title: Drug disposition model of radiolabeled etelcalcetide in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis.
abstract: Etelcalcetide (AMG 416) is an allosteric activator of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. To characterize the time course of etelcalcetide in different matrices (plasma, dialysate, urine, and feces), a drug disposition model was developed. Nonlinear mixed-effect modeling was used to describe data from six adults with CKD on hemodialysis who received a single intravenous dose of [14C]etelcalcetide (10 mg; 710 nCi) after hemodialysis (study NCT02054572). A three-compartment model with the following attributes adequately described the observed concentration-time profiles of etelcalcetide in the different matrices: biotransformation in the central compartment; elimination in dialysate, urine, and feces; and a nonspecific elimination process. The terminal half-life of total C-14 in plasma was approximately 56 days. The ratio of conjugation-deconjugation rate constants between etelcalcetide and biotransformed products was 11.3. Simulations showed that three hemodialysis sessions per week for 52 weeks would contribute to 60.1% of the total clearance of etelcalcetide following single-dose intravenous etelcalcetide administration. Minimal amounts were eliminated in urine (2.5%) and feces (5.7%), whereas nonspecific elimination accounted for 31.2% of total elimination. In addition to removal of etelcalcetide, ~10% of small-molecular weight biotransformed products was estimated to have been removed through hemodialysis and in urine. This model provided a quantitative approach to describe biotransformation, distribution, and elimination of etelcalcetide, a unique synthetic D-amino acid peptide, in the relevant patient population.
authors.affiliation: Clinical Pharmacology Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, USA.
authors.forename: Liviawati
authors.initials: L
authors.lastname: Wu
authors.affiliation: Clinical Pharmacology Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, USA. mmelhem@amgen.com.
authors.forename: Murad
authors.initials: M
authors.lastname: Melhem
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.affiliation: Clinical Pharmacology Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wu
mesh_terms: D002250:Carbon Radioisotopes; D017321:Clinical Trials, Phase I as Topic; D003198:Computer Simulation; D005243:Feces / Q000737:chemistry; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy* / Q000378:metabolism; D008954:Models, Biological; D010455:Peptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006435:Renal Dialysis / Q000009:adverse effects; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000628:therapy*; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D010455:Peptides; C583569:etelcalcetide hydrochloride
keywords: AMG 416; Drug disposition model; Etelcalcetide; Hemodialysis; Pharmacokinetics; Secondary hyperparathyroidism