The influence of dose and <Emphasis Type="Italic">N</Emphasis>-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid

Authors:	P. R. Donald D. P. Parkin H. I. Seifart H. S. Schaaf P. D. van Helden C. J. Werely F. A. Sirgel A. Venter J. S. Maritz

Affiliation:	(1) Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, P.O. Box 19063, Tygerberg, 7505, South Africa;(2) Department of Pharmacology, Faculty of Health Sciences, Stellenbosch University, P.O. Box 19063, Tygerberg, 7505, South Africa;(3) Department of Biology and Human Genetics, and the MRC Centre for Molecular and Cellular Biology, DST/NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University, P.O. Box 19063, Tygerberg, 7505, South Africa;(4) Biostatistics Unit of the South African Medical Research Council, Francie van Zyl Drive, Tygerberg, 7505, South Africa

Abstract:	Objective This study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA₉₀) 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) ${left( {{text{AUC}}_{{0 - infty }} } right)}$ and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the ${text{AUC}}_{{0 - infty }}$ and 2-h serum concentrations at which EBA₉₀ was reached. Results EBA₉₀ was reached at an ${text{AUC}}_{{0 - infty }}$ of 10.52 μg/ml per hour and 2-h serum concentrations of 2.19 μg/ml. An ${text{AUC}}_{{0 - infty }}$ of 10.52 μg/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 μg/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 ${text{AUC}}_{{0 - infty }}$ and 2-h INH serum concentrations associated with EBA₉₀, 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.

Keywords:	Isoniazid Early bactericidal activity N-acetyltransferase-2 Pharmacokinetics Pharmacodynamics
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