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

Abstract

ObjectiveThis 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.MethodsIn 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.ResultsOne 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.ConclusionOur results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.

Severe Skin Rash and Liver Toxic Effects Caused By First-Line Anti-Tuberculosis Drugs: A Case Report

“…The adverse effect of ethambutol is mainly optic nerve damages, while liver injury is very rare. Pyrazinamide could cause arthralgia, appetite decrease, fever, and liver injury [12], as well as skin rash in some cases. Multi-center studies with large sample sizes in China have shown that [13] pyrazinamide in the HRZ strategy is a relatively high risk factor for liver injury, and the liver toxicity is dependent on the dose of pyrazinamide.…”

Rol de la farmacogenómica en el régimen de tratamiento de tuberculosis

“…En Japón ya se han empezado ensayos clínicos para evaluar el cambio de régimen de tratamiento basado en los polimorfismos del gen NAT2 (37) , Azuma et al, se basaron en estudios previos de farmacocinética para determinar la dosis clínica apropiada para cada genotipo. De acuerdo con estos estudios, individuos con fenotipo lento deben recibir mitad de la dosis estándar, mientras que individuos con fenotipo rápidos deben recibir 1,5 veces la dosis estándar (38) .…”

An interlaboratory quality control programme for the measurement of tuberculosis drugs

“…Inadequate exposure to TB drugs constitutes one of the main factors underlying suboptimal treatment response and development of resistance, as evidenced by results from: the in vitro hollow fibre model [1]; clinical studies on relationships between drug concentrations and response [2-5]; a pharmacogenetic trial [6]; and a recent meta-analysis [7].More specifically, these concentration-effect evaluations suggest that clinicians should prescribe higher doses of rifampicin [2,5], that acetylator status should be used to determine the dose of isoniazid [6,7], and that higher doses and exposures to pyrazinamide may increase efficacy [4,5].Clearly, such studies also underline the relevance of careful concentration-effect evaluations during the development of new TB drugs that will eventually be applied by clinicians all over the world.Finally, these studies support the concept of therapeutic drug monitoring (TDM) of TB drugs as applied by clinicians and pharmacists in selected centres around the world [8][9][10]. In contrast to administering the same fixed dose to all patients, TDM seeks to individualise drug doses, guided by measurement of serum (or plasma) drug concentrations.…”

“…Inadequate exposure to TB drugs constitutes one of the main factors underlying suboptimal treatment response and development of resistance, as evidenced by results from: the in vitro hollow fibre model [1]; clinical studies on relationships between drug concentrations and response [2-5]; a pharmacogenetic trial [6]; and a recent meta-analysis [7].…”

“…More specifically, these concentration-effect evaluations suggest that clinicians should prescribe higher doses of rifampicin [2,5], that acetylator status should be used to determine the dose of isoniazid [6,7], and that higher doses and exposures to pyrazinamide may increase efficacy [4,5].…”