Limits...
Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Visual predictive check based on the final population pharmacokinetic/pharmacodynamic (PK/PD) model for change from baseline in parathyroid hormone (PTH; top left) and corrected calcium (Ca; top right) after administration of a single dose of etelcalcetide in study I, and for PTH (bottom left) and corrected Ca (bottom right) after repeated administration of etelcalcetide in study III. In all panels, lines represent median (solid line), 5th and 95th percentile (dashed lines) of observed change from baseline. Shaded areas represent the 95% prediction interval of the median (blue) or 5th and 95th percentile (green) from the simulations.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5036423&req=5

psp412106-fig-0003: Visual predictive check based on the final population pharmacokinetic/pharmacodynamic (PK/PD) model for change from baseline in parathyroid hormone (PTH; top left) and corrected calcium (Ca; top right) after administration of a single dose of etelcalcetide in study I, and for PTH (bottom left) and corrected Ca (bottom right) after repeated administration of etelcalcetide in study III. In all panels, lines represent median (solid line), 5th and 95th percentile (dashed lines) of observed change from baseline. Shaded areas represent the 95% prediction interval of the median (blue) or 5th and 95th percentile (green) from the simulations.

Mentions: This model was subsequently evaluated internally using simulation‐based VPC. Examples of the VPCs are shown in Figure3, both for the first few days after a single dose of etelcalcetide in study I, and for the long‐term treatment effects after repeated dosing in study III. The bulk of the data was included within the prediction interval. The VPCs confirm acceptable predictive performance for PTH and Ca. Collectively, model evaluation confirmed the stability and predictive ability of the developed model.


Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis
Visual predictive check based on the final population pharmacokinetic/pharmacodynamic (PK/PD) model for change from baseline in parathyroid hormone (PTH; top left) and corrected calcium (Ca; top right) after administration of a single dose of etelcalcetide in study I, and for PTH (bottom left) and corrected Ca (bottom right) after repeated administration of etelcalcetide in study III. In all panels, lines represent median (solid line), 5th and 95th percentile (dashed lines) of observed change from baseline. Shaded areas represent the 95% prediction interval of the median (blue) or 5th and 95th percentile (green) from the simulations.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036423&req=5

psp412106-fig-0003: Visual predictive check based on the final population pharmacokinetic/pharmacodynamic (PK/PD) model for change from baseline in parathyroid hormone (PTH; top left) and corrected calcium (Ca; top right) after administration of a single dose of etelcalcetide in study I, and for PTH (bottom left) and corrected Ca (bottom right) after repeated administration of etelcalcetide in study III. In all panels, lines represent median (solid line), 5th and 95th percentile (dashed lines) of observed change from baseline. Shaded areas represent the 95% prediction interval of the median (blue) or 5th and 95th percentile (green) from the simulations.
Mentions: This model was subsequently evaluated internally using simulation‐based VPC. Examples of the VPCs are shown in Figure3, both for the first few days after a single dose of etelcalcetide in study I, and for the long‐term treatment effects after repeated dosing in study III. The bulk of the data was included within the prediction interval. The VPCs confirm acceptable predictive performance for PTH and Ca. Collectively, model evaluation confirmed the stability and predictive ability of the developed model.

View Article: PubMed Central - PubMed

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.

No MeSH data available.