ABSTRACT
Background: and Purpose: Ritonavir-boosted lopinavir and chloroquine were withdrawn for COVID-19 treatment according to WHO recommendation.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.
Subject(s)
COVID-19 , Parkinson DiseaseABSTRACT
Ineffective selection of therapeutic drugs during an urgent situation leads to failure for COVID-19 treatment in large clinical trials, resulting in wasting time and cost. We aimed to demonstrate the utility of physiologically-based pharmacokinetic (PBPK)/pharmacodynamic (PD) modeling to support the withdrawal of chloroquine and ritonavir-boosted lopinavir (LPV/r) for COVID-19 treatment. The developed whole-body PBPK models were validated against clinical data. Model validation was performed using acceptable methods. The inhibitory effect was calculated to demonstrate drug efficacy. Various regimens of chloroquine and LPV/r for COVID-19 treatment in different clinical trials were used for a simulation. The risk of cardiotoxicity following high dose chloroquine administration was assessed. The effect of lung pH on drug concentrations in epithelial lining fluid (ELF) following a high dose of chloroquine and LPV/r was evaluated. The whole-body PBPK models were successfully developed (AAFEs of 1.2-fold). The inhibitory effect (%E) of chloroquine following high dose regimens in both ELF and bronchial epithelial cells (BEC) were lower than 2 and 1%, respectively. The corresponding values for the high dose of LPV/r were 40 and 2%, respectively. The risk of prolonged QTc in the population was higher than 20%. In addition, the %E of chloroquine was increased to 76% at pH 5.6 and decreased to 0.13% at pH 7.5. The change in pH in ELF had no influence on LPV/r concentrations. PBPK/PD modelling supports the withdrawal of chloroquine and LPV/r for COVID-19 treatment as an effective tool for the selection of therapeutic drug regimens in urgent situation.