Oral Apolipoprotein A-I Mimetic D-4F Lowers HDL-Inflammatory Index in High-Risk Patients: A First-in-Human Multiple-Dose, Randomized Controlled Trial.

Authors

Richard L. Dunbar, University of Pennsylvania
Rajesh Movva, Eastern Maine Medical CenterFollow
LeAnne T. Bloedon, Aegerion Pharmaceuticals, Inc.
Danielle Duffy, Thomas Jefferson UniversityFollow
Robert B. Norris, University of Pennsylvania
Mohamad Navab, University of California, Los Angeles
Alan M. Fogelman, University of California, Los Angeles
Daniel J. Rader, University of Pennsylvania

Document Type

Article

Publication Date

11-1-2017

Comments

This article has been peer reviewed. It is the author’s final published version in Clinical and Translational Science

Volume 10, Issue 6, November 2017, Pages 455-469.

The published version is available at DOI: 10.1111/cts.12487. Copyright © Dunbar et al.

Abstract

A single dose of the apolipoprotein (apo)A-I mimetic peptide D-4F rendered high-density lipoprotein (HDL) less inflammatory, motivating the first multiple-dose study. We aimed to assess safety/tolerability, pharmacokinetics, and pharmacodynamics of daily, orally administered D-4F. High-risk coronary heart disease (CHD) subjects added double-blinded placebo or D-4F to statin for 13 days, randomly assigned 1:3 to ascending cohorts of 100, 300, then 500 mg (n = 62; 46 men/16 women). D-4F was safe and well-tolerated. Mean ± SD plasma D-4F area under the curve (AUC, 0-8h) was 6.9 ± 5.7 ng/mL*h (100 mg), 22.7 ± 19.6 ng/mL*h (300 mg), and 104.0 ± 60.9 ng/mL*h (500 mg) among men, higher among women. Whereas placebo dropped HDL inflammatory index (HII) 28% 8 h postdose (range, 1.25-0.86), 300-500 mg D-4F effectively halved HII: 1.35-0.57 and 1.22-0.63, respectively (P < 0.03 vs. placebo). Oral D-4F peptide dose predicted HII suppression, whereas plasma D-4F exposure was dissociated, suggesting plasma penetration is unnecessary. In conclusion, oral D-4F dosing rendered HDL less inflammatory, affirming oral D-4F as a potential therapy to improve HDL function.

Recommended Citation

Dunbar, Richard L.; Movva, Rajesh; Bloedon, LeAnne T.; Duffy, Danielle; Norris, Robert B.; Navab, Mohamad; Fogelman, Alan M.; and Rader, Daniel J., "Oral Apolipoprotein A-I Mimetic D-4F Lowers HDL-Inflammatory Index in High-Risk Patients: A First-in-Human Multiple-Dose, Randomized Controlled Trial." (2017). Department of Medicine Faculty Papers. Paper 225.
https://jdc.jefferson.edu/medfp/225

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

PubMed ID

28795506