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Open Access 01-02-2017 | Original Research Article

Pharmacokinetics, Biotransformation, and Excretion of [¹⁴C]Etelcalcetide (AMG 416) Following a Single Microtracer Intravenous Dose in Patients with Chronic Kidney Disease on Hemodialysis

Authors: Raju Subramanian, Xiaochun Zhu, M. Benjamin Hock, Bethlyn J. Sloey, Benjamin Wu, Sarah F. Wilson, Ogo Egbuna, J. Greg Slatter, Jim Xiao, Gary L. Skiles

Published in: Clinical Pharmacokinetics | Issue 2/2017

Abstract

Etelcalcetide (AMG 416) is a novel synthetic peptide calcium-sensing receptor activator in clinical development as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. Etelcalcetide is composed of seven d-aminoacids with an l-cysteine linked to a d-cysteine by a disulfide bond. A single intravenous dose of [¹⁴C]etelcalcetide (10 mg; 26.3 kBq; 710 nCi) was administered to patients with CKD on hemodialysis to elucidate the pharmacokinetics, biotransformation, and excretion of etelcalcetide in this setting. Blood, dialysate, urine, and feces were collected to characterize the pharmacokinetics, biotransformation product profiles, mass balance, and formation of anti-etelcalcetide antibodies. Accelerator mass spectrometry was necessary to measure the microtracer quantities of C-14 excreted in the large volumes of dialysate and other biomatrices. An estimated 67 % of the [¹⁴C]etelcalcetide dose was recovered in dialysate, urine, and feces 176 days after dose administration. Etelcalcetide was primarily cleared by hemodialysis, with approximately 60 % of the administered dose eliminated in dialysate. Minor excretion was observed in urine and feces. Biotransformation resulted from disulfide exchange with endogenous thiols, and preserved the etelcalcetide d-amino acid backbone. Drug-related radioactivity circulated primarily as serum albumin peptide conjugate (SAPC). Following removal of plasma etelcalcetide by hemodialysis, re-equilibration occurred between SAPC and l-cysteine present in blood to partially restore the etelcalcetide plasma concentrations between dialysis sessions. No unanticipated safety signals or anti-etelcalcetide or anti-SAPC antibodies were detected.

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Title: Pharmacokinetics, Biotransformation, and Excretion of [14C]Etelcalcetide (AMG 416) Following a Single Microtracer Intravenous Dose in Patients with Chronic Kidney Disease on Hemodialysis
Authors: Raju Subramanian
Xiaochun Zhu
M. Benjamin Hock
Bethlyn J. Sloey
Benjamin Wu
Sarah F. Wilson
Ogo Egbuna
J. Greg Slatter
Jim Xiao
Gary L. Skiles
Publication date: 01-02-2017
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 2/2017
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-016-0433-0

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Pharmacokinetics, Biotransformation, and Excretion of [¹⁴C]Etelcalcetide (AMG 416) Following a Single Microtracer Intravenous Dose in Patients with Chronic Kidney Disease on Hemodialysis

Abstract

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Abstract

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