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

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 t_1/2 of 5.1 h. The apparent clearance was 33 ml/min/m² and was age-independent. The AUC_0-∞ increased in proportion to the dose, and at 200 mg/m² the median AUC_0-∞ 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 postdose and peaked 3-5 h after the dose. The glucuronide:sulfate molar AUC_0-∞ 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-∞ 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.