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 in vivo 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)0.75 * e0.13*rs17004785 * e0.39*rs4148416 * eηCL, Vc = 24.98 * (BSA/1.73) * eηvc, Q = 0.18 * (BSA/1.73)0.75 * eηQ and Vp = 4.70 * (BSA/1.73) * eηvp.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.
Keywords: Methotrexate; acute lymphoblastic leukaemia; lymphoma; paediatric; polymorphism; population pharmacokinetic model.