Ineffective of lopinavir/ritonavir and chloroquine for a COVID-19 treatment: A perspective of physiologically-based pharmacokinetic and pharmacodynamic modelling

Le résumé fourni par la source

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.

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