Abstract 1357: Population pharmacokinetic analysis of crizotinib in children with progressive/recurrent high-grade and diffuse intrinsic pontine gliomas

Abstract

Abstract Background: Crizotinib is a potent inhibitor of the tyrosine kinase anaplastic lymphoma kinase and the c-Met/hepatocyte growth factor receptor. This drug was studied in combination with dasatinib as part of a phase 1 clinical trial (NCT01644773) in children with progressive/recurrent high-grade and diffuse intrinsic pontine gliomas (HGGs and DIPGs). Activation of the c-Met pathway contributes to the formation of HGGs, and MET is the second most common amplified oncogene in DIPG. The present study aimed to characterize the pharmacokinetics of oral crizotinib in children with HGG or DIPG and evaluate the effect of patient covariates. Methods: Patients (n=34, age range 3-21 years) were treated with 100, 130, 165, or 215 mg/m2 of oral crizotinib and pharmacokinetic studies were performed after one dose of crizotinib alone (day 1 and/or 14) and with 50 or 65 mg/m2 dasatinib (day 14 or 42). Crizotinib plasma concentrations were measured up to 48 hours post-dose using a validated LC-MS/MS method with a limit of quantification of 0.01 µM. The concentrations were analyzed using a population pharmacokinetic approach with Monolix 2019R2. A covariate analysis was performed to evaluate the impact of factors including patient demographics, weight group classification (determined by BMI-for-age growth charts published by the Centers for Disease Control), kidney and liver function, and concomitant medications including dasatinib (tested as a yes/no) on crizotinib pharmacokinetic parameters. Results: Crizotinib concentrations were fitted with a two-compartment model with first-order absorption and elimination. Larger variability was observed within patient's occasions than between patients. The mean (range) dose-normalized steady-state area under the curve (AUC0-∞) and elimination half-life were 0.23 µM·h (0.1-0.34 µM·h) and 8.1 h (5.9-14 h). Population estimates for apparent central clearance (CL/F) and volume (V1/F) were 73 L/h/m2 and 146 L/m2. The absorption rate Ka (mean estimate 0.16 h-1) significantly decreased as patient age increased (p<0.001), and with concomitant dasatinib treatment (Ka = 0.16 versus 0.11 h-1, p=0.01). Crizotinib CL/F was significantly decreased in overweight patients (BMI percentile 85-95%, N=10, mean CL/F = 50 L/h/m2) and in obese patients (BMI percentile >95%, N=9, mean CL/F = 45 L/h/m2) compared to normal weight patients (mean CL/F = 90 L/h/m2, p<0.001). This resulted in increased dose-normalized AUC0-∞ from normal weight (0.18 µM·h) to overweight (0.24 µM·h) to obese patients (0.27 µM·h). Conclusion: Crizotinib pharmacokinetics was adequately characterized in children with HGG and DIPG. As also observed in adults, crizotinib exposure is significantly higher in overweight and obese patients, whom may require a dosing adjustment. Citation Format: Elizabeth Grace Gibson, Nicholas S. Selvo, Olivia Campagne, Amar Gajjar, Clinton F. Stewart. Population pharmacokinetic analysis of crizotinib in children with progressive/recurrent high-grade and diffuse intrinsic pontine gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1357.