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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.


Related in: MedlinePlus

Schematic of the pharmacokinetic/pharmacodynamic (PK/PD) model structure. Kin,PTH and Kout,PTH: the zero‐order production rate of parathyroid hormone (PTH) and the first‐order elimination rate constant for PTH, respectively. ρ0: the calcium (Ca)/calcium‐sensing receptor (CaSR) occupancy at baseline λ: a constant determining the strength of the effect of changes in ρ on PTH production Kin,Ca and Kout,Ca: the zero‐order production rate of Ca and the first‐order elimination rate for Ca, respectively. S, the slope relating changes in PTH from baseline to Ca production; Ki, the equilibrium dissociation constant for etelcalcetide at the CaSR; KD, the equilibrium dissociation constant for Ca at the CaSR; α, the cooperativity constant; Cp, etelcalcetide plasma concentration.
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psp412106-fig-0001: Schematic of the pharmacokinetic/pharmacodynamic (PK/PD) model structure. Kin,PTH and Kout,PTH: the zero‐order production rate of parathyroid hormone (PTH) and the first‐order elimination rate constant for PTH, respectively. ρ0: the calcium (Ca)/calcium‐sensing receptor (CaSR) occupancy at baseline λ: a constant determining the strength of the effect of changes in ρ on PTH production Kin,Ca and Kout,Ca: the zero‐order production rate of Ca and the first‐order elimination rate for Ca, respectively. S, the slope relating changes in PTH from baseline to Ca production; Ki, the equilibrium dissociation constant for etelcalcetide at the CaSR; KD, the equilibrium dissociation constant for Ca at the CaSR; α, the cooperativity constant; Cp, etelcalcetide plasma concentration.

Mentions: Different direct and indirect effect model structures were examined. The selected PK/PD model structure was based on the current understanding of the mechanism of action, physiological interactions, and findings from exploratory graphical analyses. The model structure is depicted in Figure1. In this model, Ca production was stimulated by increases in PTH from baseline through a linear relationship, whereas PTH production was inhibited by increases in CaSR receptor occupancy from baseline. Ca and PTH were eliminated through first‐order processes.


Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis
Schematic of the pharmacokinetic/pharmacodynamic (PK/PD) model structure. Kin,PTH and Kout,PTH: the zero‐order production rate of parathyroid hormone (PTH) and the first‐order elimination rate constant for PTH, respectively. ρ0: the calcium (Ca)/calcium‐sensing receptor (CaSR) occupancy at baseline λ: a constant determining the strength of the effect of changes in ρ on PTH production Kin,Ca and Kout,Ca: the zero‐order production rate of Ca and the first‐order elimination rate for Ca, respectively. S, the slope relating changes in PTH from baseline to Ca production; Ki, the equilibrium dissociation constant for etelcalcetide at the CaSR; KD, the equilibrium dissociation constant for Ca at the CaSR; α, the cooperativity constant; Cp, etelcalcetide plasma concentration.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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

psp412106-fig-0001: Schematic of the pharmacokinetic/pharmacodynamic (PK/PD) model structure. Kin,PTH and Kout,PTH: the zero‐order production rate of parathyroid hormone (PTH) and the first‐order elimination rate constant for PTH, respectively. ρ0: the calcium (Ca)/calcium‐sensing receptor (CaSR) occupancy at baseline λ: a constant determining the strength of the effect of changes in ρ on PTH production Kin,Ca and Kout,Ca: the zero‐order production rate of Ca and the first‐order elimination rate for Ca, respectively. S, the slope relating changes in PTH from baseline to Ca production; Ki, the equilibrium dissociation constant for etelcalcetide at the CaSR; KD, the equilibrium dissociation constant for Ca at the CaSR; α, the cooperativity constant; Cp, etelcalcetide plasma concentration.
Mentions: Different direct and indirect effect model structures were examined. The selected PK/PD model structure was based on the current understanding of the mechanism of action, physiological interactions, and findings from exploratory graphical analyses. The model structure is depicted in Figure1. In this model, Ca production was stimulated by increases in PTH from baseline through a linear relationship, whereas PTH production was inhibited by increases in CaSR receptor occupancy from baseline. Ca and PTH were eliminated through first‐order processes.

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.


Related in: MedlinePlus