2020
DOI: 10.1002/cpt.2014
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Physiologically‐Based Pharmacokinetic Modeling to Predict the Clinical Efficacy of the Coadministration of Lopinavir and Ritonavir against SARS‐CoV‐2

Abstract: Lopinavir/ritonavir, originally developed for treating 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 model of lopinavir/ritonavir in white and Chinese populati… Show more

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Cited by 8 publications
(6 citation statements)
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“…Reported in-vitro half maximal inhibitory concentration (EC50) for SARS-CoV2 is 16,400 ng/mL [ 22 ] (while the EC50 for HIV is 70 ng/mL [ 23 ]), an over 200-fold difference, suggesting that significantly higher concentrations of lopinavir are needed to enhance SARS-CoV-2 clearance. A recent physiologically-based pharmacokinetic model suggested that standard regimens of lopinavir/ritonavir are not sufficient to achieve efficacy through unbound lung concentrations [ 24 ]. In our study, trough lopinavir plasma concentrations at day 3 were more than 2-fold higher than expected with the standard dose [ 25 ], but were below the EC50 of SARS-CoV2 in 25% of participants.…”
Section: Discussionmentioning
confidence: 99%
“…Reported in-vitro half maximal inhibitory concentration (EC50) for SARS-CoV2 is 16,400 ng/mL [ 22 ] (while the EC50 for HIV is 70 ng/mL [ 23 ]), an over 200-fold difference, suggesting that significantly higher concentrations of lopinavir are needed to enhance SARS-CoV-2 clearance. A recent physiologically-based pharmacokinetic model suggested that standard regimens of lopinavir/ritonavir are not sufficient to achieve efficacy through unbound lung concentrations [ 24 ]. In our study, trough lopinavir plasma concentrations at day 3 were more than 2-fold higher than expected with the standard dose [ 25 ], but were below the EC50 of SARS-CoV2 in 25% of participants.…”
Section: Discussionmentioning
confidence: 99%
“…The package insert of the drug indicates that only 10% of the metabolism is mediated by CYP enzymes [53], so it is unclear if the higher PK values are results of renal impairment, infection-related downregulation of the metabolizing enzymes, or perhaps a combination of both. Lopinavir/ritonavir and darunavir are the anti-retroviral medications that are approved to treat HIV and are now being repurposed for SARS-CoV-2 [54][55][56]. As a result, recent PK reports on these antiviral drugs compare their median peak-trough levels in COVID-19 patients with previous studies with HIV-infected individuals.…”
Section: Pharmacokinetics Of Covid-19 Drugs In Infected Patientsmentioning
confidence: 99%
“…Reported in-vitro half maximal inhibitory concentration (EC50) for SARS-CoV2 is 16,400 ng/mL (24) (while the EC50 for HIV is 70 ng/mL (25)), an over 200-fold difference, suggesting that significantly higher concentrations of lopinavir are needed to enhance SARS-CoV-2 clearance. A recent physiologically-based pharmacokinetic model suggested that standard regimens of lopinavir/ritonavir are not sufficient to achieve efficacy through unbound lung concentrations (26). In our study, trough lopinavir plasma concentrations at day 3 were more than 2-fold higher than expected with the standard dose (27), but were below the EC50 of SARS-CoV2 in 25% of participants.…”
Section: Discussionmentioning
confidence: 99%