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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients
British Journal of Clinical Pharmacology, Volume 72, No. 1, Year 2011
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Description
AIM: This study was designed to characterize the population pharmacokinetics of isoniazid in South African pulmonary tuberculosis patients. METHODS Concentration-time measurements obtained from 235 patients receiving oral doses of isoniazid as part of routine tuberculosis chemotherapy in two clinical studies were pooled and subjected to nonlinear mixed-effects analysis. RESULTS A two-compartmental model, including first-order absorption and elimination with allometric scaling, was found to describe the observed dose-exposure relationship for oral isoniazid adequately. A mixture model was used to characterize dual rates of isoniazid elimination. Estimates of apparent clearance in slow and fast eliminators were 9.70 and 21.6lh -1, respectively. The proportion of fast eliminators in the population was estimated to be 13.2%. Central volume of distribution was estimated to be 10% smaller in female patients and clearance was found to be 17% lower in patients with HIV. Variability in absorption rate (90%) was completely interoccasional in nature, whereas in relative bioavailability, interoccasional variability (8.4%) was lower than interindividual variability (26%). Oral doses, given once daily according to dosing policies at the time, were sufficient to reach therapeutic concentrations in the majority of the studied population, regardless of eliminator phenotype. Simulations suggested that current treatment guidelines (5mgkg -1) may be suboptimal in fast eliminators with low body weight. CONCLUSIONS A population pharmacokinetic model was developed to characterize the highly variable pharmacokinetics of isoniazid in a South African pulmonary tuberculosis patient population. Current treatment guidelines may lead to underexposure in rapid isoniazid eliminators. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.
Authors & Co-Authors
Wilkins, Justin J.
South Africa, Cape Town
Faculty of Health Sciences
Sweden, Uppsala
Uppsala Universitet
Belgium, Machelen
Exprimo nv
Langdon, Grant
South Africa, Cape Town
Faculty of Health Sciences
Sweden, Uppsala
Uppsala Universitet
United Kingdom, Tadworth
Pfizer Limited, uk
McIlleron, Helen Margaret
South Africa, Cape Town
Faculty of Health Sciences
Pillai, Goonaseelan ‘Colin’
Switzerland, Basel
Novartis International ag
Smith, Peter John
South Africa, Cape Town
Faculty of Health Sciences
Simonsson, Ulrika S.H.
Sweden, Uppsala
Uppsala Universitet
Statistics
Citations: 108
Authors: 6
Affiliations: 5
Identifiers
Doi:
10.1111/j.1365-2125.2011.03940.x
ISSN:
03065251
e-ISSN:
13652125
Research Areas
Cancer
Health System And Policy
Infectious Diseases
Study Design
Cross Sectional Study
Participants Gender
Female