A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosisopen access
- Authors
- Jung, Jin Ah; Kim, Tae-Eun; Lee, Hyun; Jeong, Byeong-Ho; Park, Hye Yun; Jeon, Kyeongman; Kwon, O. Jung; Ko, Jae-Wook; Choi, Rihwa; Woo, Hye-In
- Issue Date
- Sep-2015
- Publisher
- DOVE MEDICAL PRESS LTD
- Keywords
- tuberculosis; pharmacogenomics; NAT2 genotype; INH regimen
- Citation
- DRUG DESIGN DEVELOPMENT AND THERAPY, v.9, pp.5433 - 5438
- Indexed
- SCIE
SCOPUS
- Journal Title
- DRUG DESIGN DEVELOPMENT AND THERAPY
- Volume
- 9
- Start Page
- 5433
- End Page
- 5438
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/156343
- DOI
- 10.2147/DDDT.S87131
- ISSN
- 11778881
- Abstract
- Background/aim: Isoniazid (INH) is an essential component of first-line anti-tuberculosis (TB) treatment. However, treatment with INH is complicated by polymorphisms in the expression of the enzyme system primarily responsible for its elimination, N-acetyltransferase 2 (NAT2), and its associated hepatotoxicity. The objective of this study was to develop an individualized INH dosing regimen using a pharmacogenetic-driven model and to apply this regimen in a pilot study. Methods: A total of 206 patients with TB who received anti-TB treatment were included in this prospective study. The 2-hour post-dose concentrations of INH were obtained, and their NAT2 genotype was determined using polymerase chain reaction and sequencing. A multivariate regression analysis that included the variables of age, sex, body weight, and NAT2 genotype was performed to determine the best model for estimating the INH dose that achieves a concentration of 3.0-6.0 mg/L. This dosing algorithm was then used for newly enrolled 53 patients. Results: Serum concentrations of INH were significantly lower in the rapid-acetylators than in the slow-acetylators (2.55 mg/L vs 6.78 mg/L, median, P,0.001). A multivariate stepwise linear regression analysis revealed that NAT2 and body weight independently affected INH concentrations: INH concentration (mg/L) =13.821-0.1× (body weight, kg) −2.273× (number of high activity alleles of NAT2; 0, 1, 2). In 53 newly enrolled patients, the frequency at which they were within the therapeutic range of 3.0-6.0 mg/L was higher in the model-based treatment group compared to the standard treatment group (80.8% vs 59.3%). Conclusion: The use of individualized pharmacogenetic-guided INH dosage regimens that incorporate NAT2 genotype and body weight may help to ensure achievement of therapeutic concentrations of INH in the TB patients.
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