Regpara

Regpara Mechanism of Action

Manufacturer:

Kyowa Kirin

Distributor:

DCH Auriga - Healthcare
/
Four Star
Full Prescribing Info
Action
Pharmacology: Inhibition of Parathyroid Hormone (PTH) Secretion (In Vitro): Cinacalcet was shown to inhibit PTH secretion from the bovine parathyroid cells and human parathyroid cells dose-dependently.
Suppression of Proliferation of Parathyroid Cells: Following repeated-dose oral administration to partially nephrectomized rats, cinacalcet was shown to inhibit proliferation of parathyroid cells and thereby suppress progression of parathyroid hyperplasia.
Decrease in the Serum PTH and Calcium Levels: Following single-dose oral administration to normal rats and partially nephrectomized rats, cinacalcet was shown to decrease the serum PTH and calcium levels dose-dependently.
Suppression of Bone Disorder: In patients with secondary hyperthyroidism, bone disorder develops due to increased serum PTH. Following repeated-dose oral administration to partially nephrectomized rats, cinacalcet was shown to suppress symptoms associated with bone disorder due to increased serum PTH eg, marrow fibrosis, cortical osteoporosis and decreases in cortical done density and bone strength.
Mechanism of Action: Cinacalcet exerts its effects by acting on calcium receptors on the surface of parathyroid cells. Calcium receptors control synthesis of PTH and proliferation of parathyroid cells, as well as secretion of PTH. The drug decreases the serum PTH level by acting on calcium receptors and mainly suppressing PTH secretion. Furthermore, in repeated-dose administration, its effect of suppressing proliferation of parathyroid cells is also considered to contribute to a decrease in serum PTH level.
Pharmacokinetics: Plasma Concentration Profiles After Single Oral Administration: Single oral administration of cinacalcet at doses of 25, 50 and 100 mg during fasting condition to hemodialysis patients with secondary hyperparathyroidism (Japanese) was conducted to evaluate the pharmacokinetics of cinacalcet. The plasma concentration of cinacalcet increased dose dependently both on the non-dialysis day and dialysis day, and showed biphasic elimination. The pharmacokinetic parameters are summarized as follows and the influence of hemodialysis was not remarkable. See Figures 1 and 2, and Table 1.

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Plasma Concentration Profiles After Multiple Oral Administration: The plasma trough concentration profiles of cinacalcet after multiple oral administration to hemodialysis patients with secondary hyperparathyroidism (Japanese) were examined in a period of up to 53 weeks. No tendency of increasing or decreasing over time was observed in the trough concentration and the plasma concentration was confirmed to have reached a steady state following repeated-dose administration.
Food Effect: Single oral administration at a dose of 50 mg to healthy volunteers (Japanese) was conducted to evaluate the food-effect on the pharmacokinetics of cinacalcet. The pharmacokinetic parameters of non-fasting conditions were almost similar to those of fasting condition, suggesting that the effect of food on the pharmacokinetics of cinacalcet was small.
Protein Binding: In vitro protein-binding of cinacalcet (25-100 ng/mL) in human plasma was 96.33-97.67% in males and 94.33-97.67% in females, respectively, and no sex difference was observed. The protein binding of cinacalcet was also analyzed in special population clinical studies eg, hepatic and renal impairment population (non-Japanese). The protein binding was found to be similar among normal, hepatic impairment and renal impairment population, which was 94.9-97.1% for normal and hepatic impairment population, and 92.7-95.1% for normal and renal impairment population, respectively. Cinacalcet was considered to be bound to albumin and shown to have a high affinity to the site II.
Metabolism: Single oral administration of 14C-labelled cinacalcet at a dose of 75 mg to healthy volunteers (non-Japanese) was conducted to evaluate the metabolism of cinacalcet. Cinacalcet was extensively metabolized via N-dealkylation and oxidation of the naphthalene ring.
Excretion: The urinary excretion of unchanged drug after single oral administration to healthy volunteers (Japanese) was very low, and multiple administration of cinacalcet did not influence the excretion of unchanged drug. Following single-dose oral administration of 75 mg of 14C-labelled cinacalcet to healthy volunteers (non-Japanese), cinacalcet was confirmed to be excreted mainly in urine as metabolites.
Drug Interactions: The following clinical studies with healthy volunteers (non-Japanese) were conducted to confirm the drug-drug interactions of cinacalcet. The pharmacokinetics of cinacalcet is unaffected by the drugs that alter gastric pH (calcium carbonate). The pharmacokinetics of cinacalcet is also unaffected by the phosphate binder (sevelamer HCl). Cinacalcet has no effect on the pharmacokinetics of R and S-warfarin and pharmacodynamics of warfarin (ie, prothrombin time and the activity of clotting factor VII).
Clinical Studies: Placebo-Controlled Double-Blind Comparative Study (Hemodialysis): Cinacalcet or placebo was orally administered to 143 patients with secondary hyperthyroidism on hemodialysis (cinacalcet-treated group: 72, placebo-treated group: 71) for 14 weeks with an initial dose of 25 mg once daily, which was titrated up to 100 mg. As a result, the rate of patients in whom serum intact PTH concentrations reached the target level (≤250 pg/mL) was shown to be 51.4% in the cinacalcet-treated group, which was significantly higher than 2.8% in the placebo-treated group (X2=42.521, p<0.001).
Long-Term Administration Study (Hemodialysis): Cinacalcet was orally administered to 369 patients with secondary hyperthyroidism on hemodialysis for 1 year with an initial dose of 12.5* mg or 25 mg once daily, which was titrated up to 100 mg. As a result, its effect of decreasing the serum intact PTH concentration was maintained over a long period. When the administration was completed, the rate of patients in whom serum intact PTH concentrations reached the target level (≤250 pg/mL) was shown to be 48.2%.
*The initial dose for cinacalcet is 25 mg.
General Clinical Study (Peritoneal Dialysis): Cinacalcet was orally administered to 29 patients with secondary hyperthyroidism on peritoneal hemodialysis for 16 weeks with an initial dose of 25 mg once daily which was titrated up to 100 mg. Consequently, the rate of patients in whom serum intact PTH concentrations reached the target level (≤250 pg/mL) was shown to be 24.1% when the administration was completed. Thus, it was confirmed that cinacalcet had an effect of decreasing the serum intact PTH concentration in patients with secondary hyperthyroidism on peritoneal hemodialysis.
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