Ping Chen1, Adimoolam Narayanan1, Benjamin Wu1, Per Olsson Gisleskog2, John P Gibbs1, Andrew T Chow1, Murad Melhem3. 1. Department of Clinical Pharmacology, Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA. 2. SGS Exprimo NV, Mechlin, Belgium. 3. Department of Clinical Pharmacology, Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA. mmelhem@amgen.com.
Abstract
INTRODUCTION: Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). METHODS: 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. RESULTS AND DISCUSSION: The time courses of etelcalcetide, PTH, and Ca were well-described by the model. The clearance and central volume of distribution (Vc) of etelcalcetide were 0.472 L/h and 49.9 L, respectively, while estimates of the turnover half-lives of PTH and Ca were 0.36 and 23 h, respectively. The extent of interindividual variability in model parameters was low to moderate (6-67%), and no covariates were identified as significant predictors of PK and PD variability. pcVPCs confirmed the predictive ability of the model. CONCLUSIONS: The current analysis confirms the putative mechanism of action of etelcalcetide as an allosteric activator of CaSR. Simulations showed that dose titration of etelcalcetide, rather than fixed dose, is needed to effectively decrease the PTH level in patient populations.
INTRODUCTION:Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). METHODS: 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. RESULTS AND DISCUSSION: The time courses of etelcalcetide, PTH, and Ca were well-described by the model. The clearance and central volume of distribution (Vc) of etelcalcetide were 0.472 L/h and 49.9 L, respectively, while estimates of the turnover half-lives of PTH and Ca were 0.36 and 23 h, respectively. The extent of interindividual variability in model parameters was low to moderate (6-67%), and no covariates were identified as significant predictors of PK and PD variability. pcVPCs confirmed the predictive ability of the model. CONCLUSIONS: The current analysis confirms the putative mechanism of action of etelcalcetide as an allosteric activator of CaSR. Simulations showed that dose titration of etelcalcetide, rather than fixed dose, is needed to effectively decrease the PTH level in patient populations.