Merck’s anacetrapib seems to exhibit high-density lipoprotein cholesterol (HDL-C) increases greater than those seen with other investigational drugs in the class and low-density lipoprotein cholesterol (LDL-C) lowering effects similar to statins. However, anacetrapib does not seem to increase blood pressure, suggesting that potent cholesteryl ester transfer protein (CETP) inhibition by itself might not lead to increased blood pressure, according to a study published in the Dec. 8 issue of The Lancet.
Rajesh Krishna of the Merck Research Laboratories in Rahway, N.J., and colleagues, performed a two double-blind, randomized, placebo-controlled phase I studies. In the first study, 50 patients with dyslipidaemia (LDL-C 100–190 mg/dL; 40 active, 10 placebo) aged 18–75 years received anacetrapib doses of 0, 10, 40, 150, or 300 mg orally once a day with a meal for 28 days. The researchers said that standard lipid and lipoprotein monitoring, safety monitoring and anacetrapib concentrations for pharmacokinetics were done. In the second study, 22 healthy participants aged 45–75 years received either 150 mg of anacetrapib once a day or matching placebo with a meal for 10 days in each crossover period, in a randomized sequence, with at least a 14-day washout between the treatment periods.
They wrote that their primary or secondary endpoints of safety and tolerability were assessed in both studies by monitoring clinical adverse experiences, physical examinations, vital signs, 12-lead electrocardiogram and laboratory safety.
Krishna and colleagues wrote that in the dyslipidaemia study, one patient withdrew consent and one was excluded from the data analysis for HDL-C and LDL-C because complete pre-dose measurements were unavailable. Anacetrapib produced dose-dependent lipid-altering effects with peak lipid-altering effects of 129 percent (mean 51·1 - 114·9 mg/dL) increase in HDL-C and a 38 percent (138·2 _77·6 mg/dL) decrease in LDL-C in patients with dyslipidaemia. In the 24 hour ambulatory blood pressure study in healthy persons, difference between anacetrapib and placebo groups on day 10 were 0·60 mm Hg for systolic blood pressure and 0·47 mm Hg for diastolic blood pressure.
The authors concluded that the two phase I studies suggest that anacetrapib was well tolerated, seems not to be associated with an increase in blood pressure, and exhibited dose-dependent lipid-altering effects. A dose-dependent increase in HDL-C and decrease in LDL-C were observed in patients with dyslipidaemia, reaching maximum effect at around 150–300 mg dose administered with a meal, according to the report. They said that the hypothesis that CETP inhibition pharmacologically has clinical benefit on outcome has been hindered by compound candidates that have either not interrogated the mechanism fully in terms of maximum efficacy or might have perhaps exhibited detrimental compound-specific toxicities.