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

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.

Keywords: INH regimen; NAT2 genotype; pharmacogenomics; tuberculosis.

Figure 1

Individual concentrations of isoniazid relative to body weight (A) and NAT2 genotype (B).

Figure 2

Frequency that patients were within the therapeutic range of 3.0–6.0 mg/L while using standard treatment and model-based treatment. Notes: Frequency within the therapeutic range of 3.0–6.0 mg/L was significantly lower in the group requiring dose changes in the standard treatment group compared to the model-based treatment group (P=0.013). *P<0.05.