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
Frank M Balis, Patrick A Thompson, Yael P Mosse, Susan M Blaney, Charles G Minard, Brenda J Weigel, Elizabeth Fox, Frank M Balis, Patrick A Thompson, Yael P Mosse, Susan M Blaney, Charles G Minard, Brenda J Weigel, Elizabeth Fox
Abstract
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.
Keywords: ALK; Childhood cancer; Children; Crizotinib; Pharmacokinetics.
Conflict of interest statement
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. Ethical approval The phase 1 clinical trial of crizotinib was reviewed and approved by the Institutional Review Boards at each participating institution, and the clinical trial was conducted in accordance with the ethical standards outlined in the Declaration of Helsinki and the US Federal Regulations governing research in human subjects.
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References
- Frampton JE. Crizotinib: a review of its use in the treatment of anaplastic lymphoma kinase-positive, advanced non-small cell lung cancer. Drugs. 2013;73(18):2031–2051. doi: 10.1007/s40265-013-0142-z.
- Cappuzzo F, Moro-Sibilot D, Gautschi O, Boleti E, Felip E, Groen HJ, Germonpre P, Meldgaard P, Arriola E, Steele N, Fox J, Schnell P, Engelsberg A, Wolf J. Management of crizotinib therapy for ALK-rearranged non-small cell lung carcinoma: an expert consensus. Lung Cancer. 2015;87(2):89–95. doi: 10.1016/j.lungcan.2014.12.010.
- Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–2177. doi: 10.1056/NEJMoa1408440.
- Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, Janne PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner K, Clark JW, Shaw AT. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011–1019. doi: 10.1016/S1470-2045(12)70344-3.
- Gambacorti-Passerini C, Messa C, Pogliani EM. Crizotinib in anaplastic large-cell lymphoma. N Engl J Med. 2011;364(8):775–776. doi: 10.1056/NEJMc1013224.
- Mosse YP, Lim MS, Voss SD, Wilner K, Ruffner K, Laliberte J, Rolland D, Balis FM, Maris JM, Weigel BJ, Ingle AM, Ahern C, Adamson PC, Blaney SM. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013;14(6):472–480. doi: 10.1016/S1470-2045(13)70095-0.
- Murga-Zamalloa C, Lim MS. ALK-driven tumors and targeted therapy: focus on crizotinib. Pharmacogenomics Pers Med. 2014;7:87–94.
- Xu H, O’Gorman M, Boutros T, Brega N, Kantaridis C, Tan W, Bello A. Evaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjects. J Clin Pharmacol. 2015;55(1):104–113. doi: 10.1002/jcph.356.
- Hamilton G, Rath B, Burghuber O. Pharmacokinetics of crizotinib in NSCLC patients. Expert Opin Drug Metab Toxicol. 2015;11(5):835–842. doi: 10.1517/17425255.2015.1021685.
- Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007;6(12 Pt 1):3314–3322. doi: 10.1158/1535-7163.MCT-07-0365.
- Johnson TR, Tan W, Goulet L, Smith EB, Yamazaki S, Walker GS, O’Gorman MT, Bedarida G, Zou HY, Christensen JG, Nguyen LN, Shen Z, Dalvie D, Bello A, Smith BJ. Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects. Xenobiotica. 2015;45(1):45–59. doi: 10.3109/00498254.2014.941964.
Source: PubMed