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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.


Effect of disease severity (measured by parathyroid hormone [PTH] baseline) on responses to etelcalcetide treatment: time courses of of PTH (left) and calium (Ca; right) in typical subjects with varying disease severity in response to treatment with 5 mg etelcalcetide three time a week for 8 weeks.
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psp412106-fig-0005: Effect of disease severity (measured by parathyroid hormone [PTH] baseline) on responses to etelcalcetide treatment: time courses of of PTH (left) and calium (Ca; right) in typical subjects with varying disease severity in response to treatment with 5 mg etelcalcetide three time a week for 8 weeks.

Mentions: The effect of baseline PTH, as a measure of disease severity, on the PTH and Ca responses following treatment with etelcalcetide is highlighted in Figure5. Subjects with more severe disease (higher PTH baseline) were predicted to experience less pronounced reduction in PTH, but more reduction in Ca.


Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis
Effect of disease severity (measured by parathyroid hormone [PTH] baseline) on responses to etelcalcetide treatment: time courses of of PTH (left) and calium (Ca; right) in typical subjects with varying disease severity in response to treatment with 5 mg etelcalcetide three time a week for 8 weeks.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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

psp412106-fig-0005: Effect of disease severity (measured by parathyroid hormone [PTH] baseline) on responses to etelcalcetide treatment: time courses of of PTH (left) and calium (Ca; right) in typical subjects with varying disease severity in response to treatment with 5 mg etelcalcetide three time a week for 8 weeks.
Mentions: The effect of baseline PTH, as a measure of disease severity, on the PTH and Ca responses following treatment with etelcalcetide is highlighted in Figure5. Subjects with more severe disease (higher PTH baseline) were predicted to experience less pronounced reduction in PTH, but more reduction in Ca.

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.