The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid.
OBJECTIVE
This study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA(90)) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identified pharmacokinetic values after INH doses ranging from 0.2 to 10-12 mg/kg body weight.


METHODS
INH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) (AUC(0-infinity)) and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the AUC(0-infinity) and 2-h serum concentrations at which EBA(90) was reached.


RESULTS
EBA(90) was reached at an AUC(0-infinity) of 10.52 microg/ml per hour and 2-h serum concentrations of 2.19 microg/ml. An AUC(0-infinity) of 10.52 microg/ml per hour was reached by all 66 patients receiving a 10-12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 microg/ml was reached by all 66 patients receiving 10-12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators.


CONCLUSIONS
At a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH AUC(0-infinity) and 2-h INH serum concentrations associated with EBA(90), as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH.
Donald
P R
PR
Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg 7505, South Africa. prd@sun.ac.z
Parkin
D P
DP
Seifart
H I
HI
Schaaf
H S
HS
van Helden
P D
PD
Werely
C J
CJ
Sirgel
F A
FA
Venter
A
A
Maritz
J S
JS
D000107:Acetylation; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010641:Phenotype; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid