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

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.

Below:  Visual predictive check (VPC) for isoniazid concentration versus time, stratified by NAT2 acetylator status (extensive and intermediate on the left, slow on the right). The circles represent the original data, the dashed and solid lines are the 5th, 50th, and 95th percentiles of the original data, while the shaded areas are the corresponding 95% confidence intervals for the same percentiles, as predicted by the model.

Below: Box and whisker plots showing isoniazid exposure vs. time NAT2 acetylator status (grouped as rapid or intermediate together vs. slow). The left panel displays AUC0-24 and the right panel Cmax. The dots represent individual values. Since for most subjects 2 PK profiles were available, geometric mean was used to summarize the individual values.

Full article at: http://goo.gl/ePIoOQ

By: 

Paolo Denti, Emmanuel Chigutsa, Sandra Castel, Lubbe Wiesner, Helen McIlleron

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

Kidola Jeremiah, Aase Bengaard Andersen

Department of Infectious Diseases, Odense University Hospital, Odense, Denmark

Kidola Jeremiah, George PrayGod, John Changalucha

National Institute for Medical Research, Mwanza Medical Research Centre, Mwanza, Tanzania

Daniel Faurholt-Jepsen, Henrik Friis

Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark

Nyagosya Range

National Institute for Medical Research, Muhimbili Research Centre, Dar Es Salaam, Tanzania

Christian Munch Hagen, Michael Christiansen

Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

Aase Bengaard Andersen

Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark

   

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