Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein
Authors: Boettcher Michael‐Friedrich , Heinig Roland , Schmeck Carsten , Kohlsdorfer Christian , Ludwig Matthias , Schaefer Anja , Gelfert‐Peukert Sabine , Wensing Georg , Weber Olaf 
Published: August 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesterol esters from the cardioprotective high density lipoprotein cholesterol (HDL‐C) to the proatherogenic low density lipoprotein cholesterol (LDL‐C) and very low density lipoprotein cholesterol (VLDL‐C) leading to lower concentrations of HDL‐C but raising the concentrations of proatherogenic LDL‐C and VLDL‐C.• Inhibition of CETP is considered a potential approach to treat dyslipidaemia.• Phase III studies demonstrating no benefit in regard to the defined clinical end points with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents although it has been recently discussed whether potential off‐target effects of torcetrapib could have contributed to the failure of this CETP inhibitor.• It has been suggested in recent publications to continue studying other CETP inhibitors for their potential to improve plasma lipid profiles and reduce cardiovascular risk. Currently, several compounds are being investigated in preclinical or clinical studies.WHAT THIS STUDY ADDS• This study provides information on the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of a potential new treatment for dyslipidaemia.• Data from a first in man study with the new CETP inhibitor BAY 60–5521 are presented that demonstrate that BAY 60–5521 is 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‐C could be demonstrated.AIMS 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.