Isoniazid Pharmacokinetics, Pharmacodynamics, and Dosing in South African Infants

Ther Drug Monit. 2012 Aug;34(4):446-51. doi: 10.1097/FTD.0b013e31825c4bc3.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antitubercular Agents / pharmacokinetics*
  • Antitubercular Agents / therapeutic use*
  • Area Under Curve
  • Child, Preschool
  • Double-Blind Method
  • Female
  • HIV Infections / metabolism
  • HIV Infections / microbiology
  • Humans
  • Infant
  • Isoniazid / pharmacokinetics*
  • Isoniazid / therapeutic use*
  • Male
  • Mycobacterium tuberculosis / isolation & purification
  • South Africa
  • Tuberculosis / drug therapy*
  • Tuberculosis / microbiology
  • Tuberculosis / prevention & control
  • Tuberculosis / virology

Substances

  • Antitubercular Agents
  • Isoniazid