Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants

Abstract

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·d 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 (Cmax) ≥3 mg/L, and area under the curve (AUC0-24) ≥10.52 mg·h/L.

Results: In 151 infants (53% female, 48% HIV positive) receiving a mean INH dose of 14.5 mg·kg·d, mean (±SD) Cmax 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) AUC0-24 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·d, 99% of infants aged 3-24 months have an INH Cmax ≥3 mg/L, and 98% have an INH AUC0-24 ≥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 Cmax values ≥3 mg/L and AUC0-24 values ≥10.52 mg·h/L.

Figure 1

INH Concentration data by time post-dose and visit week (red=week 0, blue=week 12, and green=week 84) in 151 South African Infants receiving isoniazid. 62 infants were sampled at first dose (week 0), 48 at week 12, 7 at week 84, 19 at both weeks 0 and 84, and 15 at both weeks 12 and 84. Three infants were sampled later than week 84 (1 at 96 weeks, 2 at 120 weeks). Mean (SD) concentrations at 1, 2, 3, and 4 hours post dose were 11.55 (4.55), 8.52 (3.95), 5.94 (2.98), and 4.58 (3.08) mg/L, respectively.

Figure 2

Mean (SD) weight-adjusted INH CL/F by NAT2 genotype (as shown in Table 1) at weeks 0, 12, and 84