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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons Ltd
2014
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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 |
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author | Suico, Jeffrey G Wang, Ming-Dauh Friedrich, Stuart Cannady, Ellen A Konkoy, Christopher S Ruotolo, Giacomo Krueger, Kathryn A |
author_facet | Suico, Jeffrey G Wang, Ming-Dauh Friedrich, Stuart Cannady, Ellen A Konkoy, Christopher S Ruotolo, Giacomo Krueger, Kathryn A |
author_sort | Suico, Jeffrey G |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4284021 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | John Wiley & Sons Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-42840212015-01-14 Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults Suico, Jeffrey G Wang, Ming-Dauh Friedrich, Stuart Cannady, Ellen A Konkoy, Christopher S Ruotolo, Giacomo Krueger, Kathryn A J Pharm Pharmacol Research Papers 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. John Wiley & Sons Ltd 2014-11 2014-06-24 /pmc/articles/PMC4284021/ /pubmed/24961753 http://dx.doi.org/10.1111/jphp.12287 Text en © 2014 Eli Lilly and Company. Journal of Pharmacy and Pharmacology published by John Wiley & Sons Ltd on behalf of Royal Pharmaceutical Society. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Research Papers Suico, Jeffrey G Wang, Ming-Dauh Friedrich, Stuart Cannady, Ellen A Konkoy, Christopher S Ruotolo, Giacomo Krueger, Kathryn A Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults |
title | Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults |
title_full | Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults |
title_fullStr | Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults |
title_full_unstemmed | Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults |
title_short | Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults |
title_sort | effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults |
topic | Research Papers |
url | 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 |
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