Physiologically-Based Pharmacokinetic Modeling to Predict the Clinical Efficacy of the Coadministration of Lopinavir and Ritonavir against SARS-CoV-2

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Physiologically-Based Pharmacokinetic Modeling to Predict the Clinical Efficacy of the Coadministration of Lopinavir and Ritonavir against SARS-CoV-2
Title:
Physiologically-Based Pharmacokinetic Modeling to Predict the Clinical Efficacy of the Coadministration of Lopinavir and Ritonavir against SARS-CoV-2
Other Titles:
Clinical Pharmacology and Therapeutics
Publication Date:
07 August 2020
Citation:
Thakur, A., Tan, S.P.F. and Chan, J.C.Y. (2020), Physiologically‐Based Pharmacokinetic Modeling to Predict the Clinical Efficacy of the Coadministration of Lopinavir and Ritonavir against SARS‐CoV‐2. Clin. Pharmacol. Ther.. Accepted Author Manuscript. doi:10.1002/cpt.2014
Abstract:
Lopinavir/ritonavir, originally developed for treating the human immunodeficiency virus (HIV), is currently undergoing clinical studies for treating the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Although recent reports suggest that lopinavir exhibits in vitro efficacy against SARS‐CoV‐2, it is a highly protein bound drug and it remains unknown if it reaches adequate in vivo unbound (free) concentrations in lung tissue. We built a physiologically‐based pharmacokinetic (PBPK) model of lopinavir/ritonavir in Caucasian and Chinese populations. Our aim was to perform pharmacokinetic/pharmacodynamic correlations by comparing simulated free plasma and lung concentration values achieved using different dosing regimens of lopinavir/ritonavir with EC50,unbound and EC90,unbound values of lopinavir against SARS‐CoV‐2. The model was validated against multiple observed clinical datasets for single and repeated dosing of lopinavir/ritonavir. Predicted pharmacokinetic parameters such as the maximum plasma concentration, area under the plasma concentration‐time profile, oral clearance, half‐life and minimum plasma concentration at steady state were within two‐fold of clinical values for both populations. Using the current lopinavir/ritonavir regimen of 400/100 mg twice daily, lopinavir does not achieve sufficient free lung concentrations for efficacy against SARS‐CoV‐2. Although the Chinese population reaches greater plasma and lung concentrations as compared to Caucasians, our simulations suggest that a significant dose increase from the current clinically used dosing regimen is necessary to reach the EC50,unbound value for both populations. Based on safety data, higher doses would likely lead to QT prolongation and gastrointestinal disorders (nausea, vomiting and diarrhea), thus, any dose adjustment must be carefully weighed alongside these safety concerns.
License type:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Funding Info:
Industry Alignment Fund – Pre-Positioning Programme (IAF-PP) grant number H18/01/a0/J14, A*STAR Graduate Academy
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