Cargando…

Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing

INTRODUCTION: Etelcalcetide, a novel calcimimetic agonist of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in chronic kidney disease patients on hemodialysis, is a d-amino acid linear heptapeptide with a d-cysteine that is linked to an l-cysteine by a disulfide bond. In...

Descripción completa

Detalles Bibliográficos
Autores principales: Edson, Katheryne Z., Wu, Benjamin M., Iyer, Abhinaya, Goodman, William, Skiles, Gary L., Subramanian, Raju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720529/
https://www.ncbi.nlm.nih.gov/pubmed/29318205
http://dx.doi.org/10.1016/j.ekir.2016.04.002
_version_ 1783284667938504704
author Edson, Katheryne Z.
Wu, Benjamin M.
Iyer, Abhinaya
Goodman, William
Skiles, Gary L.
Subramanian, Raju
author_facet Edson, Katheryne Z.
Wu, Benjamin M.
Iyer, Abhinaya
Goodman, William
Skiles, Gary L.
Subramanian, Raju
author_sort Edson, Katheryne Z.
collection PubMed
description INTRODUCTION: Etelcalcetide, a novel calcimimetic agonist of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in chronic kidney disease patients on hemodialysis, is a d-amino acid linear heptapeptide with a d-cysteine that is linked to an l-cysteine by a disulfide bond. In addition to binding to the calcium-sensing receptor, etelcalcetide is biotransformed by disulfide exchange in whole blood to predominantly form a covalent serum albumin peptide conjugate (SAPC). Key factors anticipated to affect the pharmacokinetics and disposition of etelcalcetide in chronic kidney disease patients on hemodialysis are the drug’s intrinsic dialytic properties and biotransformation kinetics. METHODS: These factors were investigated using in vitro methods, and the findings were modeled to derive corresponding kinetic rate constants. RESULTS: Biotransformation was reversible after incubation of etelcalcetide or SAPC in human whole blood. The rate of SAPC formation from etelcalcetide was 18-fold faster than the reverse process. Clearance of etelcalcetide by hemodialysis was rapid in the absence of blood and when hemodialysis was initiated immediately after addition of etelcalcetide to blood. Preincubation of etelcalcetide in blood for 3 hours before hemodialysis resulted in formation of SAPC and decreased its clearance due to the slow rate of etelcalcetide formation from SAPC. Etelcalcetide hemodialysis clearance was >16-fold faster than its biotransformation. DISCUSSION: These results indicate that etelcalcetide should be administered after hemodialysis to avoid elimination of a significant fraction of the dose.
format Online
Article
Text
id pubmed-5720529
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-57205292018-01-09 Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing Edson, Katheryne Z. Wu, Benjamin M. Iyer, Abhinaya Goodman, William Skiles, Gary L. Subramanian, Raju Kidney Int Rep Translational Research INTRODUCTION: Etelcalcetide, a novel calcimimetic agonist of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in chronic kidney disease patients on hemodialysis, is a d-amino acid linear heptapeptide with a d-cysteine that is linked to an l-cysteine by a disulfide bond. In addition to binding to the calcium-sensing receptor, etelcalcetide is biotransformed by disulfide exchange in whole blood to predominantly form a covalent serum albumin peptide conjugate (SAPC). Key factors anticipated to affect the pharmacokinetics and disposition of etelcalcetide in chronic kidney disease patients on hemodialysis are the drug’s intrinsic dialytic properties and biotransformation kinetics. METHODS: These factors were investigated using in vitro methods, and the findings were modeled to derive corresponding kinetic rate constants. RESULTS: Biotransformation was reversible after incubation of etelcalcetide or SAPC in human whole blood. The rate of SAPC formation from etelcalcetide was 18-fold faster than the reverse process. Clearance of etelcalcetide by hemodialysis was rapid in the absence of blood and when hemodialysis was initiated immediately after addition of etelcalcetide to blood. Preincubation of etelcalcetide in blood for 3 hours before hemodialysis resulted in formation of SAPC and decreased its clearance due to the slow rate of etelcalcetide formation from SAPC. Etelcalcetide hemodialysis clearance was >16-fold faster than its biotransformation. DISCUSSION: These results indicate that etelcalcetide should be administered after hemodialysis to avoid elimination of a significant fraction of the dose. Elsevier 2016-04-21 /pmc/articles/PMC5720529/ /pubmed/29318205 http://dx.doi.org/10.1016/j.ekir.2016.04.002 Text en © 2016 Amgen Inc. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Translational Research
Edson, Katheryne Z.
Wu, Benjamin M.
Iyer, Abhinaya
Goodman, William
Skiles, Gary L.
Subramanian, Raju
Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing
title Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing
title_full Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing
title_fullStr Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing
title_full_unstemmed Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing
title_short Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing
title_sort determination of etelcalcetide biotransformation and hemodialysis kinetics to guide the timing of its dosing
topic Translational Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720529/
https://www.ncbi.nlm.nih.gov/pubmed/29318205
http://dx.doi.org/10.1016/j.ekir.2016.04.002
work_keys_str_mv AT edsonkatherynez determinationofetelcalcetidebiotransformationandhemodialysiskineticstoguidethetimingofitsdosing
AT wubenjaminm determinationofetelcalcetidebiotransformationandhemodialysiskineticstoguidethetimingofitsdosing
AT iyerabhinaya determinationofetelcalcetidebiotransformationandhemodialysiskineticstoguidethetimingofitsdosing
AT goodmanwilliam determinationofetelcalcetidebiotransformationandhemodialysiskineticstoguidethetimingofitsdosing
AT skilesgaryl determinationofetelcalcetidebiotransformationandhemodialysiskineticstoguidethetimingofitsdosing
AT subramanianraju determinationofetelcalcetidebiotransformationandhemodialysiskineticstoguidethetimingofitsdosing