Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults

Abstract

ObjectivesWe investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib.MethodsHealthy volunteers received multiple daily doses of evacetrapib (10–600 mg) administered for up to 15 days in a placebo-controlled study.Key findingsMean peak plasma concentrations of evacetrapib occurred at 4–6 h and terminal half-life ranged 24–44 h. Steady state was achieved at approximately 10 days; all subjects had undetectable levels of evacetrapib 3 weeks after their last dose. The trough inhibition of cholesteryl ester transfer protein (CETP) activity was 65 and 84% at 100 and 300 mg, respectively. At the highest dose (600 mg), evacetrapib significantly inhibited CETP activity (91%), increased HDL-C (87%) and apo AI (42%), and decreased LDL-C (29%) and apo B (26%) relative to placebo. For the highest dose tested, levels of evacetrapib, CETP activity, CETP mass, HDL-C and LDL-C returned to levels at or near baseline after a 2-week washout period. Evacetrapib at the highest dose tested did not produce any significant effect on 24-h ambulatory systolic or diastolic blood pressure.ConclusionsMultiple doses of evacetrapib potently inhibited CETP activity, leading to substantial elevations in HDL-C and lowering of LDL-C. Evacetrapib was devoid of clinically relevant effects on blood pressure and mineralocorticoid levels.

The Changing Face of HDL and the Best Way to Measure It

“…The rationale for inhibiting CETP to increase HDL-C dates back to the early 1990s, when genetic studies in Japanese subjects found that individuals with CETP deficiency had increased HDL concentrations (45,46 ). Subsequent clinical studies have evaluated the HDL-raising properties of CETP inhibitors (15,36,(47)(48)(49). For example, treatment with 300 mg evacetrapib raised HDL-C concentrations by Ͼ80% in healthy volunteers, and increased total HDL-C and non-ABCA1-specific cholesterol efflux capacity (CEC) in individuals with mild dyslipidemia (36,(47)(48)(49).…”

“…Subsequent clinical studies have evaluated the HDL-raising properties of CETP inhibitors (15,36,(47)(48)(49). For example, treatment with 300 mg evacetrapib raised HDL-C concentrations by Ͼ80% in healthy volunteers, and increased total HDL-C and non-ABCA1-specific cholesterol efflux capacity (CEC) in individuals with mild dyslipidemia (36,(47)(48)(49). In patients with acute coronary syndrome (ACS), treatment with dalcetrapib, another CETP inhibitor, also significantly raised HDL-C, principally via an increase in ABCA1-mediated cholesterol efflux (15,49 ).…”

Assessment of the persistence of anacetrapib and evacetrapib concentrations using two pharmacokinetic modeling approaches

“…In multiple‐dose studies in healthy subjects, evacetrapib increased HDL‐C and decreased LDL‐C and was well‐tolerated at doses up to 600 mg . In a Phase II study in dyslipidemic patients, evacetrapib increased HDL‐C by up to 129% and decreased LDL‐C by up to 36%, and when administered alone or with statins was well‐tolerated .…”

“…So far, the empirical evidence suggests that elimination of evacetrapib is not affected by treatment duration through 12 weeks of treatment, which is the longest duration studied to date . After a single dose of evacetrapib, the apparent terminal half‐life is about 45 hours (unpublished data) and is the same after 2 weeks of dosing . A single sample was collected for measurement of evacetrapib plasma concentrations 4–6 weeks after the end of 12 weeks of once‐daily treatment.…”

Unending saga of fighting cholesterol: Evacetrapib is another fallen warrior

“…EVC became a hopeful candidate (10,11,12,13,14) for new generation of lipid modifying agents. It belongs to a class of CETP, cholesterylester transfer protein inhibitors.…”