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

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/m(2) crizotinib and 50-65 mg/m(2) 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/m(2) after single-dose and decreased to 26.5 L/h/m(2) at steady state when given alone, but not when combined with dasatinib (mean 60.8 L/h/m(2)). Overweight/obese patients exhibited lower crizotinib CL/F and apparent volume V-1/F (mean 46.2 L/h/m(2) and 73.3 L/m(2)) compared to other patients (mean 75.5 L/h/m(2) and 119.3 L/m(2), 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.