Pharmacokinetics (PK) of the angiogenesis inhibitor ABT-510 in healthy subjects

Abstract

3080 Background: ABT-510 is a subcutaneously (SC) administered nonapeptide thrombospondin analogue in phase 2 clinical development for treatment of advanced malignancies. In mouse, rat, dog and monkey, t1/2 ranged from 0.2 h (mouse) to 1.3 h (monkey); metabolism was dominated by a single peptide bond cleavage yielding two inactive peptides (including M-1) which were rapidly excreted in bile and urine. Methods: To assess the safety, tolerability and PK of ABT-510, a first-time-in-man, single-escalating-dose, double-blind study was conducted in 43 healthy male subjects (mean±SD 34±12 yrs, 76±8 kg), randomly assigned to receive ABT-510 by SC bolus (10, 50, 75, 100 or 130 mg), SC infusion of 100 mg over 24 h, or 30-minute IV infusion (10, 50 or 100 mg); one subject per group received placebo. Samples for ABT-510 and M-1 assay were collected predose and over 24 h (blood) or 48 h (urine); concentrations were determined using a validated LC/MS/MS method. Results: PK results for SC bolus groups are shown below: ABT-510 PK were dose-proportional both for IV and SC regimens. Following IV dosing, CL, Vd and t1/2 were 35±8 L/h, 44±9 L and 0.9±0.1 h. SC doses were completely bioavailable relative to IV. The SC infusion produced a mean steady-state concentration of 150 ng/mL. M-1 plasma exposure averaged 50% greater than parent drug. About 78% of the dose was recovered as M-1 in urine. ABT-510 was generally well-tolerated, most AEs were mild in severity and resolved quickly. Conclusions: ABT-510 PK were linear in the range studied, interindividual variability was low. SC doses were rapidly absorbed and completely bioavailable relative to IV. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories