Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing

Abstract

Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3-0.6 log units and exposure by 8.8-22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

Keywords: COVID-19; disease modeling; drug repurposing; pharmacometrics; viral kinetics.

FIGURE 1

Viral load profiles of SARS-CoV-2 following different treatment regimens and initiation of treatment (green: untreated, blue: on positivity (5.4 days after infection), and red: on peak (10.2 days after infection)). Lines may overlap so that only one color is visible; simulations were always run for all time points. Ct: serial cycle threshold values; ART: artemisinin; HCQ: hydroxychloroquine; IVM: ivermectin; LPV/r: lopinavir/ritonavir; NTZ: nitazoxanide. Dosing of different modeled treatment regimens: IVM 300: 300 μg/kg every 24 h for 3 days; IVM 600: IVM 600 μg/kg every day for 3 days; HCQ 200: 200 mg every 8 h for 10 days; HCQ 800/400: 800 mg every 12 h for 1 day, then 400 mg every 12 h for 9 days; NTZ 1200: NTZ 1200 mg every 6 h for 5 days; NTZ 2900: NTZ 2900 mg every 12 h for 5 days; LPV/r 400/100: LPV/r 400/100 mg every 12 h for 14 days; ART 500: ART 500 mg once a day for 5 days.

FIGURE 2

Treatment effects on viral exposure as difference in area under the curve (AUC), relative change in duration, and change in peak cycles (Ct) following different times of treatment initiation (on positivity: 5.4 days after infection, on peak: 10.2 days after infection). HCQ: hydroxychloroquine; IVM: ivermectin; NTZ: nitazoxanide; ART: artemisinin; LPV/r: lopinavir/ritonavir. Dosing of different modeled treatment regimens: HCQ 200: 200 mg every 8 h for 10 days; HCQ 800: 800 mg every 12 h for 1 day, then 400 mg every 12 h for 9 days; IVM 300: 300 μg/kg every 24 h for 3 days; IVM 600: IVM 600 μg/kg every day for 3 days; NTZ 1200: NTZ 1200 mg every 6 h for 5 days; NTZ 2900: NTZ 2900 mg every 12 h for 5 days; ART 500: ART 500 mg once a day for 5 days; LPV/r 400/100: LPV/r 400/100 mg every 12 h for 14 days.