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

Autor:	Edson KZ; Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, USA., Wu BM; Clinical Pharmacology Modeling and Simulations, Amgen Inc., Thousand Oaks, California, USA., Iyer A; Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, USA., Goodman W; Global Development, Amgen Inc., Thousand Oaks, California, USA., Skiles GL; Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, USA., Subramanian R; Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, USA.
Jazyk:	angličtina
Zdroj:	Kidney international reports [Kidney Int Rep] 2016 Apr 21; Vol. 1 (1), pp. 24-33. Date of Electronic Publication: 2016 Apr 21 (Print Publication: 2016).
DOI:	10.1016/j.ekir.2016.04.002
Abstrakt:	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.
Databáze:	MEDLINE
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