title: Pharmacokinetics, pharmacodynamics, safety, and tolerability of hyzetimibe (HS-25) in healthy Chinese subjects.
abstract: Hyzetimibe (HS-25) is a new cholesterol absorption inhibitor. We performed the first-in-human study to assess the safety, tolerability, and pharmacokinetics (including the effect of food) and pharmacodynamics (effect on blood lipid level) following single (1, 3, 5, 10, 20, and 30 mg) and multiple (5, 10, and 20 mg) ascending-dose of hyzetimibe in healthy subjects. An increase of exposure (area under the plasma concentration-time curve and maximum plasma concentration) to hyzetimibe and hyzetimibe-glucuronide (HS-25M1) was observed in an approximately dose-proportional manner. A terminal half-life of approximately 21 hours was observed with doses ranging between 5 and 30 mg. Steady state was achieved by day 8 of once-daily dosing with 1.6- and 1.2-fold accumulation for hyzetimibe and hyzetimibe-glucuronide, respectively. Food did not have any effect on hyzetimibe and hyzetimibe-glucuronide exposure. Administration of hyzetimibe once daily for 10 days reduced the levels of low-density lipoprotein cholesterol levels in healthy subjects and these recovered after discontinuation of this drug. All of the adverse events were mild or moderate in severity, and the majority of them were unrelated to hyzetimibe, with no dose-dependent trends. These findings suggest that hyzetimibe could be a potential treatment for hypercholesterolemia.
authors.affiliation: Center of Clinical Pharmacology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Zhourong
authors.initials: Z
authors.lastname: Ruan
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Jinliang
authors.initials: J
authors.lastname: Chen
authors.forename: Xuehua
authors.initials: X
authors.lastname: Zhang
authors.forename: Honggang
authors.initials: H
authors.lastname: Lou
authors.forename: Meixiang
authors.initials: M
authors.lastname: Xiang
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Shao
authors.forename: Jian'an
authors.initials: J
authors.lastname: Wang
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D044466:Asian People; D001385:Azetines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000097:blood*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D055815:Young Adult
chemical_list: C000597911:1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-4-hydroxybut-2-enyl)-4-(4-hydroxyphenyl)-2-azetidinone; D000924:Anticholesteremic Agents; D001385:Azetines; D008078:Cholesterol, LDL; D005464:Fluorobenzenes
keywords: cholesterol absorption inhibitor; first-in-human study; hyzetimibe (HS-25); pharmacodynamics; pharmacokinetics