1. Introduction
The 2019 novel coronavirus (COVID-19) is becoming a serious global health catastrophe with 80,248 confirmed cases, 27,754 recovered cases, and 2,706 deaths reported as of February 25, 2020 (Wolrdometer, 2020). Currently, there remain 49,788 infected patients, of which 40,573 cases are with mild symptoms, and 9,215 cases are those with serious conditions (Wolrdometer, 2020). Since the COVID-19 is a novel coronavirus, no specific effective treatment is currently available. Available drug regimens that can potentially represent therapeutic options for infected patients are the combination of antiretroviral drugs (lopinavir/ritonavir) as well as other antiviral medications (ganciclovir, and oseltamivir)(Chen et al., 2020; Huang et al., 2020). The use of lopinavir/ritonavir (LPV/r) for the treatment of COVID-19 was based on its efficacy against SARS-CoV(Chu et al., 2004), and the similarity between the COVID-19 genome with the human SARS-CoV(Zhu et al., 2020). However, the evidence to support the efficacy, and optimal dosage regimen of these drugs is limited. Recent data suggest that the recovery rate of currently used drug combination is less than 20% (Chen et al., 2020; Huang et al., 2020).There is an urgent need to look for other treatment regimens to broad the therapeutic options for COVID-19 to control the emerging epidemic. A recent in vitro study showed that chloroquine (an antimalarial) could inhibit COVID-19 entry, and post-entry to the infected cells, and enhance antiretroviral drug efficacy(Wang et al., 2020). Furthermore, chloroquine has been shown to moderate host immunity, supporting its antiretroviral effect (Wang et al., 2020). The combination of LPV/r, and chloroquine could represent a promising drug regimen to treat COVID-19. However, the optimal dosage regimen(s) of chloroquine in combination with LPV/r that would result in adequate plasma chloroquine concentrations has not been identified. Besides, the co-administration of chloroquine with ritonavir may pose the patients at risk of chloroquine toxicity (e.g ., retinopathy) due to the inhibitory effect of ritonavir on chloroquine metabolism (Projean et al., 2003; Yeh et al., 2006).
Physiologically-based pharmacokinetic (PBPK) modelling has been used successfully for dose optimization in various diseases (Sager, Yu, Ragueneau-Majlessi, & Isoherranen, 2015). PBPK modelling is accepted by regulatory agencies including the United States Food and Drug Administration (US FDA), and the European Medicine Agencies (EMA) to be applied as a tool to support drug regulatory submission a prediction of drug-drug interactions (DDIs) (Shebley et al., 2018).10 The present study aimed to predict optimal dosage regimens for the co-administration of LPV/r, and chloroquine for the treatment of COVID-19 using PBPK modelling.