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

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.

Human liver cytochrome P450 2D6 genotype, full-length messenger ribonucleic acid, and activity assessed with a novel cytochrome P450 2D6 substrate.

Objective: The goal of this study was to develop and validate a cytochrome P450 (CYP) 2D6 probe substrate with improved sensitivity to elucidate the relationship of CYP2D6 ribonucleic acid transcript levels, genotype, and enzyme activity in human liver biopsy samples.

Methods: CYP2D6 activity in tissue homogenates of liver biopsy specimens collected from control subjects (with no apparent liver disease), liver biopsy subjects, liver transplant subjects, and liver bank specimens was assessed with a calcimimetic, R-568, a high-clearance and specific substrate of CYP2D6. The livers were genotyped for the 6 most common CYP2D6 genetic variants (ie, *3, *4, *5, *6, *7, and *8).

In vitro studies in drug discovery and development: an analysis of study objectives and application of good laboratory practices (GLP).

In vitro drug metabolism studies play a dual role along the path from drug discovery to preclinical development. By analyzing the objectives of each type of study the question of whether to apply good laboratory practices (GLP) requirements is clarified. This review outlines the various in vitro techniques available and categorizes the goals for which they are applied as either supporting drug discovery or influencing decisions of clinical safety.