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, AUC0–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 AUC0–τ at 280 mg/m2/dose was 2.5-fold higher than the AUC0–∞ in adults receiving 250 mg (~140 mg/m2). Age, sex and drug formulation do not account for the inter-subject variability in AUC0–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.
Bibliographical noteFunding Information:
Pfizer provided crizotinib for the trial and Covance Indianapolis performed the crizotinib HPLC/MS/MS assay with funding from Pfizer. The Children???s Oncology Group held the IND under which this trial was conducted. This clinical trial was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) [Award Number UM1 CA097452], Pfizer, Inc., Cookies for Kids??? Cancer Foundation, Alex???s Lemonade Stand Center of Excellence grant, and the Children???s Oncology Group. F. Balis has research funding from United Therapeutics Corp.; Y. Mosse has research funding from Pfizer, Inc. and Novartis; E. Fox has research funding from Glaxo Smith Kline, Merck and Incyta.
© 2016, The Author(s).
Copyright 2018 Elsevier B.V., All rights reserved.
- Childhood cancer