Characterize the pharmacokinetics of oral crizotinib in children with cancer

Balis, Frank M.

Blaney, Susan M.

Fox, Elizabeth

Minard, Charles G.

Mosse, Yael P.

Thompson, Patrick A.

Weigel, Brenda J.

English

PubMed

Carolina Digital Repository

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.
              
                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.
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Frank M. Balis

Patrick A. Thompson

Yael P. Mosse

Susan M. Blaney

Charles G. Minard

Brenda J. Weigel

Elizabeth Fox

Crossref

Cancer Chemotherapy and Pharmacology

Springer - Publisher Connector

http://dx.doi.org/10.1007/s00280-016-3220-6

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

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Springer - Publisher Connector