The Influence of Human N-Acetyltransferase Genotype on the Early Bactericidal Activity of Isoniazid

Abstract

The elimination of isoniazid is subject to the influence of the N-acetyltransferase 2 (NAT2) genotype, and individuals may be homozygotic slow, heterozygotic fast, or homozygotic fast acetylators of isoniazid. The early bactericidal activity (EBA) of an antituberculosis agent can be determined by quantitative culture of Mycobacterium tuberculosis in sputum samples obtained from patients with pulmonary tuberculosis during the first days of treatment. In these studies, the EBA of isoniazid during the first 2 days of treatment was determined for 97 patients with sputum smear-positive pulmonary tuberculosis following isoniazid doses of < or =37.5 mg, 75 mg, 150 mg, 300 mg, and 600 mg. The NAT2 genotype was determined in 70 patients, and the association between EBA and genotype was examined in this subgroup. Similarly, the relationship between EBA and isoniazid serum concentration was evaluated in 87 patients. The mean EBA of isoniazid increased with dose, but it levelled off between doses of 150 mg (mean EBA, 0.572) and 300 mg (mean EBA, 0.553). Significant differences were found in the mean EBA of isoniazid between the homozygous slow acetylator group and the heterozygous fast acetylator group and between the homozygous slow acetylator group and the homozygous fast acetylator group, but not between the heterozygous fast acetylator group and the homozygous fast acetylator group. The EBA appeared to reach a maximum at a 2-h isoniazid concentration of 2-3 microg/mL. These data confirm a significant effect of NAT2 genotype on the EBA of isoniazid over a range of doses.

Population Modeling and Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Isoniazid in Lungs

“…In accordance with this finding, increasing the daily INH dose up to 600 mg gave little increase in bactericidal effects, even in FA subjects, when the MIC was at the lower end of the MIC range. Those results are in accordance with clinical studies that found no increase in the EBA when the INH dose was increased beyond 150 to 300 mg per day (6,15,38). While those studies did not report the MICs of isolated strains of M. tuberculosis, we may hypothesize that those MICs were relatively low.…”

“…However, the need for INH dose optimization and adjustment for acetylator status is controversial. Clinical studies that assessed the EBA values with various doses of INH found that the EBA seems to plateau at 300 mg daily, as no significant increase in the EBA was observed with larger INH doses (6,15,38). However, it was shown that the EBA of INH in fast acetylators was significantly lower than that in slow acetylators (15).…”

“…Clinical studies that assessed the EBA values with various doses of INH found that the EBA seems to plateau at 300 mg daily, as no significant increase in the EBA was observed with larger INH doses (6,15,38). However, it was shown that the EBA of INH in fast acetylators was significantly lower than that in slow acetylators (15). A simulation study by Gumbo et al suggested that a 300-mg daily dose of INH may be suboptimal, especially in ethnic populations with large proportions of FA individuals (14).…”

“…This PK-PD relationship was specifically studied in a mouse model of tuberculosis, in which INH plasma AUC values were correlated with the decline in the total bacterial load in lungs (13), and in a hollow-fiber in vitro model, in which the AUC values were correlated with the decline in log counts, which probably reflects the in vivo effect of INH on extracellular bacteria (14). In humans, INH AUC values have also been shown to correlate with EBA values (15).…”

The clinical role of genetic polymorphisms in drug-metabolizing enzymes

“…On the other hand, efficacy of isoniazid therapy seems to be better in SAs and significant differences in the mean early bactericidal activity of isoniazid between homozygous SAs and heterozygous or homozygous RAs could be demonstrated. 129 Individually tailored therapy with isoniazid, which could warrant optimal therapeutic efficiency and limitation of toxic effects, has not been used in clinical routine so far, although reliable genotyping or phenotyping approaches are available.…”