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Clofazimine pharmacokinetics in patients with TB: dosing implications.


ABSTRACT: BACKGROUND:Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. OBJECTIVES:To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. PATIENTS AND METHODS:Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6?months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25?mg/L. RESULTS:We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5?L/h and peripheral volume 10?500?L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200?mg daily for 2?weeks would achieve average daily concentrations above a target efficacy concentration 37?days earlier in a typical TB participant. CONCLUSIONS:Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

SUBMITTER: Abdelwahab MT 

PROVIDER: S-EPMC7566350 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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<h4>Background</h4>Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization.<h4>Objectives</h4>To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients.<h4>Patients and methods</h4>Clinical and pharmacokinetic data were obtaine  ...[more]

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