title: Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein.
abstract: OBJECTIVE
  To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP).
  
  
  METHODS
  The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10).
  
  
  RESULTS
  In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h.
  
  
  CONCLUSIONS
  BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated.
authors.affiliation: Bayer Pharma AG, 42096 Wuppertal, Germany. michael-friedrich.boettcher@bayer.com
authors.forename: Michael-Friedrich
authors.initials: MF
authors.lastname: Boettcher
authors.forename: Roland
authors.initials: R
authors.lastname: Heinig
authors.forename: Carsten
authors.initials: C
authors.lastname: Schmeck
authors.forename: Christian
authors.initials: C
authors.lastname: Kohlsdorfer
authors.forename: Matthias
authors.initials: M
authors.lastname: Ludwig
authors.forename: Anja
authors.initials: A
authors.lastname: Schaefer
authors.forename: Sabine
authors.initials: S
authors.lastname: Gelfert-Peukert
authors.forename: Georg
authors.initials: G
authors.lastname: Wensing
authors.forename: Olaf
authors.initials: O
authors.lastname: Weber
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism*; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006912:Hydroxyquinolines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: C571722:BAY 60-5521; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006912:Hydroxyquinolines