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Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhi...

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Autores principales: Kasichayanula, Sreeneeranj, Grover, Anita, Emery, Maurice G., Gibbs, Megan A., Somaratne, Ransi, Wasserman, Scott M., Gibbs, John P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999140/
https://www.ncbi.nlm.nih.gov/pubmed/29353350
http://dx.doi.org/10.1007/s40262-017-0620-7
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author Kasichayanula, Sreeneeranj
Grover, Anita
Emery, Maurice G.
Gibbs, Megan A.
Somaratne, Ransi
Wasserman, Scott M.
Gibbs, John P.
author_facet Kasichayanula, Sreeneeranj
Grover, Anita
Emery, Maurice G.
Gibbs, Megan A.
Somaratne, Ransi
Wasserman, Scott M.
Gibbs, John P.
author_sort Kasichayanula, Sreeneeranj
collection PubMed
description Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Elimination is predominantly through saturable binding to PCSK9 at lower concentrations and a nonsaturable proteolytic pathway at higher concentrations. The effective half-life of evolocumab is 11–17 days. The pharmacodynamic effects of evolocumab on PCSK9 are rapid, with maximum suppression within 4 h. At steady state, peak reduction of LDL-C occurs approximately 1 week after a subcutaneous dose of 140 mg every 2 weeks (Q2W) and 2 weeks after a subcutaneous dose 420 mg once monthly (QM), and returns towards baseline over the dosing interval. In several clinical studies, these doses of evolocumab reduced LDL-C by approximately 55–75% compared with placebo. Evolocumab also reduced lipoprotein(a) [Lp(a)] levels and improved those of other lipids in clinical studies. No clinically meaningful differences in pharmacodynamic effects on LDL-C were observed in adult subjects regardless of mild/moderate hepatic impairment, renal impairment or renal failure, body weight, race, sex, or age. No clinically meaningful differences were observed for the pharmacodynamic effects of evolocumab on LDL-C between patients who received evolocumab alone or in combination with a statin, resulting in additional lowering of LDL-C when evolocumab was combined with a statin. No dose adjustment is necessary based on patient-specific factors or concomitant medication use. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40262-017-0620-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-59991402018-06-28 Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor Kasichayanula, Sreeneeranj Grover, Anita Emery, Maurice G. Gibbs, Megan A. Somaratne, Ransi Wasserman, Scott M. Gibbs, John P. Clin Pharmacokinet Review Article Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Elimination is predominantly through saturable binding to PCSK9 at lower concentrations and a nonsaturable proteolytic pathway at higher concentrations. The effective half-life of evolocumab is 11–17 days. The pharmacodynamic effects of evolocumab on PCSK9 are rapid, with maximum suppression within 4 h. At steady state, peak reduction of LDL-C occurs approximately 1 week after a subcutaneous dose of 140 mg every 2 weeks (Q2W) and 2 weeks after a subcutaneous dose 420 mg once monthly (QM), and returns towards baseline over the dosing interval. In several clinical studies, these doses of evolocumab reduced LDL-C by approximately 55–75% compared with placebo. Evolocumab also reduced lipoprotein(a) [Lp(a)] levels and improved those of other lipids in clinical studies. No clinically meaningful differences in pharmacodynamic effects on LDL-C were observed in adult subjects regardless of mild/moderate hepatic impairment, renal impairment or renal failure, body weight, race, sex, or age. No clinically meaningful differences were observed for the pharmacodynamic effects of evolocumab on LDL-C between patients who received evolocumab alone or in combination with a statin, resulting in additional lowering of LDL-C when evolocumab was combined with a statin. No dose adjustment is necessary based on patient-specific factors or concomitant medication use. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40262-017-0620-7) contains supplementary material, which is available to authorized users. Springer International Publishing 2018-01-20 2018 /pmc/articles/PMC5999140/ /pubmed/29353350 http://dx.doi.org/10.1007/s40262-017-0620-7 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Review Article
Kasichayanula, Sreeneeranj
Grover, Anita
Emery, Maurice G.
Gibbs, Megan A.
Somaratne, Ransi
Wasserman, Scott M.
Gibbs, John P.
Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor
title Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor
title_full Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor
title_fullStr Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor
title_full_unstemmed Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor
title_short Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor
title_sort clinical pharmacokinetics and pharmacodynamics of evolocumab, a pcsk9 inhibitor
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999140/
https://www.ncbi.nlm.nih.gov/pubmed/29353350
http://dx.doi.org/10.1007/s40262-017-0620-7
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