Population Pharmacokinetic and Pharmacodynamic Modeling of Etelcalcetide in Patients with Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis

Clinical Pharmacokinetics
Ping ChenMurad Melhem

Abstract

Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). To assess titrated dosing regimens, population pharmacokinetic (PK) and PK/pharmacodynamic (PKPD) modeling of etelcalcetide was performed using NONMEM 7.2. In this analysis, plasma etelcalcetide, serum parathyroid hormone (PTH) and calcium (Ca) concentration-time data were collected from five phase I, II, and III clinical trials following single or multiple intravenous doses of etelcalcetide ranging from 2.5 to 60 mg. A semi-mechanistic model was used to describe the relationship between etelcalcetide, PTH, and Ca. This model included the role of PTH in Ca regulation, the feedback of Ca onto PTH production via the CaSR, and the activity of etelcalcetide plasma levels in increasing the sensitivity of the CaSR to Ca via the cooperative binding model. The impact of relevant covariates was evaluated by stepwise forward/backward selection. Model evaluation was based on standard goodness-of-fit plots and prediction-corrected visual predictive checks (pcVPCs). Simulation was conducted to evaluate titrated dosing regimens. The time courses of etelcalcetide, PTH, and Ca were well-des...Continue Reading

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Citations

Sep 6, 2019·Therapeutic Apheresis and Dialysis : Official Peer-reviewed Journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy·Tadao AkizawaMasafumi Fukagawa
Feb 23, 2020·International Journal of Environmental Research and Public Health·Giorgina Barbara PiccoliNicola Panocchia
Jul 1, 2020·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Julie BernardorJustine Bacchetta

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