Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Newly Diagnosed Pulmonary TB Patients in Tanzania.

Paolo Denti,John Changalucha,Sandra Castel,Lubbe Wiesner,Kidola Jeremiah,George Praygod,Aase Bengaard Andersen,Michael Christiansen,Nyagosya Range,Daniel Faurholt-Jepsen,Emmanuel Chigutsa,Helen Mcilleron,Christian Munch Hagen,Henrik Friis,Selvakumar Subbian

doi:10.1371/journal.pone.0141002

Abstract

Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients.

Highlights

The aim of anti-tuberculosis (TB) treatment is to provide a safe, effective, and fast acting therapy [1]
Pyrazinamide clearance increased with time on treatment: the model estimated 16.3% faster clearance from the data collected after more than 18 days of treatment (-6.96 Objective Function Value (OFV), p
We studied the effect of nutritional supplementation and HIV status on the pharmacokinetics of isoniazid, pyrazinamide, and ethambutol in pulmonary TB patients during the intensive phase of a standard course of TB treatment

Summary

Introduction

The aim of anti-tuberculosis (TB) treatment is to provide a safe, effective, and fast acting therapy [1]. We conducted a randomized clinical trial in Mwanza, Tanzania to examine the effect of nutritional supplementation on the pharmacokinetics of first-line anti-TB drugs in a cohort of pulmonary TB patients with or without HIV. We recently reported the positive effect on a nutritional supplementation on rifampicin exposure in the HIV co-infected patients (all ART naïve) [20]. In this analysis we aimed to investigate the effect of standard of care plus nutritional supplementation vs standard care on PK of isoniazid, pyrazinamide, and ethambutol among sputum smear positive TB patients with and without HIV. We explored the effect of other covariates, including NAT2 genotype on the PK of isoniazid

Objectives

Results

Discussion

Conclusion