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Pharmacology: Actions/effects: (1) Inhibition of PTH Secretion (in vitro): Cinacalcet was shown to inhibit PTH secretion from bovine parathyroid cells and human parathyroid cells dose-dependently.
(2) 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.
(3) 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.
(4) 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, such as marrow fibrosis, cortical osteoporosis, and decreases in cortical bone density and bone strength.
Mechanism of Actions: 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. Cinacalcet 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.
Clinical Studies: Clinical Studies for Efficacy and Safety: Phase III study in Japan (hemodialysis): Cinacalcet or placebo was orally administered to 143 patients with secondary hyperparathyroidism 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 or less) 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).
The frequency of adverse reactions was 73.6% (53/72 cases). The main adverse reactions were nausea 33.3% (24/72), stomach discomfort 22.2% (16/72), vomiting 19.4% (14/72), malaise 9.7% (7/72) and dyspepsia 8.3% (6/72).
Phase II/III studies in Japan (hemodialysis): The results of phase II/III studies in Japan of cinacalcet in 369 patients with secondary hyperparathyroidism undergoing hemodialysis were as follows: In 65 patients with secondary hyperparathyroidism undergoing hemodialysis, cinacalcet was started at the same dose as at the end of the dose-response study or lower. The dose was adjusted up to 100 mg and orally administered for 44 weeks. As a result, the rate of patients in whom serum intact PTH concentrations reached the target level (250 pg/ml or less) at the end of administration was 43.1%.
The frequency of adverse reactions was 70.8% (46/65 cases). The main adverse reactions were nausea 18.5% (12/65), abdominal distension 16.9% (11/65), stomach discomfort 13.8% (9/65), anorexia 12.3% (8/65), and upper abdominal pain, gastrointestinal upset, vomiting and decreased appetite 7.7% each (5/65).
Cinacalcet was orally administered to 105 patients with secondary hyperparathyroidism undergoing hemodialysis for 52 weeks with an initial dose of 12.5 mgNote 1) 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 or less) at the end of administration was 43.8%.
The frequency of adverse reactions was 84.8% (89/105 cases). The main adverse reactions were stomach discomfort 22.9% (24/105), hypocalcemia 21.9% (23/105), nausea 15.2% (16/105), electrocardiogram QT corrected interval prolonged 13.3% (14/105), and anorexia 11.4% (12/105).
Cinacalcet was orally administered to 199 patients with secondary hyperparathyroidism undergoing hemodialysis for 52 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 or less) at the end of administration was 57.8%.
The frequency of adverse reactions was 72.5% (145/200 cases). The main adverse reactions were stomach discomfort 21.5% (43/200), nausea 14% (28/200), vomiting 9.5% (19/200), hypocalcemia 9.0% (18/200), and anorexia 7.5% (15/200).
Note 1) The initial dose for secondary hyperparathyroidism in patients undergoing maintenance dialysis is 25 mg of cinacalcet once daily.
Phase III study in Japan (peritoneal dialysis): Cinacalcet was orally administered to 29 patients with secondary hyperparathyroidism 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 or less) 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 hyperparathyroidism on peritoneal hemodialysis.
The frequency of adverse reactions was 75.9% (22/29 cases). The main adverse reactions were nausea 41.4% (12/29), vomiting, stomach discomfort 20.7% each 6/29), anorexia 17.2% (5/29), and abdominal distension, blood calcium decreased, blood pressure decrease and hypocalcemia 6.9% each (2/29).
Pharmacokinetics: Blood level: Single administration: Healthy adult subjects: Single oral administration of cinacalcet at doses of 25, 50, and 100 mg during fasting condition to healthy adult subjects was conducted to evaluate the pharrnacokinetics of cinacalcet. The plasma concentration of cinacalcet increased dose dependently, and showed biphasic elimination. The pharmacokinetic parameters are summarized as follows. (See Figure 1 and Table 2.)
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Click on icon to see table/diagram/imageHemodialysis patients: Single oral administration of cinacalcet at doses of 25, 50, and 100 mg during fasting condition to hemodialysis patients (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 no effect of hemodialysis was observed. (See Figures 2, 3 and Table 3.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imagePlasma concentration profiles and multiple oral administration: In healthy adult subjects given multiple oral doses of cinacalcet at 50 mg for 7 days, trough plasma concentration of cinacalcet reached steady state within 7 days.
The plasma trough concentration profiles of cinacalcet after multiple oral administration to hemodialysis patients (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.
Absorption: Bioavailability: The bioavailability (mean value) of cinacalcet (25 to 100 mg) was 5.1 to 28.4% (Japan) and 7.9 to 24.4% (outside Japan).
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 condition were almost similar to those of fasting condition, suggesting that the effect of food on the pharmacokinetics of cinacalcet was small.
Distribution: In vitro protein-binding of cinacalcet (25-100 ng/ml) in human plasma was 96.67-97.67% in males and 94.33-97.67% in females, respectively, and no difference between males and females was observed. The protein binding of cinacalcet was also analyzed in special population clinical studies, such as 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 94.7-97.1% 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. [See "Precautions for co-administration" under Interactions].
Metabolism: Single oral administration of 14C-labelled cinacalcet at a dose of 75 mg to non-Japanese healthy adult subjects was conducted to evaluate the metabolism of cinacalcet. Cinacalcet was extensively metabolized via N-dealkylation and oxidation of 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 to the excretion of unchanged drug. Following single-dose oral administration of 75 mg of 14C-labelled cinacalcet to non-Japanese healthy adult subjects, cinacalcet was confirmed to be excreted mainly in urine as metabolities.
Patients with Specific Backgrounds: Patients with hepatic impairment: When the pharmacokinetics of a single oral administration of 50 mg of cinacalcet was examined in healthy subjects and patients with hepatic impairment under fasting condition, AUC increased 2.4-fold and 4.2-fold, respectively, in patients with moderate and advanced hepatic impairment by the Child-Pugh classification, compared to subjects with normal liver function. The AUC in patients with mild hepatic impairment by the Child-Pugh classification was similar to subjects with normal hepatic function. [See "Patients with Complication or History of Diseases, etc.'' under Precautions].
Drug interactions: No changes were observed in the pharmacokinetics of cinacalcet in combination with a drug which changes gastric pH (calcium carbonate) or a phosphorus adsorbent (sevelamer hydrochloride) (data from non-Japanese).
Cinacalcet has no effect on the pharmacokinetics of R and S-warfarin and pharmacodynamics of warfarin (i.e. prothrombin lime and the activity of clotting factor VII).
