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Population Pharmacokinetics of Hydroxychloroquine and 3 Metabolites in COVID-19 Patients and Pharmacokinetic/Pharmacodynamic Application.
Alvarez, Jean Claude; Davido, Benjamin; Moine, Pierre; 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.
  • Davido B; Infectious Unit, Paris-Saclay University (Versailles Saint-Quentin-en-Yvelines), Raymond Poincaré Hospital, AP-HP, 104 Boulevard Raymond Poincaré, 92380 Garches, France.
  • Moine P; Intensive Care Unit, 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.
  • Etting I; 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.
  • Annane D; Intensive Care Unit, 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; 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.
  • Simon N; Department of clinical Pharmacology, CAP-TV Aix-Marseille University, APHM, INSERM, IRD, SESSTIM, Hop Sainte Marguerite, 13000 Marseille, France.
Pharmaceuticals (Basel) ; 15(2)2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1709312
ABSTRACT
We develop a population pharmacokinetic model for hydroxychloroquine (HCQ) and three of its metabolites (desethylhydroxychloroquine, Des HCQ; desethylchloroquine, DesCQ; and didesethylchloroquine, didesCQ) in COVID-19 patients in order to determine whether a pharmacokinetic (PK)/pharmacodynamic (PD) relationship was present. The population PK of HCQ was described using non-linear mixed effects modelling. The duration of hospitalization, the number of deaths, and poor clinical outcomes (death, transfer to ICU, or hospitalization ≥ 10 d) were evaluated as PD parameters. From 100 hospitalized patients (age = 60.7 ± 16 y), 333 BHCQ and M were available for analysis. The data for BHCQ were best described by a four-compartment model with a first-order input (KA) and a first-order output. For M, the better model of the data used one compartment for each metabolite with a first-order input from HCQ and a first-order output. The fraction of HCQ converted to the metabolites was 75%. A significant relationship was observed between the duration of hospitalization and BHCQ at 48 h (r2 = 0.12; p = 0.0052) or 72 h (r2 = 0.16; p = 0.0012). At 48 h or 72 h, 87% or 91% of patients vs. 63% or 62% had a duration < 25 d with a BHCQ higher or below 200 µg/L, respectively. Clinical outcome was significantly related to BHCQ at 48 h (good outcome 369 +/- 181 µg/L vs. poor 285 +/- 144 µg/L; p = 0.0441) but not at 72 h (407 +/- 207 µg/L vs. 311 +/- 174 µg/L; p = 0.0502). The number of deaths was not significantly different according to the trough concentration (p = 0.972 and 0.836 for 48 h and 72 h, respectively).
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Full text: Available Collection: International databases Database: MEDLINE Language: English Year: 2022 Document Type: Article Affiliation country: Ph15020256

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Full text: Available Collection: International databases Database: MEDLINE Language: English Year: 2022 Document Type: Article Affiliation country: Ph15020256