Chen Bing, Shi Hao-Qiang, Feng Meihua Rose, Wang Xi-Han, Cao Xiao-Mei, Cai Wei-Min
Department of Pharmacy, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, United States.
Front Pharmacol. 2022 Jul 19;13:932686. doi: 10.3389/fphar.2022.932686. eCollection 2022.
We aimed to establish a population pharmacokinetic (PPK) model for isoniazid (INH) and its major metabolite Acetylisoniazid (AcINH) in healthy Chinese participants and tuberculosis patients and assess the role of the 2 genotype on the transformation of INH to AcINH. We also sought to estimate the INH exposure that would achieve a 90% effective concentration (EC) efficiency for patients with various genotypes. A total of 45 healthy participants and 157 tuberculosis patients were recruited. For healthy subjects, blood samples were collected 0-14 h after administration of 300 mg or 320 mg of the oral dose of INH; for tuberculosis patients who received at least seven days therapy with INH, blood samples were collected two and/or six hours after administration. The plasma concentration of INH and AcINH was determined by the reverse-phase HPLC method. genotypes were determined by allele-specific amplification. The integrated PPK model of INH and AcINH was established through nonlinear mixed-effect modeling (NONMEM). The effect of genotype and other covariates on INH and AcINH disposition was evaluated. Monte Carlo simulation was performed for estimating EC90 of INH in patients with various 2 genotypes. The estimated absorption rate constant (K), oral clearance (CL/F), and apparent volume of distribution (V/F) for INH were 3.94 ± 0.44 h, 18.2 ± 2.45 L⋅h, and 56.8 ± 5.53 L, respectively. The constant of clearance (K) and the volume of distribution (V/F) of AcINH were 0.33 ± 0.11 h and 25.7 ± 1.30 L, respectively. The fraction of AcINH formation (F) was 0.81 ± 0.076. genotypes had different effects on the CL/F and F. In subjects with only one copy of NAT2 *5, *6, and *7 alleles, the CL/F values were approximately 46.3%, 54.9%, and 74.8% of *4/*4 subjects, respectively. The F values were approximately 48.7%, 63.8%, and 86.9% of *4/*4 subjects, respectively. The probability of target attainment of INH EC in patients with various NAT2 genotypes was different. The integrated parent-metabolite PPK model accurately characterized the disposition of INH and AcINH in the Chinese population sampled, which may be useful in the individualized therapy of INH.
我们旨在为健康中国受试者和结核病患者建立异烟肼（INH）及其主要代谢产物乙酰异烟肼（AcINH）的群体药代动力学（PPK）模型，并评估两种基因型在INH向AcINH转化中的作用。我们还试图估算不同基因型患者达到90%有效浓度（EC）效率时的INH暴露量。共招募了45名健康受试者和157名结核病患者。对于健康受试者，在口服300mg或320mg INH后0至14小时采集血样；对于接受INH至少7天治疗的结核病患者，在给药后2小时和/或6小时采集血样。采用反相高效液相色谱法测定INH和AcINH的血浆浓度。通过等位基因特异性扩增确定基因型。通过非线性混合效应建模（NONMEM）建立INH和AcINH的整合PPK模型。评估基因型和其他协变量对INH和AcINH处置的影响。进行蒙特卡罗模拟以估算不同两种基因型患者的INH EC90。INH的估计吸收速率常数（K）、口服清除率（CL/F）和表观分布容积（V/F）分别为每小时3.94±0.44、18.2±2.45升·小时和56.8±5.53升。AcINH的清除常数（K）和分布容积（V/F）分别为每小时0.33±0.11和25.7±1.30升。AcINH形成分数（F）为0.81±0.076。基因型对CL/F和F有不同影响。在仅携带一份NAT2 5、6和7等位基因的受试者中，CL/F值分别约为4/4受试者的46.3%、54.9%和74.8%。F值分别约为4/*4受试者的48.7%、63.8%和86.9%。不同NAT2基因型患者达到INH EC的达标概率不同。整合的母体-代谢产物PPK模型准确地描述了所采样中国人群中INH和AcINH的处置情况，这可能有助于INH的个体化治疗。
