Abstract
Objective
Genetic polymorphisms of arylamine N-acetyltransferase 2 (NAT2) result in large interindividual differences in the plasma concentration of isoniazid (INH). We hypothesized that the internationally recommended dosage should be increased for patients with two active NAT2 alleles (RA type) in order to achieve appropriate antituberculous efficiency; however, the pharmacokinetic effects of the dose increase have not been fully addressed. To estimate an optimal dosage for RA-type patients, we conducted a dose escalation study in healthy male volunteers carrying NAT2*4/*4.
Methods
Oral doses of 300 mg, 600 mg, and 900 mg of INH were administered to eight RA-type subjects, whereas 300 mg was administered to eight IA-type subjects with one active allele (NAT2*4). The pharmacokinetic parameters were estimated from plasma INH concentrations for 24 h postdose.
Results
The ratio of the mean area under the plasma-concentration time curve (AUC) was not proportional to the doses (1:2.6:5.0 for 300:600:900-mg dose) in parallel to the plasma concentration at 1 h (C1) and 2 h (C2) after administration. Compared with the IA-type group given 300 mg, the RA-type group had lower pharmacokinetic parameters at 300 mg (AUC, 66%; C1, 72%; C2, 61%), but higher parameters at 600 mg (AUC, 175%; C1, 196%; C2, 170%). Plasma concentrations of the IA-type group were within the therapeutic range. An optimal INH dose was calculated as 430 mg (7.2 mg/kg) for RA-type subjects to obtain an AUC comparable with that in IA-type subjects dosed with 300 mg.
Conclusion
In RA-type subjects, the pharmacokinetic parameters appeared to lack linearity with the increased dose of INH. We propose that the proper daily dose for RA-type patients is 1.5-times higher than that currently recommended.
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Acknowledgements
This study was supported in part by grants from Research on Health Sciences Focusing on Drug Innovation, The Japan Health Sciences Foundation (KH31036), by the Pfizer Health Research Foundation, by Grant-in-Aid for Scientific Research (19390042), and Takeda Science Foundation. It was also supported in part by grants from Health and Labour Sciences Research Grant, by the Japanese Research Foundation for Clinical Pharmacology, by the Suzuken Memorial Foundation. We are grateful to Dr. Y. Fujio (Osaka University) for his critical review of the manuscript. Special acknowledgements go to MSc. M. Watanabe for her development of the INH determination method by HPLC. We thank Dr. T. Fukuda, MSc. M. Furutsuka, MSc. S. Nakayama, and MSc. T. Tanabe, our colleagues, for their help. We also thank Mr. M. Takebe and Dr. C. Iwata for providing the opportunity for the clinical trial. The technical assistance from all the staff of the Kitasato Institute is appreciated.
Conflict of interest statement
The study received no support from the pharmaceutical industry. None of the authors has any conflict of interest regarding this article.
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Kubota, R., Ohno, M., Hasunuma, T. et al. Dose-escalation study of isoniazid in healthy volunteers with the rapid acetylator genotype of arylamine N-acetyltransferase 2. Eur J Clin Pharmacol 63, 927–933 (2007). https://doi.org/10.1007/s00228-007-0333-1
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DOI: https://doi.org/10.1007/s00228-007-0333-1