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

Purpose Characterize the pharmacokinetics of oral crizotinib in children with cancer.MethodsSixty-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.ResultsTime 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.ConclusionsThe 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 identifierNCT00939770.

Phase 1 trial, pharmacokinetics, and pharmacodynamics of dasatinib combined with crizotinib in children with recurrent or progressive high‐grade and diffuse intrinsic pontine glioma

“…were comparable to those reported recently in children with solid tumors despite significant methodologic differences between both studies (for example, drug formulation and pharmacokinetic sampling strategy). 21 Our results demonstrating a decrease in p-AKT in PBMC after administration of dasatinib are interesting, although significant concern remains that dasatinib does not reach clinically effective concentrations in the CNS. 20,22 The longitudinal analysis of plasma HGF was performed based on the report that its expression was predictive of response to c-Met inhibition in HGG preclinical models.…”

Crizotinib in ALK+ inflammatory myofibroblastic tumors—Current experience and future perspectives

“…The pharmacokinetics of oral crizotinib in children is similar to that in adults. The COG consortium study in 79 children with refractory solid tumors or anaplastic large‐cell lymphoma found that crizotinib was well tolerated with a recommended single‐agent phase 2 dose of 280 mg/mg 2 twice daily …”

“…The COG consortium study in 79 children with refractory solid tumors or anaplastic large-cell lymphoma found that crizotinib was well tolerated with a recommended single-agent phase 2 dose of 280 mg/mg 2 twice daily. 23,38,39 Notably, one of our patients received the drug via nasogastric tube due to incompliance, which nevertheless led to CR of the tumor. Unfortunately, assessment of the serum levels had not been performed in our cases.…”

Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology

“…), the mean C min in pediatric patients was 480 ng/mL, corresponding to a free drug concentration of 50 ng/mL. 18 The unbound drug concentration of 50 ng/mL exceeds the concentration of drug producing 50% inhibition of 10 ng/mL of crizotinib in ALCL cell lines. No relationships between exposure and efficacy have been established for crizotinib in adults with NSCLC nor pediatric patients with ALCL.…”