Open AccessOral Apolipoprotein A‐I Mimetic D‐4F Lowers HDL‐Inflammatory Index in High‐Risk Patients: A First‐in‐Human Multiple‐Dose, Randomized Controlled Trial
Author(s) -
Dunbar Richard L.,
Movva Rajesh,
Bloedon LeAnne T.,
Duffy Danielle,
Norris Robert B.,
Navab Mohamad,
Fogelman Alan M.,
Rader Daniel J.
Publication year - 2017
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12487
Subject(s) - placebo , medicine , tolerability , apolipoprotein b , pharmacokinetics , dosing , pharmacodynamics , area under the curve , statin , gastroenterology , randomized controlled trial , cholesterol , endocrinology , adverse effect , pathology , alternative medicine
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.