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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.


Goodness‐of‐fit plots for the final pharmacokinetic/pharmacodynamic (PK/PD) model. (a) Parathyroid hormone (PTH) and (b) calcium (Ca). In both cases: upper left, observed vs. population predicted concentrations; upper right, observed vs. individual predictions; middle left, conditional weighted residuals vs. population predicted concentrations; middle right, conditional weighted residuals vs. time; bottom left, normalized predicted distribution errors vs. population predicted concentrations; and bottom right, normalized predicted distribution errors vs. time.
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psp412106-fig-0002: Goodness‐of‐fit plots for the final pharmacokinetic/pharmacodynamic (PK/PD) model. (a) Parathyroid hormone (PTH) and (b) calcium (Ca). In both cases: upper left, observed vs. population predicted concentrations; upper right, observed vs. individual predictions; middle left, conditional weighted residuals vs. population predicted concentrations; middle right, conditional weighted residuals vs. time; bottom left, normalized predicted distribution errors vs. population predicted concentrations; and bottom right, normalized predicted distribution errors vs. time.

Mentions: IIV was successfully estimated for s, Ki, PTH0, and Ca0. The estimated extent of IIV was moderate for s, Ki, baseline PTH, and low for baseline Ca. Additionally, estimating IIVs on the residual error magnitude for Ca and PTH resulted in a clear improvement in model fit. The covariance between IIV estimated on PTH0 and Ca0 was included in the model and resulted in improvement of fit. All PD parameters were estimated with good precision (relative standard error % <30%). The shrinkage on s, Ki, baseline PTH, and baseline Ca were 33%, 24%, 1.8%, and 3.5%, respectively. Parameter estimates and the corresponding precisions are provided in Table2. Figure2 shows the goodness‐of‐fit plots for the base structural model. There was acceptable agreement between the observed and the predicted concentrations. The conditional weighted residuals and normalized prediction distribution errors suggested the absence of time‐dependent PTH and Ca change. Residual variability was low (<20%) for Ca, but moderate for PTH (∼50%). Higher IIV was estimated for the remaining PD parameters (slope and Ki).


Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis
Goodness‐of‐fit plots for the final pharmacokinetic/pharmacodynamic (PK/PD) model. (a) Parathyroid hormone (PTH) and (b) calcium (Ca). In both cases: upper left, observed vs. population predicted concentrations; upper right, observed vs. individual predictions; middle left, conditional weighted residuals vs. population predicted concentrations; middle right, conditional weighted residuals vs. time; bottom left, normalized predicted distribution errors vs. population predicted concentrations; and bottom right, normalized predicted distribution errors vs. time.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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

psp412106-fig-0002: Goodness‐of‐fit plots for the final pharmacokinetic/pharmacodynamic (PK/PD) model. (a) Parathyroid hormone (PTH) and (b) calcium (Ca). In both cases: upper left, observed vs. population predicted concentrations; upper right, observed vs. individual predictions; middle left, conditional weighted residuals vs. population predicted concentrations; middle right, conditional weighted residuals vs. time; bottom left, normalized predicted distribution errors vs. population predicted concentrations; and bottom right, normalized predicted distribution errors vs. time.
Mentions: IIV was successfully estimated for s, Ki, PTH0, and Ca0. The estimated extent of IIV was moderate for s, Ki, baseline PTH, and low for baseline Ca. Additionally, estimating IIVs on the residual error magnitude for Ca and PTH resulted in a clear improvement in model fit. The covariance between IIV estimated on PTH0 and Ca0 was included in the model and resulted in improvement of fit. All PD parameters were estimated with good precision (relative standard error % <30%). The shrinkage on s, Ki, baseline PTH, and baseline Ca were 33%, 24%, 1.8%, and 3.5%, respectively. Parameter estimates and the corresponding precisions are provided in Table2. Figure2 shows the goodness‐of‐fit plots for the base structural model. There was acceptable agreement between the observed and the predicted concentrations. The conditional weighted residuals and normalized prediction distribution errors suggested the absence of time‐dependent PTH and Ca change. Residual variability was low (<20%) for Ca, but moderate for PTH (∼50%). Higher IIV was estimated for the remaining PD parameters (slope and Ki).

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.