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Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients
Author(s) -
Wilkins Justin J.,
Langdon Grant,
McIlleron Helen,
Pillai Goonaseelan,
Smith Peter J.,
Simonsson Ulrika S. H.
Publication year - 2011
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2011.03940.x
Subject(s) - isoniazid , pharmacokinetics , medicine , tuberculosis , population , volume of distribution , pharmacology , environmental health , pathology
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The pharmacokinetic properties of isoniazid are well characterized, having been studied in seminal work beginning in the early 1950s. Pharmacokinetic models have been published in other populations. WHAT THIS PAPER ADDS • This work provides a population model for isoniazid pharmacokinetics in a South African population from a tuberculosis‐endemic region, of potential use in investigating the complex exposure‐response relationships found in the first line treatment of pulmonary tuberculosis. Previous work has been performed in smaller groups of healthy volunteers or predominantly Caucasian or Asian patients, but the pharmacokinetics of isoniazid in the population in this study are significantly different from those previously reported in other populations. The developed model will provide a basis for estimation of optimal doses in children. 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 21.6 l h −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 (5 mg kg −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.