Dose-escalation study of isoniazid in healthy volunteers with the rapid acetylator genotype of arylamine N-acetyltransferase 2

Abstract

Genetic polymorphisms of arylamine N-acetyltransferase 2 (NAT2) result in large interindividual differences in the plasma concentration of isoniazid (INH). We hypothesized that the internationally recommended dosage should be increased for patients with two active NAT2 alleles (RA type) in order to achieve appropriate antituberculous efficiency; however, the pharmacokinetic effects of the dose increase have not been fully addressed. To estimate an optimal dosage for RA-type patients, we conducted a dose escalation study in healthy male volunteers carrying NAT2*4/*4. Oral doses of 300 mg, 600 mg, and 900 mg of INH were administered to eight RA-type subjects, whereas 300 mg was administered to eight IA-type subjects with one active allele (NAT2*4). The pharmacokinetic parameters were estimated from plasma INH concentrations for 24 h postdose. The ratio of the mean area under the plasma-concentration time curve (AUC) was not proportional to the doses (1:2.6:5.0 for 300:600:900-mg dose) in parallel to the plasma concentration at 1 h (C(1)) and 2 h (C(2)) after administration. Compared with the IA-type group given 300 mg, the RA-type group had lower pharmacokinetic parameters at 300 mg (AUC, 66%; C(1), 72%; C(2), 61%), but higher parameters at 600 mg (AUC, 175%; C(1), 196%; C(2), 170%). Plasma concentrations of the IA-type group were within the therapeutic range. An optimal INH dose was calculated as 430 mg (7.2 mg/kg) for RA-type subjects to obtain an AUC comparable with that in IA-type subjects dosed with 300 mg. In RA-type subjects, the pharmacokinetic parameters appeared to lack linearity with the increased dose of INH. We propose that the proper daily dose for RA-type patients is 1.5-times higher than that currently recommended.