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Population pharmacokinetics of lopinavir/ritonavir in Covid-19 patients.
Alvarez, Jean Claude; Moine, Pierre; Davido, Benjamin; Etting, Isabelle; Annane, Djillali; Larabi, Islam Amine; Simon, Nicolas.
  • Alvarez JC; Department of Pharmacology and Toxicology, Paris-Saclay University (Versailles Saint-Quentin-en-Yvelines), Inserm U-1173, FHU Sepsis, Raymond Poincaré Hospital, AP-HP, 104 Boulevard Raymond Poincaré, 92380, Garches, France. jean-claude.alvarez@aphp.fr.
  • Moine P; Laboratoire de Pharmacologie-Toxicologie, Université de Versailles Saint-Quentin-en-Yvelines, Inserm U-1173, Hôpital Raymond Poincaré, AP-HP, 104, Boulevard R. Poincaré, 92380, Garches, France. jean-claude.alvarez@aphp.fr.
  • Davido B; Intensive care unit, Paris-Saclay University (Versailles Saint-Quentin-en-Yvelines), Inserm U-1173, Raymond Poincaré hospital, AP-HP, 104 Boulevard Raymond Poincaré, 92380, Garches, France.
  • Etting I; Infectious Unit, Paris-Saclay University (Versailles Saint-Quentin-en-Yvelines), Raymond Poincaré hospital, AP-HP, 104 Boulevard Raymond Poincaré, 92380, Garches, France.
  • Annane D; Department of Pharmacology and Toxicology, Paris-Saclay University (Versailles Saint-Quentin-en-Yvelines), Inserm U-1173, FHU Sepsis, Raymond Poincaré Hospital, AP-HP, 104 Boulevard Raymond Poincaré, 92380, Garches, France.
  • Larabi IA; Intensive care unit, Paris-Saclay University (Versailles Saint-Quentin-en-Yvelines), Inserm U-1173, Raymond Poincaré hospital, AP-HP, 104 Boulevard Raymond Poincaré, 92380, Garches, France.
  • Simon N; Department of Pharmacology and Toxicology, Paris-Saclay University (Versailles Saint-Quentin-en-Yvelines), Inserm U-1173, FHU Sepsis, Raymond Poincaré Hospital, AP-HP, 104 Boulevard Raymond Poincaré, 92380, Garches, France.
Eur J Clin Pharmacol ; 77(3): 389-397, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1064451
Semantic information from SemMedBD (by NLM)
1. lopinavir / ritonavir TREATS COVID-19
Subject
lopinavir / ritonavir
Predicate
TREATS
Object
COVID-19
2. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
3. lopinavir / ritonavir TREATS Patients
Subject
lopinavir / ritonavir
Predicate
TREATS
Object
Patients
4. ritonavir TREATS COVID-19
Subject
ritonavir
Predicate
TREATS
Object
COVID-19
5. ritonavir TREATS Patients
Subject
ritonavir
Predicate
TREATS
Object
Patients
6. Vero Cells LOCATION_OF 2019 novel coronavirus
Subject
Vero Cells
Predicate
LOCATION_OF
Object
2019 novel coronavirus
7. lopinavir / ritonavir TREATS COVID-19
Subject
lopinavir / ritonavir
Predicate
TREATS
Object
COVID-19
8. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
9. lopinavir / ritonavir TREATS Patients
Subject
lopinavir / ritonavir
Predicate
TREATS
Object
Patients
10. ritonavir TREATS COVID-19
Subject
ritonavir
Predicate
TREATS
Object
COVID-19
11. ritonavir TREATS Patients
Subject
ritonavir
Predicate
TREATS
Object
Patients
12. Vero Cells LOCATION_OF 2019 novel coronavirus
Subject
Vero Cells
Predicate
LOCATION_OF
Object
2019 novel coronavirus
ABSTRACT

OBJECTIVE:

To develop a population pharmacokinetic model for lopinavir boosted by ritonavir in coronavirus disease 2019 (Covid-19) patients.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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%.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Ritonavir / Lopinavir / COVID-19 Type of study: Prognostic study Limits: Aged / Animals / Female / Humans / Male / Middle aged Language: English Journal: Eur J Clin Pharmacol Year: 2021 Document Type: Article Affiliation country: S00228-020-03020-w

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Ritonavir / Lopinavir / COVID-19 Type of study: Prognostic study Limits: Aged / Animals / Female / Humans / Male / Middle aged Language: English Journal: Eur J Clin Pharmacol Year: 2021 Document Type: Article Affiliation country: S00228-020-03020-w