Population Pharmacokinetics of Pegasparaginase in pediatric ALL patients: Age as a significant covariate

Abstract

Abstract Purpose Pegasparaginase is essential in treating acute lymphoblastic leukemia (ALL). However, there is considerable variability in its pharmacokinetics, affecting the safety and efficacy of this drug. We aimed to develop a population pharmacokinetic (PopPK) model of pegasparaginase to identify covariates that might help to explain this variability. Quantitative assessments of the pharmacokinetics, efficacy, and safety of pegasparaginase in this patient population would help to optimize the dosing regimen. Methods PopPK analysis of pharmacokinetic data obtained from 29 pediatric ALL patients was accomplished using Phoenix® NLME software. The effect of various covariates (age, BSA, liver function parameters, etc.) on the pharmacokinetics of pegasparaginase was evaluated. The impact of the identified covariates on the safety and efficacy of pegasparaginase parameters was also assessed. Results A one-compartment model with first-order absorption and elimination adequately described the pegasparaginase pharmacokinetics. The patient's age was a clinically significant covariate for pegasparaginase disposition. Cmax in older age group children (> 120 months) was significantly low, resulting in overall lower exposure (AUC) when compared with the younger age group (≤ 120 months). Modifying the dose according to the formula (4* age in months + 715) IU/m2 BSA, predicted to achieve similar exposure across all the age groups in pediatric ALL patients. Conclusions The developed population pharmacokinetic model helped to establish age as a significant covariate for pegasparaginase pharmacokinetics, suggesting age-based dosing over and above the current BSA-based dosing practices could achieve uniform exposure in all age groups.