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

Elizabeth Fox, John M. Maris, Susan L. Cohn, Wendy Goodspeed, Anne Goodwin, Marie Kromplewski, Diane Medina, Hao Xiong, Andrew Krivoshik, Brigitte Widemann, Peter C. Adamson, Frank M. Balis

Research output: Contribution to journalArticle

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 postdose 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 doseproportional and age-independent with minimal intra-and inter-patient variability in children.

Original languageEnglish (US)
Pages (from-to)737-743
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number4
DOIs
StatePublished - Sep 1 2010

    Fingerprint

Keywords

  • Neuroblastoma
  • Pharmacokinetics
  • Tubulin binding agent

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Fox, E., Maris, J. M., Cohn, S. L., Goodspeed, W., Goodwin, A., Kromplewski, M., Medina, D., Xiong, H., Krivoshik, A., Widemann, B., Adamson, P. C., & Balis, F. M. (2010). Pharmacokinetics of orally administered ABT-751 in children with neuroblastoma and other solid tumors. Cancer Chemotherapy and Pharmacology, 66(4), 737-743. https://doi.org/10.1007/s00280-009-1218-z