Influence of NAT2 Genotype and Maturation on Isoniazid Exposure in Low-Birth-Weight and Preterm Infants With or Without Human Immunodeficiency Virus (HIV) Exposure.
Clin Infect Dis
; 75(6): 1037-1045, 2022 09 29.
Article
in En
| MEDLINE
| ID: mdl-35134861
ABSTRACT
BACKGROUND:
Isoniazid (INH) metabolism depends on the N-acetyl transferase 2 (NAT2) enzyme, whose maturation process remains unknown in low birth weight (LBW) and preterm infants. We aimed to assess INH exposure and safety in infants receiving oral tuberculosis prevention.METHODS:
This population pharmacokinetics (PK) analysis used INH and N-acetyl-isoniazid (ACL) concentrations in infants (BW ≤ 4 kg), including preterm, with follow-up for 6 months. PK parameters were described using nonlinear mixed effects modeling. Simulations were performed to assess INH exposure and optimal dosing regimens, using 2 targets Cmax at 3-6 mg/L and area under the curve (AUC) ≥ 10.52 mg h/L.RESULTS:
We included 57 infants (79% preterm, 84% LBW) in the PK analysis, with a median (range) gestational age of 34 (28.7-39.4) weeks. At the time of sampling, postnatal age was 2.3 (0.2-7.3) months and weight (WT) was 3.7 (0.9-9.3) kg. NAT2 genotype was available in 43 (75.4%) patients (10 slow, 26 intermediate, and 7 fast metabolizers). Ninety percent of NAT2 maturation was attained by 4.4 post-natal months. WT, postmenstrual age, and NAT2 genotype significantly influenced INH exposure, with a 5-fold difference in AUC between slow and fast metabolizers for the same dose. INH appeared safe across the broad range of exposure for 61 infants included in the safety analysis.CONCLUSIONS:
In LBW/preterm infants, INH dosing needs frequent adjustment to account for growth and maturation. Pharmacogenetics-based dosing regimens is the most powerful approach to deliver safe and equalized exposures for all infants, because NAT2 genotype highly impacts INH pharmacokinetic variability.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Arylamine N-Acetyltransferase
/
Tuberculosis
/
HIV Infections
Type of study:
Prognostic_studies
Limits:
Child, preschool
/
Humans
/
Infant
/
Newborn
Language:
En
Journal:
Clin Infect Dis
Journal subject:
DOENCAS TRANSMISSIVEIS
Year:
2022
Document type:
Article
Affiliation country:
United States