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

Abstract

Purpose: Crizotinib, a potent oral tyrosine kinase inhibitor, was evaluated in combination with dasatinib in a phase 1 trial (NCT01644773) in children with progressive or recurrent high-grade and diffuse intrinsic pontine gliomas (HGG and DIPG). This study aimed to characterize the pharmacokinetics of crizotinib in this population and identify significant covariates.

Methods: Patients (N = 36, age range 2.9-21.3 years) were treated orally once or twice-daily with 100-215 mg/m2 crizotinib and 50-65 mg/m2 dasatinib. Pharmacokinetic studies were performed for crizotinib alone after the first dose and at steady state, and for the drug combination at steady state. Crizotinib plasma concentrations were measured using a validated LC-MS/MS method. Population modeling was performed (Monolix) and the impact of factors including patient demographics and co-medications were investigated on crizotinib pharmacokinetics.

Results: Crizotinib concentrations were described with a linear two-compartment model and absorption lag time. Concomitant dasatinib and overweight/obese status significantly influenced crizotinib pharmacokinetics, resulting in clinically relevant impact (> 20%) on drug exposure. Crizotinib mean apparent clearance (CL/F) was 66.7 L/h/m2 after single-dose and decreased to 26.5 L/h/m2 at steady state when given alone, but not when combined with dasatinib (mean 60.8 L/h/m2). Overweight/obese patients exhibited lower crizotinib CL/F and apparent volume V1/F (mean 46.2 L/h/m2 and 73.3 L/m2) compared to other patients (mean 75.5 L/h/m2 and 119.3 L/m2, p < 0.001).

Conclusion: A potential pharmacokinetic interaction was observed between crizotinib and dasatinib in children with HGG and DIPG. Further, crizotinib exposure was significantly higher in overweight/obese patients, who may require a dosing adjustment.

Keywords: Crizotinib; Dasatinib; High-grade glioma; Pediatric; Pharmacokinetic modeling.

Conflict of interest statement

Conflict of interest: The authors declare they have no conflict of interest in this work. During the entire time of the analysis of the clinical data and of the preparation of the manuscript, Dr. Gibson was working at St Jude Children’s Research Hospital. The Bristol Myers Squibb company was not involved in this study.

© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Figures

Fig. 1

Crizotinib pharmacokinetic parameters and covariate relationships. Distribution of absorption lag-time in patients taking crizotinib as suspension versus whole capsule (a). Scatterplot of absorption rate ka versus age and co-dasatinib (b). Distribution of apparent oral clearance CL/F (c) and volume V1/F (d) in normal weight patients versus overweight/obese patients. Distribution of CL/F after single-dose versus at steady state with or without co-dasatinib (e). Individual changes in CL/F from single-dose to steady-state with or without co-dasatinib (f). In panels a, c, d, and e, the distribution of variables is shown using Tukey boxplots.

Fig. 2

Diagnostic plots for the crizotinib population pharmacokinetic model. Observations versus population (a) and individual (b) predictions. Normalized prediction distribution errors [NPDE] versus time (c) and population predictions (d). Prediction-corrected visual predictive checks after single-dose (e) and at steady state (f). In panels e and f, solid lines and shaded areas represent the 5th, 50th, and 95th percentiles and their corresponding 90% confidence intervals of the model simulations.

Fig. 3

Forest plots of covariate effects on steady-state crizotinib exposure. Crizotinib exposure was measured as area under the curve AUCss,0–24h and maximum concentration CMAX after multiple doses of 215 mg/m2 once-daily. Each covariate effect is represented by the fold change in parameter relative to the reference, calculated as the geometric mean ratio (GMR) and 90% confidence interval (CI). The solid vertical line indicates the ratio of 1 which corresponds to the typical patient (11-years old, normal weight group, taking crizotinib as suspension, without dasatinib).