Department of Pharmacy, Shenzhen Children's Hospital, Shenzhen, China.
Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Xenobiotica. 2022 Mar;52(3):265-273. doi: 10.1080/00498254.2022.2069060. Epub 2022 Apr 28.
This study aimed to identify physiological and pharmacogenomic covariates and develop a population pharmacokinetic model of high-dose methotrexate (HD-MTX) in Chinese paediatric patients with acute lymphoblastic leukaemia (ALL) and malignant lymphoma.A total of 731 MTX courses and 1658 MTX plasm concentrations from 205 paediatric patients with ALL and malignant lymphoma were analysing using a non-linear mixed-effects model technique. 47 SNPs in 16 MTX-related genes were genotyped and screened as covariates. A PPK model was established to determine the influence of covariates, such as body surface area (BSA), age, laboratory test value, and SNPs on the pharmacokinetic process of HD-MTX.Two-compartmental model with allometric scaling using BSA could nicely characterise the behaviour of HD-MTX. After accounting for body size, rs17004785 and rs4148416 were the covariates that influence MTX clearance (CL). The PPK model obtained was: CL = 9.33 * (BSA/1.73) * e * e * e, Vc = 24.98 * (BSA/1.73) * e, = 0.18 * (BSA/1.73) * e and Vp = 4.70 * (BSA/1.73) * e.The established model combined with the Bayesian approach could estimate individual pharmacokinetic parameters and optimise personalised HD-MTX therapy for paediatric patients with ALL and malignant lymphoma.
本研究旨在鉴定生理和药物基因组学协变量，并建立中国儿童急性淋巴细胞白血病（ALL）和恶性淋巴瘤患者大剂量甲氨蝶呤（HD-MTX）的群体药代动力学模型。共分析了 205 例 ALL 和恶性淋巴瘤患儿的 731 个 MTX 疗程和 1658 个 MTX 血浆浓度，采用非线性混合效应模型技术。对 16 个 MTX 相关基因中的 47 个 SNP 进行了基因分型和筛选作为协变量。建立 PPK 模型以确定协变量（如体表面积（BSA）、年龄、实验室检查值和 SNPs）对 HD-MTX 药代动力学过程的影响。使用 BSA 的两室模型和比例缩放可以很好地描述 HD-MTX 的行为。在考虑到体型后，rs17004785 和 rs4148416 是影响 MTX 清除率（CL）的协变量。获得的 PPK 模型为：CL=9.33*（BSA/1.73）eee，Vc=24.98（BSA/1.73）e，Vp=4.70（BSA/1.73）*e。建立的模型结合贝叶斯方法可以估计个体药代动力学参数，并优化儿童 ALL 和恶性淋巴瘤患者的个性化 HD-MTX 治疗。
