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Model-Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co-Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy.

Authors :
Sundell, Jesper
Bienvenu, Emile
Janzén, David
Birgersson, Sofia
Äbelö, Angela
Ashton, Michael
Source :
Clinical Pharmacology & Therapeutics; Jul2020, Vol. 108 Issue 1, p73-80, 8p
Publication Year :
2020

Abstract

Tuberculosis is the most common cause of death in HIV-infected patients. Isoniazid is used as a first-line drug to treat tuberculosis infection. However, variability in isoniazid pharmacokinetics can result in hepatotoxicity or treatment failure. Determination of clinical factors affecting isoniazid pharmacokinetics and metabolic pathways in HIV co-infected patients is therefore critical. Plasma levels of isoniazid, acetyl-isoniazid, and isonicotinic acid from 63 patients co-infected with tuberculosis and HIV were analyzed by liquid chromatography with tandem mass spectrometry followed by nonlinear mixed-effects modeling. Patients were genotyped to determine acetylator status. Patients were either on concomitant efavirenz-based antiretroviral therapy or HIV treatment naïve. Clearances of isoniazid were 1.3-fold and 2.3-fold higher in intermediate and rapid acetylators, respectively, compared with slow acetylators. Patients on concomitant efavirenz-based antiretroviral therapy had 64% and 80% higher population predicted clearances of acetyl-isoniazid and isonicotinic acid, respectively, compared with patients who were HIV treatment naïve. Both sex and CD4 cell count affected the bioavailability of isoniazid. Variability in isoniazid exposure could be reduced by dose adaptions based on acetylator type and sex in addition to the currently used weight bands. A novel dosing strategy that has the potential to reduce isoniazid-related toxicity and treatment failure is presented. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00099236
Volume :
108
Issue :
1
Database :
Complementary Index
Journal :
Clinical Pharmacology & Therapeutics
Publication Type :
Academic Journal
Accession number :
144606357
Full Text :
https://doi.org/10.1002/cpt.1806