A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis

作者：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; Koh Won Jung^*; Lee Soo Youn

来源：Drug Design, Development and Therapy, 2015, 9: 5433.

DOI：10.2147/DDDT.S87131

• tuberculosis
• pharmacogenomics
• NAT2 genotype
• INH regimen

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) = 13.821-0.1x (body weight, kg) -2.273x (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.

• 出版日期2015