Population pharmacokinetics of lopinavir/ritonavir in Covid-19 patients.

To develop a population pharmacokinetic model for lopinavir boosted by ritonavir in coronavirus disease 2019 (Covid-19) patients. Concentrations of lopinavir/ritonavir were assayed by an accredited LC-MS/MS method. The population pharmacokinetics of lopinavir was described using non-linear mixed-effects modeling (NONMEM version 7.4). After determination of the base model that better described the data set, the influence of covariates (age, body weight, height, body mass index (BMI), gender, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), C reactive protein (CRP), and trough ritonavir concentrations) was tested on the model. From 13 hospitalized patients (4 females, 9 males, age = 64 ± 16 years), 70 lopinavir/ritonavir plasma concentrations were available for analysis. The data were best described by a one-compartment model with a first-order input (KA). Among the covariates tested on the PK parameters, only the ritonavir trough concentrations had a significant effect on CL/F and improved the fit. Model-based simulations with the final parameter estimates under a regimen lopinavir/ritonavir 400/100 mg b.i.d. showed a high variability with median concentration between 20 and 30 mg/L (Cmin/Cmax) and the 90% prediction intervals within the range 1-100 mg/L. According to the estimated 50% effective concentration of lopinavir against SARS-CoV-2 virus in Vero E6 cells (16.7 mg/L), our model showed that at steady state, a dose of 400 mg b.i.d. led to 40% of patients below the minimum effective concentration while a dose of 1200 mg b.i.d. will reduce this proportion to 22%.

Citation

Jean Claude Alvarez, Pierre Moine, Benjamin Davido, Isabelle Etting, Djillali Annane, Islam Amine Larabi, Nicolas Simon, Garches COVID-19 Collaborative Group*Ambrosi, Xavier, Amthor, Suzanne, Bounab, Rania, Chentouh, Ryme, Clair, Bernard, Fayssoil, Abdallah, Friedman, Diane, Heming, Nicholas, Maxime, Virginie, Niel Duriez, Myriam, Orlikowski, David, Santi, Francesca, Villart, Maryvonne, Michelon Hugues, Abbar, Baptiste, Dray, Juliah, Tamayo, Juan, Pascault, Alice, Zini; Justine, Bennington, Steven, Moucachen, Myriam, Gay, Pierre, Luxman, Majistor, Kochbati, Elias, Martinez, Valéria, Guichard, Léa, Trabelsi, Chawki, Boutros, Marie, Schitter, Sebastien, Meuleye, Simone, Reysz, Suzanne, Khiter, Hakim, Dosne Blachier, Brigitte, Bron, Anne Lyse, Defouchecour, Etiennette, Hamon Pietrin, Damien, Coester, Denys, Bergounioux Jean, Omar, Amal, Guillon, Maud, Amthor, Helge, Prigent, Helene, Lofaso, Frédéric, Denys Pierre, Bensmail, Djamel, Joussain, Charles, Malot, Claire, Lansaman, Thibaut, Leotard, Antoine, Le Liepvre, Hélène, Rech, Celia, Paquereau, Julie, Kagane, Lauren, Levy, Jonathan, Chkron, Elsa, Angioni, Florence, Karabulut, Céline, Lemoine, Jérôme, Vibert, Julien, Trystram, Noémie, Christian Perronne, Véronique Perronne, Aurélien Dinh, Pierre de Truchis, Soline Simeon, Bessis Simon, Morgan Matt, Hélène Mascitti, Stéphanie Landowski, Pascal Crenn, Aurélie Le Gal, Aymeric Lanore, Julia Nguyen Van Thang, Louis Jacob, Nicolas Kiavue, Marc Hobeika, Jean Louis Gaillard, Jean Louis Hermann, Martin Rottman, Anne Laure Roux, Marie-Anne Welti, Elyanne Gault, Christine Lawrence. Population pharmacokinetics of lopinavir/ritonavir in Covid-19 patients. European journal of clinical pharmacology. 2021 Mar;77(3):389-397

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PMID: 33048175

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