Using the population pharmacokinetic model and Monte Carlo simulation to explore the optimal dosing regimen for isoniazid injection in patients with lymphatic tuberculosis
Objective Using the nonlinear mixed-effects method(NLME)to develop a pharmacokinetic(PPK)model of isoniazid(INH)injection in a population of Chinese patients with lymphatic tuberculosis,Monte Carlo simulation was used to optimize the dosing regimen of isoniazid injection in patients with lymphatic tuberculosis of different NAT2 metabolism genotypes.Method Twenty-eight patients with lymphatic tuberculosis from Wuhan Lung Hospital were included,and 66 blood drug concentration data and related clinical information were collected.The NLME method was used to establish a PPK model to investigate the effect of factors such as NAT2 metabolism genotype on the in vivo pharmacokinetic profile of isoniazid injection.Diagnostic plots,the bootstrap method,normalized prediction distribution error(NPDE)and the visual predictive check(VPC)test were used to evaluate the prediction performance of the PPK model.Monte Carlo simulation was used to explore the drug dosing regimen for patients with different NAT2 metabolizing genotypes.Results Isoniazid injection was characterized by a two-compartment model of primary absorption,and the NAT2 metabolism genotype was an important factor influencing its clearance.Clearance rates for patients with fast,intermediate and slow metabolism genotypes were 53.7,44.6,and 25.4 L/h,respectively,with an apparent volume of distribution of 29.8 L.Model evaluation showed reliable estimation of model parameters and model stability.Monte Carlo simulation results showed that the optimal dosage of isoniazid injection administered to patients with NAT2 fast,intermediate,and slow metabolism genotypes of lymphoid tuberculosis was 600 mg,450 mg,and 300 mg,respectively.Conclusion In this study,a PPK model for isoniazid injection in Chinese lymphatic tuberculosis patients was successfully established the effects of NAT2 metabolic genes on the PK of isoniazid(INH)injection were quantitatively described,and the optimal dosing regimen for patients with different genotypes was formulated,which provided a reference for the individualization of isoniazid treatment.
Isoniazid injectionPopulation pharmacokineticsMonte Carlo simulationLymphatic tuberculosis
万方数据
维普
