Background/aimIsoniazid (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.MethodsA 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.ResultsSerum 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%).ConclusionThe 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.

Objectives: We performed a prospective study to determine whether weight gain predicts future ultrasonographically detected fatty liver (USFL) in a lean adult population. Methods: Among 15 347 Korean male workers, aged 30-59 years, who participated in a health check-up programme in 2002, a USFL-free cohort of 4246 nondiabetic men was followed until September 2007. Alcohol consumption was assessed by a questionnaire. Weight change for each subject was calculated as the difference between baseline and subsequent measurements. Biochemical tests for liver and metabolic function were done. The primary outcome was ultrasound-diagnosed fatty liver. A standard Cox proportional hazards model and time-dependent Cox model were performed.

The association between the 6-thioguanine nucleotide (6-TGN) level and clinical remission in Crohn’s disease (CD) remains controversial. Thiopurine-induced leukopenia is a life-threatening complication of CD in Asians that was recently shown to strongly correlate with NUDT15 genetic variants. This study aimed to determine the relationship between thiopurine metabolite levels and therapeutic response, and to investigate the association of NUDT15, TPMT, and thiopurine metabolites with leukopenia in patients with CD. We enrolled 165 adult patients with CD undergoing thiopurine treatment. Clinical evaluation and laboratory examinations were carried out every 2–3 months. We measured thiopurine metabolites levels and genotyped NUDT15 and TPMT. During the median 12-month observational period, 95 (67.9%) patients exhibited clinical response and 45 (32.1%) did not respond to the treatment. The median 6-TGN level was significantly higher in responders than in non-responders (P < 0.001). The odds ratio of patients with a 6-TGN level ≥230 pmol/8 × 108 red blood cells for showing a clinical response was 4.63 (95% CI 1.62–11.9). NUDT15 variant types were strongly associated with developing leukopenia. Patients with NUDT15 homozygous variant genotype developed severe early leukopenia with an average reduction of 88.2% (range, 84–94%) from the baseline white blood cell count at 4 weeks. Our findings support the role of therapeutic drug monitoring in thiopurine maintenance treatment to optimize thiopurine therapy, especially, for non-responding CD patients. Thiopurine treatment should not be recommended to patients with NUDT15 homozygous variant genotype due to severe early leukopenia.