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Population pharmacokinetic study of tacrolimus in pediatric patients with primary nephrotic syndrome: A comparison of linear and nonlinear Michaelis-Menten pharmacokinetic model.
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2019-12-18 , DOI: 10.1016/j.ejps.2019.105199 Lingfei Huang 1 , Yixi Liu 2 , Zheng Jiao 3 , Junyan Wang 1 , Luo Fang 1 , Jianhua Mao 4
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2019-12-18 , DOI: 10.1016/j.ejps.2019.105199 Lingfei Huang 1 , Yixi Liu 2 , Zheng Jiao 3 , Junyan Wang 1 , Luo Fang 1 , Jianhua Mao 4
Affiliation
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BACKGROUND
Little is known about the population pharmacokinetics (PPK) of tacrolimus (TAC) in pediatric patients with primary nephrotic syndrome (PNS). In this study, we aimed to compare the predictive performance between nonlinear and linear PK models and investigate the significant factors influencing TAC PK characteristics in pediatric PNS.
METHODS
Data were obtained from 71 pediatric patients with PNS, along with 525 TAC trough concentrations at steady-state. Patients' demographic, medical, and treatment details were collected. Genetic polymorphisms of CYP3A4*1G, CYP3A5*3, and ABCB1-C3435T were analyzed. The PPK models were developed using nonlinear mixed-effects model (NONMEM®) software. Two modeling strategies, linear compartmental and nonlinear Michaelis-Menten (MM) models, were evaluated and compared.
RESULTS
Body weight, age, daily dose of TAC, co-therapy drugs (including azole antifungal agents and diltiazem), and CYP3A5*3 genotype were the important factors in the final linear model (one-compartment model), whereas only body weight, co-therapy drugs, and CYP3A5*3 genotype were the important factors in the final nonlinear MM model. Apparent clearance and volume of distribution in the final linear model were 7.13 L/h and 142 L, respectively. The maximal dose rate (Vmax) of the nonlinear MM model was 1.92 mg/day and the average concentration at steady-state at half-Vmax (Km) was 1.98 ng/mL. The nonlinear model described the data better than the linear model. Dosing regimens were proposed based on the nonlinear PK model.
CONCLUSION
Our findings demonstrated that the nonlinear MM model showed better predictive performance than the linear compartmental model, providing reliable support for optimizing TAC dosing and adjustment in children with PNS.
中文翻译：
他克莫司在原发性肾病综合征儿科患者中的群体药代动力学研究：线性和非线性Michaelis-Menten药代动力学模型的比较。
背景技术关于他克莫司（TAC）在患有原发性肾病综合征（PNS）的小儿患者中的群体药代动力学（PPK）知之甚少。在这项研究中，我们旨在比较非线性和线性PK模型之间的预测性能，并研究影响小儿PNS中TAC PK特性的重要因素。方法收集了71名小儿PNS患者的数据，以及稳态时525个TAC谷浓度。收集了患者的人口统计，医疗和治疗详细信息。分析了CYP3A4 * 1G，CYP3A5 * 3和ABCB1-C3435T的遗传多态性。PPK模型是使用非线性混合效应模型（NONMEM®）软件开发的。评估并比较了两种建模策略，即线性隔室模型和非线性Michaelis-Menten（MM）模型。结果体重，年龄，在最终线性模型（单室模型）中，TAC的日剂量，联合治疗药物（包括唑类抗真菌药和地尔硫卓）和CYP3A5 * 3基因型是重要因素，而仅体重，联合治疗药物和CYP3A5 * 3基因型是最终非线性MM模型的重要因素。最终线性模型中的表观清除率和分布体积分别为7.13 L / h和142L。非线性MM模型的最大剂量率（Vmax）为1.92 mg / day，在稳态时的平均浓度为半Vmax（Km）为1.98 ng / mL。非线性模型比线性模型更好地描述了数据。基于非线性PK模型，提出了给药方案。结论我们的研究结果表明，非线性MM模型比线性隔室模型具有更好的预测性能，
更新日期：2019-12-18
中文翻译：
他克莫司在原发性肾病综合征儿科患者中的群体药代动力学研究：线性和非线性Michaelis-Menten药代动力学模型的比较。
背景技术关于他克莫司（TAC）在患有原发性肾病综合征（PNS）的小儿患者中的群体药代动力学（PPK）知之甚少。在这项研究中，我们旨在比较非线性和线性PK模型之间的预测性能，并研究影响小儿PNS中TAC PK特性的重要因素。方法收集了71名小儿PNS患者的数据，以及稳态时525个TAC谷浓度。收集了患者的人口统计，医疗和治疗详细信息。分析了CYP3A4 * 1G，CYP3A5 * 3和ABCB1-C3435T的遗传多态性。PPK模型是使用非线性混合效应模型（NONMEM®）软件开发的。评估并比较了两种建模策略，即线性隔室模型和非线性Michaelis-Menten（MM）模型。结果体重，年龄，在最终线性模型（单室模型）中，TAC的日剂量，联合治疗药物（包括唑类抗真菌药和地尔硫卓）和CYP3A5 * 3基因型是重要因素，而仅体重，联合治疗药物和CYP3A5 * 3基因型是最终非线性MM模型的重要因素。最终线性模型中的表观清除率和分布体积分别为7.13 L / h和142L。非线性MM模型的最大剂量率（Vmax）为1.92 mg / day，在稳态时的平均浓度为半Vmax（Km）为1.98 ng / mL。非线性模型比线性模型更好地描述了数据。基于非线性PK模型，提出了给药方案。结论我们的研究结果表明，非线性MM模型比线性隔室模型具有更好的预测性能，
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