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Drug Des Devel Ther. 2015 Sep 30;9:5433-8. doi: 10.2147/DDDT.S87131. eCollection 2015.

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

Author information

1
Department of Clinical Pharmacology, Inje University College of Medicine, Inje University Busan Paik Hospital, Busan, Korea.
2
Department of Clinical Pharmacology, Konkuk University Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
3
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.
4
Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
5
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
6
Department of Laboratory Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea.
7
Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

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

PMID:
26491254
PMCID:
PMC4598210
DOI:
10.2147/DDDT.S87131
[Indexed for MEDLINE]
Free PMC Article

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