S. Rhee,1 K. Shin,2 S. Yi,1 Y. Choi,1 F. Jiang,1 S. Yoon,1 J. Cho,1 K. Yu1; 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea, Republic of, 2Kyungpook National University College of Pharmacy, Daegu, Korea, Republic of

BACKGROUND: DA-3091 is a biodegradable poly d,l-lactide-co-glycolide microsphere formulation of exenatide, a glucagon-like peptide-1 analog. This first-in-human study investigated the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of DA-3091 after a single subcutaneous injection in healthy volunteers.
METHODS: A dose block-randomized, double-blind, placebo-controlled, dose-escalation (0.5, 1, 2 and 4 mg) study was conducted in 28 healthy male subjects. Eight or 4 (0.5 mg) subjects in each dose group randomly received DA-3091 or placebo in a ratio of 3:1. Serial blood samples were collected up to 84 days post dose. Serum exenatide concentrations were determined by enzyme immunoassay and PK parameters were estimated using non-compartmental analysis. Oral glucose tolerance tests were repeated weekly up to 42 days.
RESULTS: DA-3091 was rapidly absorbed within 3 h post dose, followed by a very slow release and elimination of exenatide, resulting in its concentrations >50 pg/mL up to 28 days after dose at 2 and 4 mg and a mean residence time of 590-680 h. Various insulin secretion indices including the ratio of area under the insulin curve to area under the glucose curve were increased from baseline, and the degree of increments was greater in the 1, 2, and 4 mg dose groups than in placebo. There was no serious adverse event or clinically significant abnormality considered related to DA-3091.
CONCLUSION: DA-3091 showed biphasic PK profile (initial rapid absorption followed by slow release and elimination for long time), and was well tolerated in the dose range of 0.5-4 mg after a single subcutaneous injection. DA-3091 may be used in diabetic patients with less frequent injection.