title: Pharmacokinetics, pharmacodynamics and safety of CKD-519, a CETP inhibitor, in healthy subjects.
abstract: CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of dyslipidemia to raise high-density lipoprotein cholesterol. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of CKD-519 in healthy adult subjects. A randomized, double-blinded, placebo-controlled, single ascending dose study was performed. Eight healthy subjects were enrolled in each CKD-519 dose group (25, 50, 100, 200, or 400 mg) and randomized to CKD-519 (n=6) or matching placebo (n=2). CKD-519 reached the maximum plasma concentration (Cmax) at 5-6 h post-dose, and had a long terminal half-life ranging between 40-70 h. The area under the plasma concentration-time curve (AUC) and Cmaxincreased with the dose, however, Cmaxand AUC normalized by dose decreased with each incremental dose. CETP activity decreased with dose, and the maximum decrease (63%-83%) was observed at 6-8 h post-dose. A sigmoid Emaxmodel best described the relationship between CKD-519 plasma concentrations and CETP activity with an EC50of 17.3 ng/mL. Overall, 11 adverse events (AEs) were observed. All AEs were mild or moderate in intensity, and resolved without any complications. There were no clinically significant effects on blood pressure. In conclusion, single doses of CKD-519 up to 400 mg were well tolerated and showed potent inhibition of CETP activity.
authors.affiliation: Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul.
authors.forename: Choon Ok
authors.initials: CO
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Medicines and Regulatory Science, Colleges of Medicine and Pharmacy, Yonsei University, Incheon.
authors.forename: Eun Sil
authors.initials: ES
authors.lastname: Oh
authors.affiliation: Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul.
authors.forename: Chungam
authors.initials: C
authors.lastname: Choi
authors.affiliation: Chong Kun Dang Clinical Research, Chong Kun Dang Pharmaceutical Corp.
authors.forename: Yeonjoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Chong Kun Dang Research Institute, Chong Kun Dang Pharmaceutical Corp.
authors.forename: Sera
authors.initials: S
authors.lastname: Lee
authors.affiliation: Chong Kun Dang Research Institute, Chong Kun Dang Pharmaceutical Corp.
authors.forename: Semi
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul; Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Park
mesh_terms: D000328:Adult; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage / Q000493:pharmacokinetics; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: C506642:CETP protein, human; C000620552:CKD-519; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006845:Hydrocarbons, Fluorinated; D000960:Hypolipidemic Agents; D010080:Oxazoles
keywords: CKD-519; cholesteryl ester transfer protein inhibitor; pharmacodynamics; pharmacokinetics