK parameters. PK results were linear and well-behaved across the four single-dose regimens, demonstrating systemic exposure with minimal systemic effects. Ribavirin absorption reached Cmax within 2 hrs across all cohorts. The t1/2 was similar across all cohorts. CONCLUSIONS : Four single-dose regimens of ribavirin aerosol demonstrated systemic exposure with minimal systemic effects. These results support preliminary efficacy and safety data in COVID-19 patients and continued clinical development of ribavirin aerosol as a treatment option for SARS-CoV-2 and its variants. (Table Presented).