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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.


Simulated time courses of change from baseline in parathyroid hormone (PTH; top) and calcium (Ca) upon postdialysis administration of 5 mg etelcalcetide three times a week for 1 month. Shaded areas represent the 95% prediction interval of the median (black) from the simulations.
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psp412106-fig-0004: Simulated time courses of change from baseline in parathyroid hormone (PTH; top) and calcium (Ca) upon postdialysis administration of 5 mg etelcalcetide three times a week for 1 month. Shaded areas represent the 95% prediction interval of the median (black) from the simulations.

Mentions: The effects of etelcalcetide administration on PTH and Ca following 5 mg TIW administration for 1 month are shown in Figure4. Following the administration of multiple doses, a significant drop (median approximately ∼50%) in PTH from baseline was predicted. The pattern and extent of PTH reduction were predicted to be maintained upon repeated TIW administration (Figure4a). Delayed and less pronounced patterns of response in Ca levels to etelcalcetide repeated administration were predicted. After the first dose, <5% change in Ca from baseline is predicted. Upon TIW administration, a gradual reduction in Ca levels from baseline is predicted. On a median level, <8% change in Ca levels was predicted at the end of 1 month of TIW administration. Moreover, simulations suggested minimal differences in the changes in predialysis Ca and PTH from baseline levels are predicted on weeks 3 and 4.


Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis
Simulated time courses of change from baseline in parathyroid hormone (PTH; top) and calcium (Ca) upon postdialysis administration of 5 mg etelcalcetide three times a week for 1 month. Shaded areas represent the 95% prediction interval of the median (black) from the simulations.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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

psp412106-fig-0004: Simulated time courses of change from baseline in parathyroid hormone (PTH; top) and calcium (Ca) upon postdialysis administration of 5 mg etelcalcetide three times a week for 1 month. Shaded areas represent the 95% prediction interval of the median (black) from the simulations.
Mentions: The effects of etelcalcetide administration on PTH and Ca following 5 mg TIW administration for 1 month are shown in Figure4. Following the administration of multiple doses, a significant drop (median approximately ∼50%) in PTH from baseline was predicted. The pattern and extent of PTH reduction were predicted to be maintained upon repeated TIW administration (Figure4a). Delayed and less pronounced patterns of response in Ca levels to etelcalcetide repeated administration were predicted. After the first dose, <5% change in Ca from baseline is predicted. Upon TIW administration, a gradual reduction in Ca levels from baseline is predicted. On a median level, <8% change in Ca levels was predicted at the end of 1 month of TIW administration. Moreover, simulations suggested minimal differences in the changes in predialysis Ca and PTH from baseline levels are predicted on weeks 3 and 4.

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&#8208;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.