title: 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.
abstract: OBJECTIVE
  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-τwas 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-τat 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-τat 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.
  NCT00939770.
authors.affiliation: The Children's Hospital of Philadelphia, 3501 Civic Center Blvd, CTRB-4024, Philadelphia, PA, 19104, USA. balisf@email.chop.edu.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.affiliation: University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, 27599, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Thompson
authors.affiliation: The Children's Hospital of Philadelphia, 3501 Civic Center Blvd, CTRB-4024, Philadelphia, PA, 19104, USA.
authors.forename: Yael P
authors.initials: YP
authors.lastname: Mosse
authors.affiliation: Baylor College of Medicine, Dan L Duncan Comprehensive Cancer Center, Houston, TX, 77030, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.affiliation: Baylor College of Medicine, Dan L Duncan Comprehensive Cancer Center, Houston, TX, 77030, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Minard
authors.affiliation: University of Minnesota, Masonic Cancer Center, Minneapolis, MN, 55455, USA.|The Children's Oncology Group Operations Center, Monrovia, CA, 91016, USA.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.affiliation: The Children's Hospital of Philadelphia, 3501 Civic Center Blvd, CTRB-4024, Philadelphia, PA, 19104, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D000077547:Crizotinib; D005260:Female; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib
keywords: ALK; Childhood cancer; Children; Crizotinib; Pharmacokinetics