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.