title: ApoA-IMilano phospholipid complex (ETC-216) infusion in human volunteers. Insights into the phenotypic characteristics of ApoA-IMilano carriers.
abstract: Epidemiological studies support an inverse correlation between HDL-C and cardiovascular disease. However, low HDL-C levels do not always segregate with premature disease. These include, LCAT deficiency and the apolipoproteinA-IMilano (AIM) variant. AIM has a cysteine for arginine at position 173 in the otherwise cysteine free protein permitting AIM homodimerization and apoA-II heterodimerization. We relate the biochemical characteristics of low HDL-C phenotype AIM carriers to lipoprotein changes in humans administered recombinant dimeric AIM/palmitoyl-oleoyl phosphatidyl choline (ETC-216). Pharmacokinetic analysis of infused ETC-216 suggest a slow distribution of AIM into peripheral tissue and an extremely long terminal half-life in plasma. Following ETC-216 administration to normal human volunteers, an initial dose-dependent HDL-C elevation was observed. Thereafter, subjects transiently acquired a lipoprotein profile similar to that of AIM carriers, including reduced HDL-C and mild hypertriglyceridemia. The time-dependent changes in plasma lipids/lipoproteins may support an increased tissue cholesterol removing capacity of ETC-216. These findings provide mechanistic insight into the rapid removal of atheromatous plaques observed in humans, possibly linked to enhanced cholesterol removal capacity of ETC-216.
authors.affiliation: Department of Pharmacology, The First/Original Esperion Therapeutics, Inc. Ann Arbor, MI, United States. Electronic address: cbisgaier@gemphire.com.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bisgaier
authors.affiliation: Department of Pharmacology, The First/Original Esperion Therapeutics, Inc. Ann Arbor, MI, United States.
authors.forename: Rose
authors.initials: R
authors.lastname: Ackermann
authors.affiliation: Department of Genomics, The First/Original Esperion Therapeutics, Inc. Ann Arbor, MI, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rea
authors.affiliation: Department of Formulation, The First/Original Esperion Therapeutics, Inc. Ann Arbor, MI, United States.
authors.forename: Wendi V
authors.initials: WV
authors.lastname: Rodrigueza
authors.affiliation: Department of Clinical Research, The First/Original Esperion Therapeutics, Inc. Ann Arbor, MI, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hartman
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D016632:Apolipoprotein A-I / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000235:genetics / Q000493:pharmacokinetics; D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006207:Half-Life; D064368:Healthy Volunteers; D006579:Heterozygote; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000139:chemically induced / Q000235:genetics; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D010641:Phenotype; D010713:Phosphatidylcholines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D015415:Biomarkers; D008076:Cholesterol, HDL; C474616:ETC216; D010713:Phosphatidylcholines; D014280:Triglycerides; C080631:apolipoprotein A-I Milano
keywords: ApoA-Milano; First-in-man; HDL therapy; Pharmacokinetics; Reverse cholesterol transport; Synthetic HDL