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

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.

Fig 1. Flow chart for pulmonary TB-positive patients randomized to receive a nutritional supplement or no supplement and followed for the effects of nutritional supplementation on Isoniazid, Pyrazinamide and Ethambutal exposure at the end of the second month of intensive phase of treatment.

Fig 2. 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 5^th, 50^th, and 95^th percentiles of the original data, while the shaded areas are the corresponding 95% confidence intervals for the same percentiles, as predicted by the model.

Fig 3. Box and whisker plots showing isoniazid exposure vs. time NAT2 acetylator status (grouped as rapid or intermediate together vs. slow).

The left panel displays AUC_0-24 and the right panel C_max. The dots represent individual values. Since for most subjects 2 PK profiles were available, geometric mean was used to summarize the individual values.

Fig 4. Visual predictive check (VPC) for pyrazinamide concentration versus time, stratified by time on TB treatment.

The circles represent the original data, the dashed and solid lines are the 5^th, 50^th, and 95^th percentiles of the original data, while the shaded areas are the corresponding 95% confidence intervals for the same percentiles, as predicted by the model.

Fig 5. Box and whisker plots showing pyrazinamide exposure vs. time on TB treatment (approximately less or more than 2 weeks).

The left panel displays AUC_0-24 and the right panel C_max. The dots represent individual values. When 2 PK profiles were available in the same stratum, geometric mean was used to summarize the value.

Fig 6. Visual predictive check (VPC) for ethambutol concentration versus time.

The circles represent the original data, the dashed and solid lines are the 5^th, 50^th, and 95^th percentiles of the original data, while the shaded areas are the corresponding 95% confidence intervals for the same percentiles, as predicted by the model.

Fig 7. In the left panels, scatter plots showing ethambutol exposure vs. patient age.

In the right small panels, box and whiskers plots summarizing the same values. The top panels refer to AUC_0-24 and the bottom panels to C_max. For all patients for whom 2 PK profiles were available, geometric mean was used to obtain summary values.