Isoniazid and its hydrazine metabolite in patients with tuberculosis

Objective: The serum profiles of isoniazid and its hydrazine metabolite wer e investigated in patients with tuberculosis in steady-state conditions in the hope of identifying a pharmacokinetic approach that could be useful in the clinical assessment of other patients with the same disease state. Patients and Study Design: Isoniazid was coadministered with the other drug s included in the antitubercular regimen (rifampicin, ethambutol, streptomy cin, morinamide). Concentrations of isoniazid and its hydrazine metabolite were measured in the collected serum samples by high performance liquid chr omatography. The pharmacokinetic parameters of isoniazid were estimated by WINNONLIN. Since an isoniazid serum concentration of 1.5 mg/L 3 hours after (C-3) the administration of the dose (D) was demonstrated to be therapeuti cally efficacious with minimal neurotoxic adverse effects, the theoretical dosage adjustment (D-a) required to achieve this optimal concentration in a ll our patients was calculated according to the inactivator index (I-3) met hod proposed by Vivien et al. [I-3 = (C-3 + 0.6)/D]; [D-a = 2.1/I-3]. Results: A large interindividual pharmacokinetic variability was observed [ especially for maximum concentration (C-max), trough levels, area under the curve (AUC), and hydrazine metabolite production] not only according to th e acetylator status as expected, but inside each group as well. The mean D- a was significantly lower than the mean D in the slow acetylators (2.32 +/- 0.78 vs 4.75 +/- 0.47 mg/kg; p < 0.00001), while no statistically signific ant difference was found in the rapid acetylators (4.16 +/- 3.07 vs 4.68 +/ - 0.81 mg/kg; p = 0.53). Conclusion: Our findings suggest that slow acetylators show a mean daily is oniazid exposure (AUC) two-fold higher than rapid acetylators (36.42 +/- 11 .53 vs 16.50 +/- 7.02 mg/L.h; p < 0.0001) when nearly equal isoniazid daily doses are administered (4.75 + 0.47 vs 4.68 + 0.81 mg/kg; p = 0.81) and no peculiar pathophysiological conditions affecting isoniazid disposition are present. It might be speculated that slow acetylators may often benefit fr om reduced doses (<5 mg/kg), since this strategy could either guarantee eff icacy and reach the desired C-max and C-3 levels, or minimise potential tox icity risks lowering isoniazid daily exposure and fluctuations of hydrazine metabolite serum concentrations. However, care should be exercised and the rapeutic drug monitoring needs to be performed in all patients, especially when peculiar pathophysiological conditions such as malabsorption - could a ffect the drug's pharmacokinetics.