Pharmacogenetic variability and the probability of site of action target attainment during tuberculosis meningitis treatment: A physiologically based pharmacokinetic modeling and simulations study.

Autor: Mehta K; Leiden University, Leiden, the Netherlands. Electronic address: k.m.mehta@lacdr.leidenuniv.nl., Narayanan N; Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ, USA., Heysell SK; University of Virginia, Division of Infectious Diseases and International Health, Charlottesville, VA, USA., Bisson GP; University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA., Subbian S; Public Health Research Institute, New Jersey Medical School, Newark, NJ, USA., Kurepina N; Center for Discovery & Innovation, Hackensack Meridian Health, Nutley, NJ, USA., Kreiswirth BN; Center for Discovery & Innovation, Hackensack Meridian Health, Nutley, NJ, USA., Vinnard C; Rutgers University, New Jersey Medical School, Newark, NJ, USA.
Jazyk: angličtina
Zdroj: Tuberculosis (Edinburgh, Scotland) [Tuberculosis (Edinb)] 2022 Dec; Vol. 137, pp. 102271. Date of Electronic Publication: 2022 Oct 20.
DOI: 10.1016/j.tube.2022.102271
Abstrakt: Objective and Methods: Our objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted.
Results: The rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing.
Conclusion: In this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies.
(Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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