Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

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 13 th 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.

A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19

“…The physiologically-based pharmacokinetic (PBPK) modelling reported the optimal doses of nitazoxanide as 1200 mg four times, 1600 mg three times, 2900 mg twice daily in the fasted state and 700 mg four times, 900 mg three times and 1400 mg twice daily when given with food, to provide its plasma and lung concentrations well above its reported in vitro 90% effective concentration (EC 90 ) against SARS-CoV-2 (4.64 μM or 1.43 μg/ml) ( Rajoli et al, 2020 ). Furthermore, one study utilized the ratio of C max /EC 90 based on approved human dose of nitazoxanide, which exhibited the ratio value above 1 indicating plasma C max concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication ( Arshad et al, 2020 ). Interestingly, nitazoxanide is well tolerated up to 4 g daily dose and its LD 50 is higher than 10,000 mg/kg, indicating high safety.…”

“…A significant finding is the ability of nitazoxanide to promote balance between pro-inflammatory and anti-inflammatory responses in humans, which could play a crucial role in COVID-19 by curbing the hyperinflammatory cytokine storm ( Jasenosky et al, 2019 ; Martins-Filho et al, 2020 ; Rossignol, 2016 ; Shakya et al, 2018a ). Repurposing nitazoxanide against COVID-19 has been suggested in many reports ( Alonso and Farina, 2020 ; Arshad et al, 2020 ; Bobrowski et al, 2020 ; Chibber et al, 2020 ; Mahmoud et al, 2020 ; Martins-Filho et al, 2020 ; Padmanabhan, 2020 ; Padmanabhan and Padmanabhan, 2020 ; Pepperrell et al, 2020 ; Rajoli et al, 2020 ). The approval of a number of clinical trials with nitazoxanide further substantiates this hypothesis ( https://clinicaltrials.gov/ ) (Nitazoxanide clinical trials, 2020).…”

<p>Trend Dynamics of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission in 16 Cities of Hubei Province, China</p>

“…[25][26][27] Two other drugs named ivermectin and nitazoxanide have recently been reported to show an activity against SARS-CoV-2 in vitro and are approved/ licensed for the treatment of some other human infections. 28,29 Recently, various articles have been published reporting individual cases, hazardous health effects, poor quarantine, and risk of pandemics, genetic make-up, clinical interventions and disease manifestations. Here, we will accurately report the incidence of SARS-CoV-2 in 16 different cities of Hubei, China, with particular emphasis on the incidence of infected cases in different cities of Hubei province with respect to time (Jan-11 to Feb-24, 2020).…”

Safety perspectives on presently considered drugs for the treatment of COVID‐19

“…A C max of 51.5 μgÁml −1 was found to occur 2 h post-administration, but plasma concentrations decreased rapidly due to the relatively short half-life of favipiravir (between 2 and 5.5 h) (Madelain et al, 2016). However, both C max and half-life increase slightly after multiple doses, and it has been suggested that favipiravir is capable of reaching a C max in humans sufficient to inhibit 90% of SARS-CoV-2 replication, thus establishing it as an important compound in the ongoing search for COVID-19 therapies (Arshad et al, 2020 suggesting that high tissue penetration would be likely (Madelain et al, 2016;PMDA, 2014). in vivo work in mice showed that the halflife of favipiravir in the lungs is double than that of favipiravir in plasma, indicating slower elimination from the lungs (PMDA, 2014).…”