Pharmacokinetics of orally administered ABT-751 in children with neuroblastoma and other solid tumors.
OBJECTIVE
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.
Fox
Elizabeth
E
Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892-1101, USA. foxb@mail.nih.gov
Maris
John M
JM
Cohn
Susan L
SL
Goodspeed
Wendy
W
Goodwin
Anne
A
Kromplewski
Marie
M
Medina
Diane
D
Xiong
Hao
H
Krivoshik
Andrew
A
Widemann
Brigitte
B
Adamson
Peter C
PC
Balis
Frank M
FM
D000293:Adolescent; D019540:Area Under Curve; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism*; D013431:Sulfates / Q000378:metabolism; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome
C490492:ABT751; D020719:Glucuronides; D013431:Sulfates; D013449:Sulfonamides