Abstract 1496: Oral Administration of the Apolipoprotein A-I Mimetic Peptide D-4F in Humans with CHD Improves HDL Anti-Inflammatory Function After a Single Dose
Background: Low levels of high-density lipoprotein cholesterol (HDL-C) and its associated lipoprotein, apolipoprotein A-I (apoA-I), are independent risk factors for coronary heart disease (CHD). ApoA-I is widely recognized to be involved in the initial steps of macrophage reverse cholesterol transport and may be critical to the anti-inflammatory and anti-oxidant effects of HDL. D-4F is a synthetic apoA-I mimetic peptide that when administered orally markedly reduces atherosclerosis in mice.
Methods: We conducted a phase I ascending dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single oral dose of D-4F or matching placebo provided as a solution in 50 patients with CHD or equivalent risk. Ten subjects per dose group were randomized to 30, 100, 300, or 500 mg D-4F or matching placebo (8:2, D-4F:placebo) and fasted for 2 hours after study drug administration, with the exception of an additional 10 subjects receiving 500 mg or matching placebo with a standardized meal.
Results: D-4F was detectable in plasma at each dose with a Tmax of 30 min, 1 hr, and 2 hr for 30, 100, and ≥ 300 mg, respectively. The AUC(0-t) was 27.81 ng*hr/mL and 54.71 ng*hr/mL for the 300 and 500 mg dose groups, respectively and 17.96 ng*hr/mL for the 500 mg dose given with food. There were no clinically significant changes in clinical or laboratory parameters. D-4F resulted in a significant improvement in the HDL anti-inflammatory index at 2, 4, and 8 hours compared to baseline (p<0.01 for all time points), whereas the placebo group had no significant change. At hour 4, the improvement in HDL inflammatory index was significant compared to the placebo group (p=0.02).
Conclusions: A single oral dose of D-4F is absorbed and well tolerated. Bioavailability of D-4F is low, but improved when food is delayed for 2 hours post-dose. HDL anti-inflammatory function improved significantly after a single dose of D-4F. This study proves that D-4F is orally bioavailable and has measurable effects on HDL anti-inflammatory function in high risk patients after a single dose.