A phase I multiple-dose escalation study characterizing pharmacokinetics and safety of ABT-578 in healthy subjects.

ABT-578, a sirolimus analog, is being developed for administration from drug-eluting stents to prevent postimplantation neointimal hyperplasia. The purpose of this Study was to evaluate the safety, tolerability, and pharmacokinetics of multiple doses of ABT-578. Healthy Subjects randomly received placebo or ABT-578 (200, 400, or 800 mu g) as daily intravenous infusions for 14 days. ABT-578 blood pharmacokinetics and urine excretion on days 1 and 14 were determined. The effect of ABT-578 on mitogen-stimuluted lymphocyte proliferation was assessed. ABT-578 pharmocokinetics was described by a 3-compartment open model. The mean CL, V-ss, and t(1/2) ranges were 4.0 to 4.6 L/h, 92.5 to 118.0 L, and 24.7 to 31.0 hours, respectively. ABT-578 pharmocokinetics was dose and time invariant. Approximately 0.1% of ABT-578 was excreted in the Urine. ABT-578 was well tolerated, and no systemic changes were observed in the mitogen-stimuluted lymphocyte proliferation. ABT-578 was shown to be safe over a wide range of systemic exposures.