First-dose and steady-state pharmacokinetics of orally administered crizotinib in children with solid tumors: a report on ADVL0912 from the Children’s Oncology Group Phase 1/Pilot Consortium

Purpose: Characterize the pharmacokinetics of oral crizotinib in children with cancer. Methods: Sixty-four children with solid tumors or anaplastic large-cell lymphoma (ALCL) enrolled on a phase 1/2 trial of the ALK, MET and ROS1 inhibitor, crizotinib, had pharmacokinetic sampling after the first dose (n = 15) or at steady state (n = 49). Dose levels studied were 100, 130, 165, 215, 280 and 365 mg/m²/dose administered twice daily. Two capsule and two oral liquid formulations were used over the course of the trial. Crizotinib was quantified with a validated HPLC/tandem mass spectrometry method with a lower limit of detection of 0.2 ng/mL. Pharmacokinetic parameters were derived using non-compartmental analysis. Results: Time to peak plasma concentration was 4 h. At 280 mg/m² (MTD), mean (±SD) steady-state peak plasma concentration was 717 ± 201 ng/mL, and steady-state trough plasma concentration was 480 ± 176 ng/mL. At steady state, AUC_0–τ was proportional to dose over the dose range of 215–365 mg/m²/dose. Apparent clearance of crizotinib was 731 ± 241 mL/min/m². Steady-state AUC_0–τ at 280 mg/m²/dose was 2.5-fold higher than the AUC_0–∞ in adults receiving 250 mg (~140 mg/m²). Age, sex and drug formulation do not account for the inter-subject variability in AUC_0–τ at steady state. The accumulation index was 4.9, and the half-life estimated from the accumulation index was 36 h. Conclusions: The pharmacokinetics of oral crizotinib in children is similar to that in adults. Steady-state trough-free crizotinib concentrations in plasma at the MTD exceed inhibitory concentrations of crizotinib in ALCL cell lines. ClinicalTrials.gov identifier: NCT00939770.