HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

AbstractPURPOSE:
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/m(2)/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 t (1/2) of 5.1 h. The apparent clearance was 33 ml/min/m(2) and was age-independent. The AUC(0-infinity) increased in proportion to the dose, and at 200 mg/m(2) the median AUC(0-infinity) was 91 mcg h/ml and the C (ave) 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 AUC(0-infinity) 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. AUC(0-infinity) 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.
AuthorsElizabeth 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
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 66 Issue 4 Pg. 737-43 (Sep 2010) ISSN: 1432-0843 [Electronic] Germany
PMID20044751 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References
  • ABT751
  • Glucuronides
  • Sulfates
  • Sulfonamides
Topics
  • Adolescent
  • Area Under Curve
  • Biotransformation
  • Child
  • Child, Preschool
  • Chromatography, High Pressure Liquid
  • Dose-Response Relationship, Drug
  • Female
  • Glucuronides (metabolism)
  • Humans
  • Male
  • Mass Spectrometry
  • Neoplasm Recurrence, Local
  • Neuroblastoma (drug therapy, metabolism)
  • Sulfates (metabolism)
  • Sulfonamides (pharmacokinetics, therapeutic use)
  • Treatment Outcome

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: