Pharmacokinetic population of isoniazid in Tunisian tuberculosis patients.

Abstract Aims To develop a pharmacokinetic model of isoniazid (INH) concentration taking into account demographic factors and genetic variables (N-acetyltransferase 2 (NAT2) genotype) and to propose an initial INH dosage that could maximize the probability of achieving desired INH concentrations. Methods We performed a retrospective analysis of INH concentration data collected from Tunisian tuberculosis patients. Results A total of 118 patients were included in the study. The one-compartment model (V, Ke) was found to show a good prediction performance. The multivariate analysis has shown that only NAT2 affected significantly both V and Ke. The internal validation of final model showed a correlation (r²) of individual predicted (IPRED) C3 versus observed C3 of 0.95. The external validation has shown that the %MAPE and %RMSE were 9.11% [0.62%-35.8%] and 11.6%. The Monte-Carlo simulation showed that a dose of at least 225 mg/24 h and at least 450 mg/24H allows the attainment of a therapeutic concentration in more than 80% of patients, in NAT2 slow acetylator group and NAT2 rapid/intermediate acetylator group, respectively. Conclusion The current pk model allows the optimization of individual dosing regimens of INH in Tunisian and North African tuberculosis patients. This tool may allow improving efficacy of INH and preventing its toxicity in this population.