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

Abstract

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.

Peak Plasma Concentration of Azithromycin and Treatment Responses in Mycobacterium avium Complex Lung Disease

“…Although the use of TDM in the treatment of patients with tuberculosis has become more widely accepted (23)(24)(25)(26), there are few reports of the clinical usefulness of TDM in patients with NTM lung disease (13)(14)(15). We previously reported that low plasma CLR concentrations were common in patients treated for MAC-LD, although we found no association between low plasma CLR concentrations and treatment outcomes (14).…”

Genotype and allele frequencies of isoniazid-metabolizing enzymes NAT2 and GSTM1 in Latvian tuberculosis patients

“…Although the acetylation polymorphism of NAT2 enzyme was discovered over 50 years ago following differences observed in TB patients to INH toxicity such as the occurrence of peripheral neuritis [13], in later studies the NAT2 slow acetylator genotype was proposed be a significant risk factor for ATLI [14e18]. Moreover, it was shown that individual dosing of INH according to NAT2 status improved treatment and reduced side effects [19,20]. The status of NAT2 activity depends on the number of active alleles (NAT2*4, *12 and *13), and a slow acetylator phenotype is generally observed for individuals with two germ-line copies of alleles that contain any of several single-nt substitutions [3,21].…”

Evaluation of acetylator phenotype of isoniazid among tuberculosis patients in delta state Nigeria: update on management of toxicity

“…8 This is due to genetic acetylation polymorphism phenomena, which has both therapeutic and toxic consequences. The patients with lower blood levels acetylate the drug more rapidly while those with higher level of INH acetylate it more slowly.…”

“…However, it is worth appreciating that slow acetylators had a higher risk of ATLI and it is acknowledged that knowledge of patient"s phenotype will be useful for the clinical prediction and prevention of ATLI. [8][9][10] Fast and slow acetylator statuses are inherited in simple Mendelian manner with the fast acetylation gene being autosomal dorminant. 11 This accounts for the difference in acetylation rate among individuals and ethnic groups, and thus the variation in blood levels of INH.…”

“…25 Furthermore, whether a patient is a fast acetylator (requiring long term drug regimen) or a slow acetylator (requiring short term drug regiment) is now a subject of research interest, but acetylation phenotype has yet to be on the post-treatment or pretreatment laboratory testing list; probably because there is still controversy over the necessity of acetylation monitoring including the role of genetics. [8][9][10][25][26][27][28] The implication is that every patient in the population is still being treated in a similar manner without pathologybased evidence as if they are all fast acetylators.…”