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

摘要: Characterize the pharmacokinetics of oral crizotinib in children with cancer. Sixty-four solid tumors or anaplastic large-cell lymphoma (ALCL) enrolled on a phase 1/2 trial ALK, MET and ROS1 inhibitor, crizotinib, had pharmacokinetic sampling after first dose (n = 15) at steady state (n = 49). Dose levels studied were 100, 130, 165, 215, 280 365 mg/m2/dose administered twice daily. Two capsule two liquid formulations used over course trial. Crizotinib was quantified validated HPLC/tandem mass spectrometry method lower limit detection 0.2 ng/mL. Pharmacokinetic parameters derived using non-compartmental analysis. Time to peak plasma concentration 4 h. At 280 mg/m2 (MTD), mean (±SD) steady-state 717 ± 201 ng/mL, trough 480 ± 176 ng/mL. state, AUC0–τ proportional range 215–365 mg/m2/dose. Apparent clearance 731 ± 241 mL/min/m2. Steady-state 280 mg/m2/dose 2.5-fold higher than AUC0–∞ adults receiving 250 mg (~140 mg/m2). Age, sex drug formulation do not account for inter-subject variability state. The accumulation index 4.9, half-life estimated from 36 h. is similar that adults. trough-free concentrations MTD exceed inhibitory ALCL cell lines. NCT00939770.