Isoniazid pharmacokinetics in children treated for respiratory tuberculosis.
OBJECTIVE
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.
Schaaf
H S
HS
Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, Tygerberg Children's Hospital, South Africa. hss@sun.ac.za
Parkin
D P
DP
Seifart
H I
HI
Werely
C J
CJ
Hesseling
P B
PB
van Helden
P D
PD
Maritz
J S
JS
Donald
P R
PR
D000293:Adolescent; D000328:Adult; D000375:Aging / Q000097:blood; D000704:Analysis of Variance; D000995:Antitubercular Agents / Q000097:blood* / Q000627:therapeutic use; D019540:Area Under Curve; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007538:Isoniazid / Q000097:blood* / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000097:blood* / Q000188:drug therapy / Q000235:genetics
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid