ABSTRACT
BackgroundMolnupiravir was licensed for treating high-risk patients with COVID-19 based on data from unvaccinated adults. AGILE CST-2 (NCT04746183) Phase II reports safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals. MethodsAdult out-patients with PCR-confirmed SARS-CoV-2 infection within five days of symptom onset were randomly assigned 1:1 to receive molnupiravir (800mg twice daily for five days) or placebo. The primary outcome was time to swab PCR-negativity, compared using a Bayesian model for estimating the probability of a superior virological response (Hazard Ratio>1) for molnupiravir over placebo. Secondary outcomes included change in viral titre at day 5, safety and tolerability, clinical progression and patient reported outcome measures. We analysed outcomes after the last participant reached day 29. FindingsOf 180 participants randomised (90 molnupiravir, 90 placebo), 50% were vaccinated. Infections with SARS-CoV-2 variants Delta (40%), Alpha (21%), Omicron (21%) and EU1 (16%) were represented. The median time to negative-PCR was 8 versus 11 days for molnupiravir and placebo (HR=1{middle dot}30, 95% CrI 0{middle dot}92-1{middle dot}71, p=0{middle dot}07 by Logrank and p=0{middle dot}03 by Breslow-Gehan tests). Although small numbers precluded subgroup analysis, no obvious differences were observed between vaccinated and unvaccinated participants. Using a two-point prior the probability of molnupiravir being superior to placebo (HR>1) was 75{middle dot}4%, which was just below our defined threshold of 80% for establishing superiority. Using an uninformative continuous prior, the probability of HR>1 was 94{middle dot}7%. As an exploratory analysis, the change in viral titre on day 5 (end of treatment) was significantly greater with molnupiravir compared with placebo. A total of 4 participants reported severe adverse events (grade 3+), 3 of whom were in the placebo arm. InterpretationWe found molnupiravir to be well-tolerated, with evidence for high probability of antiviral efficacy in a population of vaccinated and unvaccinated individuals infected with a broad range of viral variants. FundingFunded by Ridgeback Biotherapeutics and UK National Institute for Health and Care Research infrastructure funding. The AGILE platform infrastructure is supported by the Medical Research Council (grant number MR/V028391/1) and the Wellcome Trust (grant number 221590/Z/20/Z).
ABSTRACT
BackgroundAGILE is a phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. MethodsWe undertook a dose-escalating, open-label, randomised-controlled (standard-of-care) Bayesian adaptive phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomised 2:1 in groups of 6 participants to 300mg, 600mg and 800mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was higher than 25%. Secondary outcomes included safety, clinical progression, pharmacokinetics and virologic responses. ResultsOf 103 volunteers screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 400, 600 or 800mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800mg molnupiravir respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild ([≤]grade 2). The probability of [≥]30% excess toxicity over controls at 800mg was estimated at 0.9%. ConclusionMolnupiravir was safe and well tolerated; a dose of 800mg twice-daily for 5 days was recommended for Phase II evaluation.
ABSTRACT
BackgroundThe role of favipiravir as a treatment for COVID-19 is unclear, with discrepant activity against SARS-CoV-2 in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. In Vero-E6 cells, high concentrations are needed to inhibit SARS-CoV-2 replication. The purpose of this analysis was to use available data to simulate intracellular pharmacokinetics of favipiravir ribofuranosyl-5-triphosphate (FAVI-RTP) to better understand the putative applicability as a COVID-19 intervention. MethodsPreviously published in vitro data for the intracellular production and elimination of FAVI- RTP in MDCK cells incubated with parent favipiravir was fitted with a mathematical model to describe the time course of intracellular FAVI-RTP concentrations as a function of incubation concentration of parent favipiravir. Parameter estimates from this model fitting were then combined with a previously published population PK model for the plasma exposure of parent favipiravir in Chinese patients with severe influenza (the modelled free plasma concentration of favipiravir substituting for in vitro incubation concentration) to predict the human intracellular FAVI-RTP pharmacokinetics. ResultsIn vitro FAVI-RTP data was adequately described as a function of in vitro incubation media concentrations of parent favipiravir with an empirical model, noting that the model simplifies and consolidates various processes and is used under various assumptions and within certain limits. Parameter estimates from the fittings to in vitro data predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP when driven by a predicted free plasma concentration profile. ConclusionThis modelling approach has several important limitations that are discussed in the main text of the manuscript. However, the simulations indicate that despite rapid clearance of the parent drug from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life. Population average intracellular FAVI-RTP concentrations are estimated to maintain the Km for the SARS-CoV-2 polymerase for 3 days following 800 mg BID dosing and 9 days following 1200 mg BID dosing after a 1600 mg BID loading dose on day 1. Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.
ABSTRACT
BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic by the World Health Organisation and urgent treatment and prevention strategies are needed. Many clinical trials have been initiated with existing medications, but assessments of the expected plasma and lung exposures at the selected doses have not featured in the prioritisation process. Although no antiviral data is currently available for the major phenolic circulating metabolite of nitazoxanide (known as tizoxanide), the parent ester drug has been shown to exhibit in vitro activity against SARS-CoV-2. Nitazoxanide is an anthelmintic drug and its metabolite tizoxanide has been described to have broad antiviral activity against influenza and other coronaviruses. The present study used physiologically-based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported nitazoxanide 90% effective concentration (EC90) against SARS-CoV-2. MethodsA whole-body PBPK model was constructed for oral administration of nitazoxanide and validated against available tizoxanide pharmacokinetic data for healthy individuals receiving single doses between 500 mg - 4000 mg with and without food. Additional validation against multiple-dose pharmacokinetic data when given with food was conducted. The validated model was then used to predict alternative doses expected to maintain tizoxanide plasma and lung concentrations over the reported nitazoxanide EC90 in >90% of the simulated population. Optimal design software PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. ResultsThe PBPK model was validated with AAFE values between 1.01 - 1.58 and a difference less than 2-fold between observed and simulated values for all the reported clinical doses. The model predicted optimal doses of 1200 mg QID, 1600 mg TID, 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food, to provide tizoxanide plasma and lung concentrations over the reported in vitro EC90 of nitazoxanide against SARS-CoV-2. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12h post dose was estimated. ConclusionThe PBPK model predicted that it was possible to achieve plasma and lung tizoxanide concentrations, using proven safe doses of nitazoxanide, that exceed the EC90 for SARS-CoV-2. The PBPK model describing tizoxanide plasma pharmacokinetics after oral administration of nitazoxanide was successfully validated against clinical data. This dose prediction assumes that the tizoxanide metabolite has activity against SARS-CoV-2 similar to that reported for nitazoxanide, as has been reported for other viruses. The model and the reported dosing strategies provide a rational basis for the design (optimising plasma and lung exposures) of future clinical trials of nitazoxanide in the treatment or prevention of SARS-CoV-2 infection.
ABSTRACT
There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.
