Isoniazid Pharmacokinetics, Pharmacodynamics, and Dosing in South African Infants

Aims: There are limited data on isoniazid (INH) pharmacokinetics in infants and young children and, therefore, uncertainty on appropriate dosing. Methods: Pharmacokinetic data were obtained from perinatally HIV-exposed South African infants aged 3-24 months receiving INH 10-20 mg.kg(-1).d(-1) orally for Mycobacterium tuberculosis prophylaxis. INH pharmacokinetic parameters were characterized using a population pharmacokinetic approach. Dosing simulations were performed to evaluate weight-based INH doses in children based on N-acetyltransferase 2 enzyme (NAT2) genotype, age, maximum concentrations (C-max) >= 3 mg/L, and area under the curve (AUC(0-24)) >= 10.52 mg.h/L. Results: In 151 infants (53% female, 48% HIV positive) receiving a mean INH dose of 14.5 mg.kg(-1).d(-1), mean (+/- SD) C-max at 3, 6, and 23 months of age were 10.0 (3.5), 8.6 (2.6), and 9.3 (3.8) mg/L, respectively, mean (+/- SD) AUC(0-24) were 53.6 (26.8), 42 (19.9), and 44 (30.7) mg.h/L, respectively, and mean(+/- SD) half-lives were 2.1 (0.7), 1.9 (0.6), and 1.8 (0.9) hours, respectively. A trimodal apparent oral clearance of INH as a function of the NAT2 genotype was apparent as early as 3 months. INH was well tolerated. At an average INH dose of 14.5 mg.kg(-1).d(-1), 99% of infants aged 3-24 months have an INH C-max >= 3 mg/L, and 98% have an INH AUC(0-24) > 10.52 mg.h/L. Conclusions: INH at an average dose of 14.5 mg/kg once daily was well tolerated in infants and achieved INH C-max values >= 3 mg/L and AUC(0-24) values > 10.52 mg.h/L.