title: Prediction of a potentially effective dose in humans for BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically-based pharmacokinetic modelling.
abstract: OBJECTIVE
  The purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60-5521, in humans.
  
  
  METHODS
  A combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60-5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose.
  
  
  RESULTS
  The PBPK approach predicts a greater extent of distribution for BAY 60-5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life. The combined approach led to an estimate of a potentially effective dose for BAY 60-5521 of 51 mg in humans.
  
  
  CONCLUSIONS
  The approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60-5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study.
authors.affiliation: Bayer HealthCare AG, Bayer HealthCare Pharmaceuticals Global Drug Discovery, Wuppertal, Germany. olaf.weber@bayer.com
authors.forename: Olaf
authors.initials: O
authors.lastname: Weber
authors.forename: Stefan
authors.initials: S
authors.lastname: Willmann
authors.forename: Hilmar
authors.initials: H
authors.lastname: Bischoff
authors.forename: Volkhart
authors.initials: V
authors.lastname: Li
authors.forename: Alexandros
authors.initials: A
authors.lastname: Vakalopoulos
authors.forename: Klemens
authors.initials: K
authors.lastname: Lustig
authors.forename: Frank-Thorsten
authors.initials: FT
authors.lastname: Hafner
authors.forename: Roland
authors.initials: R
authors.lastname: Heinig
authors.forename: Carsten
authors.initials: C
authors.lastname: Schmeck
authors.forename: Klaus
authors.initials: K
authors.lastname: Buehner
mesh_terms: D000818:Animals; D001699:Biometry; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006912:Hydroxyquinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar
chemical_list: C571722:BAY 60-5521; D053480:Cholesterol Ester Transfer Proteins; D006912:Hydroxyquinolines