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Population Pharmacokinetics and Pharmacogenetics of Ethambutol in Adult Patients Coinfected with Tuberculosis and HIV

Journal article
Authors Jesper Sundell
E. Bienvenu
Sofia Birgersson
Angela Äbelö
Michael Ashton
Published in Antimicrobial Agents and Chemotherapy
Volume 64
Issue 2
Pages 9
ISSN 0066-4804
Publication year 2020
Published at Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 9
Language en
Links dx.doi.org/10.1128/aac.01583-19
Keywords antimicrobial agents, clinical therapeutics, pharmacology, population, pharmacokinetics, antituberculosis drugs, body-size, clearance, rifampin, food, cytochrome-p450, pyrazinamide, children, cyp1a2, impact, Microbiology, Pharmacology & Pharmacy
Subject categories Pharmacology

Abstract

This study aimed to characterize the population pharmacokinetics and pharmacogenetics of ethambutol in tuberculosis-HIV-coinfected adult patients. Ethambutol plasma concentrations, determined by liquid chromatography-tandem mass spectrometry, in 63 patients receiving ethambutol as part of rifampin-based fixed-dose combination therapy for tuberculosis were analyzed using nonlinear mixed-effects modeling. A one-compartment disposition model with first-order elimination and four transit compartments prior to first-order absorption was found to adequately describe the concentration-time profiles of ethambutol in plasma. Body weight was implemented as an allometric function on the clearance and volume parameters. Estimates of oral clearance and volume of distribution were 77.4 liters/h and 76.2 liters, respectively. A G/A mutation with regard to CYP1A2 2159 G>A was associated with a 50% reduction in relative bioavailability. Simulations revealed that doses of 30 mg/kg of body weight and 50 mg/kg for G/G and G/A carriers, respectively, would result in clinically adequate exposure. The results presented here suggest that CYP1A2 polymorphism affects ethambutol exposure in this population and that current treatment guidelines may result in underexposure in patients coinfected with tuberculosis and HIV. Based on simulations, a dose increase from 15 to 20 mg/kg to 30 mg/kg is suggested. However, the 50-mg/kg dose required to reach therapeutic exposure in G/A carriers may be inappropriate due to the dose-dependent toxicity of ethambutol. Additional studies are required to further investigate CYP450 polymorphism effects on ethambutol pharmacokinetics.

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