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
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...
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Published in | Cancer chemotherapy and pharmacology Vol. 79; no. 1; pp. 181 - 187 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Berlin/Heidelberg
Springer Berlin Heidelberg
01.01.2017
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | 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/m
2
/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/m
2
(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, AUC
0–
τ
was proportional to dose over the dose range of 215–365 mg/m
2
/dose. Apparent clearance of crizotinib was 731 ± 241 mL/min/m
2
. Steady-state AUC
0–
τ
at 280 mg/m
2
/dose was 2.5-fold higher than the AUC
0–
∞
in adults receiving 250 mg (~140 mg/m
2
). Age, sex and drug formulation do not account for the inter-subject variability in AUC
0–
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0344-5704 1432-0843 |
DOI: | 10.1007/s00280-016-3220-6 |