There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90) values recalculated from in vitro anti‐SARS‐CoV‐2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax) at an approved dose in humans (Cmax/EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax/EC90 ratio above 1. A more in‐depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir‐boosted), and sulfadoxine achieved plasma concentrations above their reported anti‐SARS‐CoV‐2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated to derive a lung Cmax/half‐maximal effective concentration (EC50) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir‐boosted), tipranavir (ritonavir‐boosted), ivermectin, azithromycin, and lopinavir (ritonavir‐boosted) were all predicted to achieve lung concentrations over 10‐fold higher than their reported EC50. Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8‐fold and 1.5‐fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds 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 lungs, in order to maximize the potential for success of proposed human clinical trials.

PCR of upper respiratory specimens is the diagnostic standard for severe acute respiratory syndrome coronavirus 2 infection. However, saliva sampling is an easy alternative to nasal and throat swabbing. We found similar viral loads in saliva samples and in nasal and throat swab samples from 110 patients with coronavirus disease.

The rapidly growing COVID-19 pandemic is the most serious global health crisis since the “Spanish flu” of 1918. There is currently no proven effective drug treatment or prophylaxis for this coronavirus infection. While developing safe and effective vaccines is one of the key focuses, a number of existing antiviral drugs are being evaluated for their potency and efficiency against SARS-CoV-2 in vitro and in the clinic. Here, we review the significant potential of nitazoxanide (NTZ) as an antiviral agent that can be repurposed as a treatment for COVID-19. Originally, NTZ was developed as an antiparasitic agent especially against Cryptosporidium spp.; it was later shown to possess potent activity against a broad range of both RNA and DNA viruses, including influenza A, hepatitis B and C, and coronaviruses. Recent in vitro assessment of NTZ has confirmed its promising activity against SARS-CoV-2 with an EC 50 of 2.12 μM. Here we examine its drug properties, antiviral activity against different viruses, clinical trials outcomes, and mechanisms of antiviral action from the literature in order to highlight the therapeutic potential for the treatment of COVID-19. Furthermore, in preliminary PK/PD analyses using clinical data reported in the literature, comparison of simulated TIZ (active metabolite of NTZ) exposures at two doses with the in vitro potency of NTZ against SARS-CoV-2 gives further support for drug repurposing with potential in combination chemotherapy approaches. The review concludes with details of second generation thiazolides under development that could lead to improved antiviral therapies for future indications.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. 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 SARS-CoV-2 EC 90. Methods: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC 90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. Results: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated. Conclusion: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial. The authors confirm that the PI for this paper is Andrew Owen and the study informs dosing optimisation using a mathematical model without any involvement of actual patients.

BackgroundInnovative approaches are needed to complement existing tools for malaria elimination. Ivermectin is a broad spectrum antiparasitic endectocide clinically used for onchocerciasis and lymphatic filariasis control at single doses of 150 to 200 mcg/kg. It also shortens the lifespan of mosquitoes that feed on individuals recently treated with ivermectin. However, the effect after a 150 to 200 mcg/kg oral dose is short-lived (6 to 11 days). Modeling suggests higher doses, which prolong the mosquitocidal effects, are needed to make a significant contribution to malaria elimination. Ivermectin has a wide therapeutic index and previous studies have shown doses up to 2000 mcg/kg (ie, 10 times the US Food and Drug Administration approved dose) are well tolerated and safe; the highest dose used for onchocerciasis is a single dose of 800 mcg/kg.ObjectiveThe aim of this study is to determine the safety, tolerability, and efficacy of ivermectin doses of 0, 300, and 600 mcg/kg/day for 3 days, when provided with a standard 3-day course of the antimalarial dihydroartemisinin-piperaquine (DP), on mosquito survival.MethodsThis is a double-blind, randomized, placebo-controlled, parallel-group, 3-arm, dose-finding trial in adults with uncomplicated malaria. Monte Carlo simulations based on pharmacokinetic modeling were performed to determine the optimum dosing regimens to be tested. Modeling showed that a 3-day regimen of 600 mcg/kg/day achieved similar median (5 to 95 percentiles) maximum drug concentrations (Cmax) of ivermectin to a single of dose of 800 mcg/kg, while increasing the median time above the lethal concentration 50% (LC50, 16 ng/mL) from 1.9 days (1.0 to 5.7) to 6.8 (3.8 to 13.4) days. The 300 mcg/kg/day dose was chosen at 50% of the higher dose to allow evaluation of the dose response. Mosquito survival will be assessed daily up to 28 days in laboratory-reared Anopheles gambiae s.s. populations fed on patients’ blood taken at days 0, 2 (Cmax), 7 (primary outcome), 10, 14, 21, and 28 after the start of treatment. Safety outcomes include QT-prolongation and mydriasis. The trial will be conducted in 6 health facilities in western Kenya and requires a sample size of 141 participants (47 per arm). Sub-studies include (1) rich pharmacokinetics and (2) direct skin versus membrane feeding assays.ResultsRecruitment started July 20, 2015. Data collection was completed July 2, 2016. Unblinding and analysis will commence once the database has been completed, cleaned, and locked.ConclusionsHigh-dose ivermectin, if found to be safe and well tolerated, might offer a promising new tool for malaria elimination.