Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants
Jennifer J Kiser1, Rui Zhu, David Z DʼArgenio
1University of Colorado Denver, Aurora, Colorado, USA.
Insights
Isoniazid (INH) dosing for infants and children is uncertain. A 14.5 mg/kg daily dose of INH was well tolerated and achieved therapeutic drug concentrations in infants aged 3-24 months.
Area of Science:
- Pediatric Pharmacology
- Infectious Disease Management
- Pharmacokinetic Research
Background:
- Limited pharmacokinetic data for isoniazid (INH) in infants and young children leads to dosing uncertainty.
- Accurate INH dosing is critical for effective tuberculosis prophylaxis in vulnerable populations.
Purpose of the Study:
- To characterize INH pharmacokinetics in South African infants aged 3-24 months.
- To evaluate the safety and efficacy of weight-based INH doses for tuberculosis prophylaxis.
- To determine appropriate INH dosing strategies considering age and N-acetyltransferase 2 (NAT2) genotype.
Main Methods:
- Population pharmacokinetic analysis of INH data from 151 perinatally HIV-exposed infants.
- Dosing simulations based on NAT2 genotype, age, Cmax (≥3 mg/L), and AUC0-24 (≥10.52 mg·h/L).
- Evaluation of INH safety and tolerability in the study population.
Main Results:
- Mean INH dose was 14.5 mg·kg·d; pharmacokinetic parameters (Cmax, AUC0-24, half-life) were determined at 3, 6, and 23 months.
- Apparent oral clearance of INH showed trimodal distribution related to NAT2 genotype by 3 months.
- At the average dose, 99% achieved target Cmax and 98% achieved target AUC0-24.
Conclusions:
- A daily isoniazid dose of 14.5 mg/kg is well-tolerated in infants aged 3-24 months.
- This dosage achieves therapeutic concentrations (Cmax ≥3 mg/L and AUC0-24 ≥10.52 mg·h/L) for tuberculosis prophylaxis.
- Findings support optimized INH dosing strategies for pediatric populations.
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.
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