Dataset Information

Population Pharmacokinetics of Hydroxychloroquine and 3 Metabolites in COVID-19 Patients and Pharmacokinetic/Pharmacodynamic Application.

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).

SUBMITTER: Alvarez JC

PROVIDER: S-EPMC8877570 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Population Pharmacokinetics of Hydroxychloroquine and 3 Metabolites in COVID-19 Patients and Pharmacokinetic/Pharmacodynamic Application.

Alvarez Jean Claude JC Davido Benjamin B Moine Pierre P Etting Isabelle I Annane Djillali D Larabi Islam Amine IA Simon Nicolas N

Pharmaceuticals (Basel, Switzerland) 20220221 2

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, tr ...[more]

PMID: 35215368

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Project description:Background and objectiveIn the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the interleukin (IL)-6 receptor antagonist tocilizumab improves outcome, including survival in intensive care unit (ICU)-admitted coronavirus disease 2019 (COVID)-19 patients. Therefore tocilizumab has been added to many COVID-19 treatment guidelines. Because obesity is a risk factor for the development of severe COVID-19, concerns have been raised about overtreatment, as well as undertreatment, through weight-based dosing of tocilizumab. The currently applied dose of 8 mg/kg is based on the use of this drug for other indications, however it has not formally been investigated for COVID-19. In this study, the pharmacokinetics and pharmacodynamics of tocilizumab were investigated in ICU-admitted COVID-19 patients.MethodsThis was an open-label, single-centre, observational population pharmacokinetic and descriptive pharmacodynamic evaluation study. Enrolled patients, with polymerase chain reaction-confirmed COVID-19 were admitted to the ICU for mechanical ventilation or high flow nasal canula oxygen support. All patients were 18 years of age or older and received intravenous tocilizumab 8 mg/kg (maximum 800 mg) within 24 h after admission to the ICU and received dexamethasone 6 mg daily as concomitant therapy. For evaluation of the pharmacokinetics and pharmacodynamics of tocilizumab, all time points from day 0 to 20 days after dose administration were eligible for collection. A nonlinear mixed-effects model was developed to characterize the population pharmacokinetic parameters of tocilizumab in ICU-admitted COVID-19 patients. Covariate analysis was performed to identify potential covariates for dose individualization. For the development of alternative dosing schedules, Monte Carlo simulations using the final model were performed.ResultsOverall, 29 patients were enrolled between 15 December 2020 and 15 March 2021. A total of 139 tocilizumab plasma samples were obtained covering the pharmacokinetic curve of day 0 to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and nonlinear clearance (CL) was developed and validated. Average CL was estimated to be 0.725 L/day, average volume of distribution (Vd) was 4.34 L, maximum elimination rate (Vmax) was 4.19 μg/day, and concentration at which the elimination pathway is half saturated (Km) was 0.22 μg/mL. Interindividual variability was identified for CL (18.9%) and Vd (21%). Average area under the concentration versus time curve from time zero to infinity of the first dose (AUCinf 1st DOSE) was 938 [±190] μg/mL*days. All patients had tocilizumab exposure above 1 μg/mL for at least 15 days. Bodyweight-based dosing increases variability in exposure compared with fixed dosing.ConclusionsThis study provides evidence to support a fixed dose of tocilizumab 600 mg in COVID-19 patients. Fixed dosing is a safe, logistically attractive, and drug expenses saving alternative compared with the current 8 mg/kg recommendation.

Project description:This analysis aimed to characterize the pharmacokinetics (PK) and PK/pharmacodynamic (PK/PD) relationship of riociguat and its metabolite M1 in patients with chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH). Blood samples were collected in two phase 3 studies-PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 12 weeks; PAH) and CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 16 weeks; CTEPH)-and long-term extensions. Patients were initially randomized to receive placebo or riociguat, and they received riociguat in the extensions. Nonlinear mixed-effects modeling was used to develop a population PK model describing riociguat PK. PK/PD relationships were investigated by comparing derived PK parameters with changes in PD parameters. Covariate analyses included smoking status, bosentan comedication, bilirubin levels, and baseline creatinine clearance. The PK of riociguat/M1 was described by a one-compartment model. Mean population estimates for riociguat absorption rate constant, clearance, and volume of distribution were 2.17/h, 1.81 L/h, and 32.3 L, respectively; for M1 they were 0.258/h, 3.16 L/h, and 124 L. Interindividual variability was moderate for riociguat and moderate to high for M1. There was no evidence of time- or dose-dependent changes in riociguat/M1 PK. Riociguat clearance was higher in smokers (120% increase) and bosentan-treated patients (36% increase) than in nonsmokers and those not receiving bosentan. There was an inverse correlation between bilirubin and riociguat clearance. In PK/PD analyses, 6-minute walk distance was related to hemodynamic parameters, particularly pulmonary vascular resistance. Riociguat PK were described by a one-compartment model. Effects of covariates on riociguat and M1 PK were established, and a PK/PD relationship was demonstrated. (ClinicalTrials.gov identifiers: PATENT-1, NCT00810693; PATENT-2, NCT00863681; CHEST-1, NCT00855465; CHEST-2, NCT00910429.).

Dataset Information

Population Pharmacokinetics of Hydroxychloroquine and 3 Metabolites in COVID-19 Patients and Pharmacokinetic/Pharmacodynamic Application.

Publications

Population Pharmacokinetics of Hydroxychloroquine and 3 Metabolites in COVID-19 Patients and Pharmacokinetic/Pharmacodynamic Application.

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