Optimal Dose and #Safety of Intravenous #Favipiravir in Hospitalized Patients With #COVID19: A Dose-Escalating, Randomized Controlled Phase Ib Study
Abstract
AGILE (NCT04746183) is a Phase Ib/IIa platform, evaluating candidates to treat COVID-19. Candidate Specific Trial 6 evaluated the safety and optimal dose of a novel intravenous formulation of favipiravir in a dose-escalating, open-label, randomized, controlled, Bayesian adaptive Phase Ib trial. Hospitalized adults with PCR-confirmed SARS-CoV-2 infection, within 14 days of symptomatic COVID-19 were randomized 2:1 in groups of 6 (n = 4 favipiravir, n = 2 standard of care) to ascending doses of intravenous favipiravir twice daily (b.i.d.) for 7 days or standard of care. Clinical data, safety evaluations, virology and pharmacokinetic samples were collected. The primary outcome was safety. Secondary outcomes included clinical, pharmacokinetic and virological endpoints. Twenty-four participants enrolled between September 10, 2022 and November 1, 2023 [10/24 female; median age 74 years (range 52–93)]. Favipiravir was well tolerated despite a high background rate of unrelated adverse events. No dose limiting toxicities were observed, with a model-predicted dose limiting toxicity risk of 16.8% and probability of unacceptable toxicity of 2.7% at the highest dose level. No serious adverse events were deemed related to favipiravir but an expected association with asymptomatic, transient hyperuricemia was observed. Favipiravir exposures increased disproportionally to dose with significant accumulation in plasma, but with marked variability between participants within each cohort. This novel formulation of favipiravir was safe at sustained high doses that reached pre-specified pharmacokinetic targets in a study group with frailty and complex health profiles. We consider doses up to 2,400 mg b.i.d. to be safe for further evaluation.
Study Highlights
-- WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
- Pre-clinical studies of favipiravir describe broad spectrum antiviral activity, positioning it as a therapeutic candidate for many RNA viruses. An oral formulation of favipiravir has been widely studied as a treatment for COVID-19 in clinical trials. Pharmacokinetic modeling suggests the doses used in many of these trials may not have reached effective plasma concentrations.
-- WHAT QUESTION DID THIS STUDY ADDRESS?
- Was a novel intravenous formulation of favipiravir safe and well tolerated in patients hospitalized with COVID-19? Were pre-specified pharmacokinetic parameters met at doses modeled to be effective for the treatment of COVID-19?
-- WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
- We demonstrate that high doses of intravenous favipiravir are safe and well tolerated in a frail and co-morbid population who are likely to be eligible for antiviral treatment but are often excluded from early phase clinical trials. We characterize the pharmacokinetic profile of intravenous favipiravir at high doses and recommend an optimal dose to be used in future Phase II studies.
-- HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
- There is an ongoing unmet need for antivirals to effectively treat COVID-19; however, the significance of these safety and pharmacokinetic data go beyond COVID-19. High doses of favipiravir have a use case against RNA viruses with pandemic potential including viral hemorrhagic fevers and pandemic influenza. The intravenous formulation may be particularly relevant in severely unwell patients for whom oral dosing is not possible or in whom GI absorption is affected. The pharmacokinetic characterization from this study will be used to inform doses for use against a range of significant pathogens. Early phase clinical trials of IV favipiravir in Crimean-Congo Haemorrhagic Fever are ongoing.
Source:
Link: https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.70261
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