Pharmacokinetics of Isoniazid in Low-Birth-Weight and Premature Infants

Abstract

dIsoniazid (INH) is recommended for use as posttuberculosis exposure preventive therapy in children. However, no pharmacokinetic data are available for INH treatment in low-birth-weight (LBW) infants, who undergo substantial developmental and physiological changes. Our objectives in this study were to determine the pharmacokinetic parameters of INH at a dose of 10 mg/kg of body weight/day and to define its pharmacokinetics relative to the arylamine N-acetyltransferase-2 (NAT2) genotype. An intensive prospective pharmacokinetic sampling study was conducted at Tygerberg Children's Hospital, South Africa, in which we measured INH blood plasma concentrations at 2, 3, 4 and 5 h postdose. Twenty LBW infants (14 male, 16 exposed to HIV) were studied. The median birth weight was 1,575 g (interquartile range, 1,190 to 2,035 g) and the median gestational age was 35 weeks (interquartile range, 34 to 38 weeks). The NAT2 acetylation statuses of the infants were homozygous slow (SS) (5 infants), heterozygous intermediate (FS) (11 infants), and homozygous fast (FF) (4 infants). Using a noncompartmental analysis approach, the median maximum drug concentration in blood serum (C max ) was 5.63 g/ml, the time after drug administration to reach C max T max ) was 2 h, the area under the concentration-time curve from 2 to 5 h (AUC 2-5 ) was 13.56 g · h/ml, the half-life (t 1/2 ) was 4.69 h, and the elimination constant rate (k el ) was 0.15 h ؊1 . The alanine aminotransferase levels were normal, apart from 2 isolated values at two and three times above the normal levels. Only the three-times-elevated value was repeated at 6 months and normalized. All LBW infants achieved target INH blood plasma concentrations comparable to the adult values. Reduced elimination was observed in smaller and younger infants and in slow acetylators, cautioning against higher doses. The safety data, although limited, were reassuring. More data, however, are required for newborn infants.

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines

“…Infant INH concentrations also compared well with other pediatric pharmacokinetic studies with similar 2-hour concentrations reported of 4.5, 5.6, and 3.9 to 8.6, following 10 to 15 mg/kg (7,27,38). The effect of acetylator status on INH exposures is not reported here (future work).…”

Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India

“…Therefore, it was decided that further optimization of the dose regimen for isoniazid was not necessary. Even if the dosing for children aged 2–16 years seems to be adequate, this cannot be assumed to be true for younger children (age <2 years) as enzyme maturation needs to be taken into account for this group .…”

PharmGKB summary

“…Due to reduced metabolism, NAT2 slow acetylators have reduced clearance and increased exposure to INH and hydrazine compared to rapid acetylators [63, 66–70]. NAT2 slow acetylator profile (or two slow NAT2 alleles) has therefore been associated with an increased risk of hepatotoxicity/ liver injury/ hepatitis induced by anti-TB drug treatment as compared to rapid acetylators (and sometimes intermediates) in many studies [43–46, 71–87].…”