Isoniazid population pharmacokinetics in HIV perinatally exposed infants.

摘要

Pediatric tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection results in considerable childhood morbidity and mortality. Results of a randomized, double-blind, controlled trial of isoniazid for prevention of tuberculosis disease and latent infection in South African infants with perinatal HIV exposure were used to investigate the roles of NAT2 genotype and enzyme maturation on isoniazid pharmacokinetics. Plasma concentration-time measurements of isoniazid from 151 infants (starting at 3-4 months of age) receiving isoniazid 10-20 mg/kg/d orally during the course of the 24-month study were incorporated in a population analysis. Traditional stepwise stage 2 covariate modeling was first used to explore the relationship between pharmacokinetic parameters and subject-specific covariates: NAT2 genotype, body weight, age, sex, and HIV infection status. The modeling results were not satisfactory due to the limitations of the traditional stepwise covariate modeling approach. Therefore, a new population model (enzyme maturation model) that can separate the effect of enzyme maturation, size, and relative bioavailability changes was developed to describe the enzyme maturation processes for NAT2 enzyme having three genotypes (FF-Fast, FS-Intermediate, and SS-Slow acetylators). The results showed a different NAT2 enzyme maturation profile for each of the three acetylation groups, with the 70kg body weight normalized typical apparent clearance for the fast and intermediate acetylators increasing from 14.25 L/h and 10.88 L/h at 3 months of age to 22.84 L/h and 15.58 L/h at 24 months of age respectively, with no significant change in the apparent clearance of the slow group during this period.;Using the INH study data as a test case, we also explored the issue of incorporating covariate models in stage 1 versus stage 2 at the hierarchical population model. Based on the modeling results, similarities and differences between these two covariate modeling methods were discussed.;Stage 2 enzyme maturation model was used in the simulation for dosing recommendation of isoniazid in infants. With 5% simulated population having max Cmax 3 mg/L as the cutoff value, simulation results indicated that the mean body weight normalized isoniazid dosing (14.5 mg/kg/d) used in the clinical trial should be recommended as the isoniazid dose regimen for infants. This enzyme maturation modeling approach that separates size change and maturation has potential application for other drugs used in neonates and infants having premature enzyme system.