The Failure of Repurposing Drug Therapies Based on in vitro and in vivo Studies: A Case Study of COVID-19

Abstract

Ineffective selection of therapeutic drugs during an urgent situation leads to failure of COVID-19 treatment in large clinical trials, wasting time and money. We aimed to demonstrate the utility of physiologically-based pharmacokinetic (PBPK)/pharmacodynamic (PD) modeling to support the withdrawal of chloroquine (CQ) 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. In different clinical trials, various regimens of CQ and LPV/r for COVID-19 treatment were used for simulation. The risk of cardiotoxicity following high-dose CQ administration was assessed. The effect of lung pH on drug concentrations in epithelial lining fluid (ELF) following a high CQ dose and LPV/r was evaluated. The whole-body PBPK models were successfully developed (AAFEs of 1.2-fold). The inhibitory effect (%E) of CQ following high-dose regimens in both ELF and bronchial epithelial cells (BEC) was 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 CQ was increased to 76% at pH 5.6 and decreased to 0.13% at pH 7.5. The change in pH in ELF did not influence LPV/r concentrations. PBPK/PD modeling supports the withdrawal of CQ and LPV/r for COVID-19 treatment as an effective tool for selecting therapeutic drug regimens in urgent situations.