title: Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis.
abstract: Etelcalcetide is a novel calcimimetic in development for the treatment of secondary hyperparathyroidism (SHPT). A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed relating etelcalcetide exposures to markers of efficacy (parathyroid hormone [PTH]) and safety (calcium) using data from three clinical studies. The semimechanistic model was developed that included allosteric activation pharmacology and understanding of calcium homeostasis. The temporal profiles for all biomarkers were well described by the model. The cooperativity constant was 4.94, confirming allosteric activation mechanism. Subjects with more severe disease (higher PTH baseline) were predicted to experience less pronounced reduction in PTH (percentage change from baseline), but more reduction in calcium (Ca; percentage change from baseline). There was no evidence that dose adjustment by any covariate was needed. Model-based simulations provided quantitative support to several elements of dosing, such as starting dose, monitoring, and titration timing for registration trials.
authors.affiliation: Department of Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.affiliation: SGS Exprimo NV, Mechelen, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Olsson Gisleskog
authors.affiliation: Department of Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, California, USA.|Current address: Janssen Research & Development, Beerse, Belgium.
authors.forename: J J
authors.initials: JJ
authors.lastname: Perez-Ruixo
authors.affiliation: Department of Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, California, USA.|Clovis Oncology Inc., San Francisco, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xiao
authors.affiliation: SGS Exprimo NV, Mechelen, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Wilkins
authors.affiliation: Department of Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: A
authors.initials: A
authors.lastname: Narayanan
authors.affiliation: Department of Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Gibbs
authors.affiliation: Department of Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, California, USA. mmelhem@amgen.com.
authors.forename: M
authors.initials: M
authors.lastname: Melhem
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D032701:Biomimetics; D002118:Calcium / Q000097:blood*; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010455:Peptides / Q000097:blood* / Q000627:therapeutic use; D006435:Renal Dialysis / Q000706:statistics & numerical data*; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000188:drug therapy; D055815:Young Adult
chemical_list: D010455:Peptides; C583569:etelcalcetide hydrochloride; D002118:Calcium