Isoniazid pharmacokinetics in children treated for respiratory tuberculosis

Date
2005
Authors
Schaaf H.S.
Parkin D.P.
Seifart H.I.
Werely C.J.
Hesseling P.B.
Van Helden P.D.
Maritz J.S.
Donald P.R.
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Aims: To define the pharmacokinetics of isoniazid (INH) in children with tuberculosis in relation to the N-acetyltransferase 2 (NAT2) genotype. Methods: The first order elimination rate constant (k) and area under the concentration curve (AUC) were calculated in 64 children <13 years of age (median 3.8) with respiratory tuberculosis from INH concentrations determined 2-5 hours after a 10 mg/kg INH dose. The NAT2 genotype was determined; 25 children were classified as homozygous slow (SS), 24 as heterozygous fast (FS), and 15 as homozygous fast (FF) acetylators. Results: The mean (SD) k values of the genotypes differed significantly from one another: SS 0.254 (0.046), FS 0.513 (0.074), FF 0.653 (0.117). Within each genotype a median regression of k on age showed a significant decrease in k with age. The mean (SD) INH concentrations (mg/l) two hours after INH administration were SS 8.599 (1.974), FS 5.131 (1.864), and FF 3.938 (1.754). A within genotype regression of 2-hour INH concentrations on age showed a significant increase with age. A within genotype regression of 3-hour, 4-hour, and 5-hour concentrations on age also showed a significant increase with age in each instance. In ethnically similar adults, mean (SD) 2-hour INH concentrations (mg/l) for each genotype were significantly higher than the children's: SS 10.942 (1.740), FS 8.702 (1.841), and FF 6.031 (1.431). Conclusions: Younger children eliminate INH faster than older children and, as a group, faster than adults, and require a higher mg/kg body weight INH dose to achieve serum concentrations comparable to adults.
Description
Keywords
acyltransferase, isoniazid, acetylator phenotype, adolescent, adult, age, area under the curve, article, body weight, child, dose calculation, drug blood level, drug elimination, ethnology, genotype, heterozygosity, homozygosity, human, infant, lung tuberculosis, major clinical study, nucleotide sequence, pharmacogenetics, priority journal, regression analysis, Adolescent, Adult, Aging, Analysis of Variance, Antitubercular Agents, Area Under Curve, Arylamine N-Acetyltransferase, Child, Child, Preschool, Genotype, Heterozygote, Homozygote, Humans, Infant, Infant, Newborn, Isoniazid, Tuberculosis, Pulmonary
Citation
Archives of Disease in Childhood
90
6