Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Medicine, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Clin Transl Sci. 2017 Nov;10(6):455-469. doi: 10.1111/cts.12487. Epub 2017 Aug 9.
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/mLh (100 mg), 22.7 ± 19.6 ng/mLh (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.
单次给予载脂蛋白（apo）A-I 模拟肽 D-4F 可降低高密度脂蛋白（HDL）的炎症反应，从而推动了首次多剂量研究。我们旨在评估每日口服 D-4F 的安全性/耐受性、药代动力学和药效学。高风险冠心病（CHD）患者在他汀类药物的基础上加用双盲安慰剂或 D-4F 治疗 13 天，随机分为 1:3 接受 100、300、500mg 递增剂量组（n=62；46 名男性/16 名女性）。D-4F 安全且耐受良好。男性的平均±SD 血浆 D-4F 曲线下面积（AUC，0-8h）分别为 6.9±5.7ng/mLh（100mg）、22.7±19.6ng/mLh（300mg）和 104.0±60.9ng/mL*h（500mg），女性更高。安慰剂给药后 8 小时 HDL 炎症指数（HII）下降 28%（范围，1.25-0.86），而 300-500mg D-4F 可有效使 HII 减半：分别为 1.35-0.57 和 1.22-0.63（与安慰剂相比，P<0.03）。口服 D-4F 肽剂量可预测 HII 抑制作用，而血浆 D-4F 暴露则不同，提示血浆穿透性并非必需。总之，口服 D-4F 给药可降低 HDL 的炎症反应，证实口服 D-4F 可能是改善 HDL 功能的潜在治疗方法。
