Background and Purpose: Ritonavir-boosted lopinavir and chloroquine were withdrawn for COVID-19 treatment according to WHO recommendation. However, lopinavir is still being used for COVID-19 treatment in a clinical practice guideline without supportive evidence. We demonstrated the utility of physiologically-based pharmacokinetic (PBPK)/pharmacodynamic (PD) models to support clinical use of lopinavir and the withdrawal of chloroquine for COVID-19 treatment. Experimental approach: The developed whole-body PBPK models were validated against clinical data. Model validation was performed using acceptable methods. The inhibitory effect (%E) was calculated to demonstrate drug efficacy. The recommended drug regimen for COVID-19 was the combination of 400/100 mg lopinavir/ritonavir given twice daily and 300 mg base chloroquine given twice daily for 14 days. Key Results: This study successfully developed whole-body PBPK models (AAFEs of 1.2-fold). For patients with a 70 kg body weight, %E for chloroquine in epithelial lining fluid (ELF) and bronchial epithelial cells (BEC) were about 2% and 12%, respectively. The corresponding values for lopinavir were 66% and 87.4%, respectively. With the increased body weight to 90 kg, %E for lopinavir in BEC dramatically dropped to lower than 60%, while that in ELF was slightly decreased (86.87%). Conclusion and Implications: The results support the decision of withdrawing chloroquine and using lopinavir in asymptomatic (with positive antigen kit test) or mild COVID-19 cases. In addition, results support the administration of antiviral drugs within the ten days of infection to prevent treatment failure.

Abstract Background and Purpose: The 2019 novel coronavirus (COVID-19) has been spread out since December 2019 from China to 29 countries. No effective treatment is currently available, although the combination regimen of the antiretroviral drugs– lopinavir/ritonavir (LPV/r), with other antiviral drugs have been using, but the evidences are limited. A recent in vitro study showed that chloroquine could inhibit COVID-19 to cells, and enhance antiviral efficacy. This study aimed to predict the optimal dose regimens of LPV/r, and chloroquine in combination as a potential treatment of COVID-19 infection, using the physiologically-based pharmacokinetic (PBPK) modelling. Experimental approach: The whole PBPK models were constructed. The predicted plasma drug concentrations were compared with the published clinical data. The validated models were used to predict optimal dosage regimens of LPV/r, and chloroquine co-administration. The optimal dose regimen was determined based on the efficacy, and toxicity reported in the published data. Key Results: The average errors of the predicted values were within 30% of the observed data. The proposed optimal dosage regimen is the once-daily dose of 800/200 mg LPV/r co-administered with chloroquine at a loading dose of 1,000 mg, followed by twice-daily dose of 500 mg for 8 doses on the second day, and the twice-daily dose of 400 mg for 18 doses. Conclusion and Implications: PBPK modelling successfully predicted pharmacokinetic profiles within an acceptable range of errors. The study provides a focus for clinical studies to confirm the efficacy of the proposed dosage regimen as a novel treatment for COVID-19 infection.