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

OBJECTIVES: We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib. METHODS: Healthy volunteers received multiple daily doses of evacetrapib (10–600 mg) administered for up to 15 days in a placebo-controlled study. KEY FINDINGS: Mean peak plasma concentrations...

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Detalles Bibliográficos
Autores principales: Suico, Jeffrey G, Wang, Ming-Dauh, Friedrich, Stuart, Cannady, Ellen A, Konkoy, Christopher S, Ruotolo, Giacomo, Krueger, Kathryn A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284021/
https://www.ncbi.nlm.nih.gov/pubmed/24961753
http://dx.doi.org/10.1111/jphp.12287
Descripción
Sumario:OBJECTIVES: We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib. METHODS: Healthy volunteers received multiple daily doses of evacetrapib (10–600 mg) administered for up to 15 days in a placebo-controlled study. KEY FINDINGS: Mean 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. CONCLUSIONS: Multiple 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.