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


CONCLUSIONS
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.
Department of Clinical Pharmacology, Inje University College of Medicine, Inje University Busan Paik Hospital, Busan, Korea.
Jin Ah
JA
Jung
Department of Clinical Pharmacology, Konkuk University Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Tae-Eun
TE
Kim
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.
Hyun
H
Lee
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.
Byeong-Ho
BH
Jeong
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.
Hye Yun
HY
Park
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.
Kyeongman
K
Jeon
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.
O Jung
OJ
Kwon
Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jae-Wook
JW
Ko
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Rihwa
R
Choi
Department of Laboratory Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea.
Hye-In
HI
Woo
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.
Won-Jung
WJ
Koh
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.
Soo-Youn
SY
Lee
D000328:Adult; D000368:Aged; D000465:Algorithms; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D001835:Body Weight; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D016014:Linear Models; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D010597:Pharmacogenetics; D010641:Phenotype; D057285:Precision Medicine; D011446:Prospective Studies; D016896:Treatment Outcome; D014376:Tuberculosis / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid
INH regimen; NAT2 genotype; pharmacogenomics; tuberculosis