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PHARMACOKINETICS

A Phase I Multiple-Dose Escalation Study Characterizing Pharmacokinetics and Safety of ABT-578 in Healthy Subjects

Chetan S. Karyekar, MD, PhD, Rajendra S. Pradhan, PhD, Tony Freeney, BS, Qin Ji, PhD, Timi Edeki, MD, PhD (FCP), Wenzi Chiu, PhD, Walid M. Awni, PhD, Charles Locke, PhD, Lewis B. Schwartz, MD, Richard G. Granneman, PhD and Robert O'Dea, MD, PhD

From Abbott Laboratories, Abbott Park, Illinois.

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 µg) 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-stimulated lymphocyte proliferation was assessed. ABT-578 pharmacokinetics was described by a 3-compartment open model. The mean CL, Vss, and t1/2 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 pharmacokinetics 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-stimulated lymphocyte proliferation. ABT-578 was shown to be safe over a wide range of systemic exposures.

Key Words: ABT-578 • pharmacokinetics • safety • multiple dose

Address for reprints: Rajendra S. Pradhan, PhD, Department R4PK, Building AP13 A-3, 100 Abbott Park Road, Abbott Park, IL 60064.


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