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NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy.
- Source :
-
European Journal of Clinical Pharmacology . May2013, Vol. 69 Issue 5, p1091-1101. 11p. 1 Diagram, 3 Charts, 4 Graphs. - Publication Year :
- 2013
-
Abstract
- Objective: This study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene ( NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis. Methods: In a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2*4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2*4: intermediate acetylators; 2.5 mg/kg, patients without NAT2*4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the8th week. Results: One hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen. Conclusion: Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PHARMACOGENOMICS
*DRUG therapy for tuberculosis
*ANALYSIS of variance
*CHI-squared test
*CONFIDENCE intervals
*DRUG side effects
*EPIDEMIOLOGY
*FISHER exact test
*HEPATOTOXICOLOGY
*ISONIAZID
*RESEARCH
*RESEARCH funding
*STATISTICAL hypothesis testing
*STATISTICS
*T-test (Statistics)
*U-statistics
*DATA analysis
*RANDOMIZED controlled trials
*DATA analysis software
*DESCRIPTIVE statistics
*DISEASE complications
Subjects
Details
- Language :
- English
- ISSN :
- 00316970
- Volume :
- 69
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- European Journal of Clinical Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 87390957
- Full Text :
- https://doi.org/10.1007/s00228-012-1429-9