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

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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.

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Acknowledgement

Dr. Don Parkin died during the preparation of the manuscript. His co-authors would like to acknowledge the significant role he played in all of our studies of the pharmacology of isoniazid.

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Authors and Affiliations

  1. Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, P.O. Box 19063, Tygerberg, 7505, South Africa

    P. R. Donald & H. S. Schaaf

  2. Department of Pharmacology, Faculty of Health Sciences, Stellenbosch University, P.O. Box 19063, Tygerberg, 7505, South Africa

    D. P. Parkin & H. I. Seifart

  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

    P. D. van Helden, C. J. Werely, F. A. Sirgel & A. Venter

  4. Biostatistics Unit of the South African Medical Research Council, Francie van Zyl Drive, Tygerberg, 7505, South Africa

    J. S. Maritz

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  1. P. R. Donald
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Correspondence to P. R. Donald.

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Donald, P.R., Parkin, D.P., Seifart, H.I. et al. The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid. Eur J Clin Pharmacol 63, 633–639 (2007). https://doi.org/10.1007/s00228-007-0305-5

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  • DOI: https://doi.org/10.1007/s00228-007-0305-5

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