A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis
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.
To read the article in full, click here.
Source:
Dove Medical Press
