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


Dr Olaf Weber, Bayer HealthCare AG, Bayer HealthCare Pharmaceuticals Global Drug Discovery, D-42096 Wuppertal, Germany. Tel.: +49 214 30 33567, Fax: +49 2143 0963 3567. E-mail:



• Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from the atheroprotective high density lipoprotein (HDL) to the proatherogenic low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL) leading to lower concentrations of HDL but raising the concentrations of proatherogenic LDL and VLDL. Inhibition of CETP is considered a potential approach to treat dyslipidaemia.


• The study provides information on preclinical pharmacokinetics (PK) and pharmacodynamics (PD) as well as information on physiologically-based pharmacokinetic modelling of a novel inhibitor of CETP, BAY 60–5521, as an approach to support the prediction of a potentially effective dose in humans.

AIMS 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.

CONCLUSION 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.