Cancer Chemotherapy and Pharmacology

, Volume 66, Issue 4, pp 737–743

Pharmacokinetics of orally administered ABT-751 in children with neuroblastoma and other solid tumors

Authors

    • Pediatric Oncology BranchNational Cancer Institute
  • John M. Maris
    • Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine
  • Susan L. Cohn
    • University of Chicago
  • Wendy Goodspeed
    • Pediatric Oncology BranchNational Cancer Institute
  • Anne Goodwin
    • Pediatric Oncology BranchNational Cancer Institute
  • Marie Kromplewski
    • Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine
  • Diane Medina
    • Abbott Laboratories
  • Hao Xiong
    • Abbott Laboratories
  • Andrew Krivoshik
    • Abbott Laboratories
  • Brigitte Widemann
    • Pediatric Oncology BranchNational Cancer Institute
  • Peter C. Adamson
    • Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine
  • Frank M. Balis
    • Pediatric Oncology BranchNational Cancer Institute
    • Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine
Original Article

DOI: 10.1007/s00280-009-1218-z

Cite this article as:
Fox, E., Maris, J.M., Cohn, S.L. et al. Cancer Chemother Pharmacol (2010) 66: 737. doi:10.1007/s00280-009-1218-z

Abstract

Purpose

To describe the pharmacokinetics of orally administered ABT-751 and its conjugated metabolites in children with neuroblastoma and other solid tumors and to relate pharmacokinetic parameters to toxicity and therapeutic outcomes.

Methods

Patients (median age, 11 years) with neuroblastoma (n = 37) or other solid tumors (n = 25) had pharmacokinetic sampling after the first dose of ABT-751 (75–250 mg/m2/day) on a 7-day or 21-day schedule. ABT-751 and its glucuronide and sulfate metabolites were quantified with an HPLC/MS/MS assay. Pharmacokinetic parameters were derived with non-compartmental methods. The relative bioavailability of more water soluble capsule and suspension formulations was assessed.

Results

ABT-751 peaked in plasma at 2 h and declined monoexponentially with a t1/2 of 5.1 h. The apparent clearance was 33 ml/min/m2 and was age-independent. The AUC0–∞ increased in proportion to the dose, and at 200 mg/m2 the median AUC0–∞ was 91 mcg h/ml and the Cave was 3.9 mcg/ml. Inter-and intra-patient variability was low. The metabolites were detected in plasma 30 min post-dose and peaked 3–5 h after the dose. The glucuronide:sulfate molar AUC0–∞ ratio was 0.57. Less than 1% of the dose was excreted in urine as parent drug; 13% of the dose was excreted as sulfate metabolite and 10% as glucuronide metabolite. The relative bioavailability of the water soluble capsule and suspension formulations was 105 and 93%, respectively. AUC0–∞ was higher in patients experiencing dose-limiting toxicity.

Conclusions

Oral ABT-751 pharmacokinetics was dose-proportional and age-independent with minimal intra- and inter-patient variability in children.

Keywords

PharmacokineticsTubulin binding agentNeuroblastoma

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© US Government 2009