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.
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Paolo
P
Denti
Department of Infectious Diseases, Odense University Hospital, Odense, Denmark; National Institute for Medical Research, Mwanza Medical Research Centre, Mwanza, Tanzania.
Kidola
K
Jeremiah
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Emmanuel
E
Chigutsa
Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Daniel
D
Faurholt-Jepsen
National Institute for Medical Research, Mwanza Medical Research Centre, Mwanza, Tanzania.
George
G
PrayGod
National Institute for Medical Research, Muhimbili Research Centre, Dar Es Salaam, Tanzania.
Nyagosya
N
Range
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Sandra
S
Castel
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Lubbe
L
Wiesner
Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Christian Munch
CM
Hagen
Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Michael
M
Christiansen
National Institute for Medical Research, Mwanza Medical Research Centre, Mwanza, Tanzania.
John
J
Changalucha
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Helen
H
McIlleron
Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Henrik
H
Friis
Department of Infectious Diseases, Odense University Hospital, Odense, Denmark; Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
Aase Bengaard
AB
Andersen
D000328:Adult; D000995:Antitubercular Agents; D004977:Ethambutol / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D011718:Pyrazinamide / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013636:Tanzania; D014397:Tuberculosis, Pulmonary / Q000097:blood* / Q000188:drug therapy / Q000378:metabolism
D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid