Nonclinical Pharmacokinetics, Disposition, and Drug-Drug Interaction Potential of a Novel d-Amino Acid Peptide Agonist of the Calcium-Sensing Receptor AMG 416 (Etelcalcetide)

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Raju SubramanianGary L Skiles

Abstract

AMG 416 (etelcalcetide) is a novel synthetic peptide agonist of the calcium-sensing receptor composed of a linear chain of seven d-amino acids (referred to as the d-amino acid backbone) with a d-cysteine linked to an l-cysteine via a disulfide bond. AMG 416 contains four basic d-arginine residues and is a +4 charged peptide at physiologic pH with a mol. wt. of 1048.3 Da. The pharmacokinetics (PK), disposition, and potential of AMG 416 to cause drug-drug interaction were investigated in nonclinical studies with two single (14)C-labels placed either at a potentially metabolically labile acetyl position or on the d-alanine next to d-cysteine in the interior of the d-amino acid backbone. After i.v. dosing, the PK and disposition of AMG 416 were similar in male and female rats. Radioactivity rapidly distributed to most tissues in rats with intact kidneys, and renal elimination was the predominant clearance pathway. No strain-dependent differences were observed. In bilaterally nephrectomized rats, minimal radioactivity (1.2%) was excreted via nonrenal pathways. Biotransformation occurred primarily via disulfide exchange with endogenous thiol-containing molecules in whole blood rather than metabolism by enzymes, such as proteases or c...Continue Reading

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Citations

Dec 3, 2016·Drugs·Hannah A Blair
Mar 10, 2017·Expert Opinion on Pharmacotherapy·Naoto HamanoMasafumi Fukagawa
May 8, 2018·Pharmaceuticals·Othman Al MusaimiFernando Albericio
Dec 26, 2017·Hospital Pharmacy·Danial E Baker
Jul 25, 2019·Journal of Clinical Medicine·Domenico RussoVincenzo Antonio Panuccio
Jun 20, 2020·Molecular Informatics·Bárbara I Díaz-EufracioJosé L Medina-Franco

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