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Journal of Lipid Research, Vol. 49, 1344-1352, June 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients^*

LeAnne T. Bloedon^*, Richard Dunbar^*, Danielle Duffy^*, Paula Pinell-Salles^*, Robert Norris, Bruce J. DeGroot, Rajesh Movva, Mohamad Navab^**, Alan M. Fogelman^** and Daniel J. Rader^1,*

^* Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160
Pennsylvania Hospital, Philadelphia, PA 19107
MDS Pharma Services, Lincoln, NE 68502
^** Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1736

^* Partial data were presented at the American Heart Association's 2006 Scientific Sessions. This work was supported in part by Grant M01-RR00040 (General Clinical Research Center) from the National Institutes of Health. In addition, Bruin Pharma provided financial support.

Published, JLR Papers in Press, March 6, 2008.

¹ To whom correspondence should be addressed. e-mail: rader{at}mail.med.upenn.edu

Patients with coronary heart disease or equivalent risk received a single dose of 30, 100, 300, or 500 mg of unformulated D-4F (n = 8, each dose) or placebo (n = 8) under fasting conditions. An additional 10 patients received 500 mg (n = 8) or placebo (n = 2) with a low-fat meal. There were no significant trends in any safety parameter. D-4F was detectable in plasma at all doses with a T_max of 30 min, 1 h, and 2 h for 30, 100, and 300 mg, respectively. The area under the curve_(0–t) was 27.81 ng/hr/ml and 54.71 ng/hr/ml for the 300 mg and 500 mg dose groups, respectively, and 17.96 ng/hr/ml for the 500mg dose given with food. HDL from each time point for each subject was tested for its ability to inhibit LDL-induced monocyte chemotactic activity in cultures of human aortic endothelial cells. The values obtained were normalized to 1.0 for LDL alone to obtain the HDL inflammatory index. This index significantly improved at 4 h at the 300 mg dose and at 2 h at the 500 mg dose compared with placebo (P < 0.05). There were no changes in plasma lipid or lipoprotein levels. We conclude that unformulated D-4F has low bioavailability that is improved under fasting conditions, and that a single dose of D-4F is safe and well tolerated and may improve the HDL anti-inflammatory index.

Supplementary key words HDL cholesterol • inflammation • atherosclerosis

Abbreviations: AE, adverse event; apoA-I, apolipoprotein A-I; AUC, area under the curve; CHD, coronary heart disease; ECG, electrocardiogram; T2DM, type 2 diabetes mellitus; TC, total cholesterol

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