Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands
Pharmacotherapeutic group: Calcium homeostasis, anti-parathyroid agents
ATC code: H05BX01
The calcium sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Cinacalcet is a calcimimetic agent which directly lowers PTH levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.
Reductions in PTH levels correlate with cinacalcet concentration.
After steady state is reached, serum calcium concentrations remain constant over the dosing interval.
Three, 6-month, double-blind, placebo-controlled clinical studies were conducted in ESRD patients with uncontrolled secondary HPT receiving dialysis (n=1,136). Demographic and baseline characteristics were representative of the dialysis patient population with secondary HPT. Mean baseline iPTH concentrations across the 3 studies were 733 and 683 pg/mL (77.8 and 72.4 pmol/L) for the cinacalcet and placebo groups, respectively. 66% of patients were receiving vitamin D sterols at study entry, and >90% were receiving phosphate binders. Significant reductions in iPTH, serum calcium-phosphorus product (Ca x P), calcium, and phosphorus were observed in the cinacalcet-treated patients compared with placebo-treated patients receiving standard of care, and the results were consistent across the 3 studies. In each of the studies, the primary endpoint (proportion of patients with an iPTH ≤250 pg/mL (≤26.5 pmol/L)) was achieved by 41%, 46%, and 35% of patients receiving cinacalcet, compared with 4%, 7%, and 6% of patients receiving placebo. Approximately 60% of cinacalcet-treated patients achieved a ≥30% reduction in iPTH levels, and this effect was consistent across the spectrum of baseline iPTH levels. The mean reductions in serum Ca x P, calcium, and phosphorus were 14%, 7% and 8%, respectively.
Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment. Cinacalcet decreased iPTH and Ca x P, calcium and phosphorus levels regardless of baseline iPTH or Ca x P level, dialysis modality (PD versus HD), duration of dialysis, and whether or not vitamin D sterols were administered.
Reductions in PTH were associated with non-significant reductions of bone metabolism markers (bone specific alkaline phosphatase, N-telopeptide, bone turnover and bone fibrosis). In post-hoc analyses of pooled data from 6 and 12 months clinical studies, Kaplan-Meier estimates of bone fracture and parathyroidectomy were lower in the cinacalcet group compared with the control group.
Investigational studies in patients with CKD and secondary HPT not undergoing dialysis indicated that cinacalcet reduced PTH levels to a similar extent as in patients with ESRD and secondary HPT receiving dialysis. However, efficacy, safety, optimal doses and treatment targets have not been established in treatment of predialytic renal failure patients. These studies show that CKD patients not undergoing dialysis treated with cinacalcet have an increased risk for hypocalcaemia compared with cinacalcet-treated ESRD patients receiving dialysis, which may be due to lower baseline calcium levels and/or the presence of residual kidney function.
EVOLVE (EValuation Of Cinacalcet Therapy to Lower CardioVascular Events) was a randomised, double-blind clinical study evaluating cinacalcet versus placebo for the reduction of the risk of all-cause mortality and cardiovascular events in 3,883 patients with secondary HPT and CKD receiving dialysis. The study did not meet its primary objective of demonstrating a reduction in risk of all-cause mortality or cardiovascular events including myocardial infarction, hospitalisation for unstable angina, heart failure or peripheral vascular event (HR 0.93; 95% CI: 0.85, 1.02; p=0.112). After adjusting for baseline characteristics in a secondary analysis, the HR for the primary composite endpoint was 0.88; 95% CI: 0.79, 0.97.
The efficacy and safety of cinacalcet for the treatment of secondary HPT in paediatric patients with ESRD receiving dialysis was evaluated in two randomised controlled studies and one single-arm study.
Study 1 was a double-blind, placebo-controlled study in which 43 patients aged 6 to <18 years were randomised to receive either cinacalcet (n=22) or placebo (n=21). The study consisted of a 24-week dose titration period followed by a 6-week efficacy assessment phase (EAP), and a 30-week open- label extension. The mean age at baseline was 13 (range 6 to 18) years. The majority of patients (91%) were using vitamin D sterols at baseline. The mean (SD) iPTH concentrations at baseline were 757.1 (440.1) pg/mL for the cinacalcet group and 795.8 (537.9) pg/mL for the placebo group. The mean (SD) corrected total serum calcium concentrations at baseline were 9.9 (0.5) mg/dL for the cinacalcet group and 9.9 (0.6) mg/dL for the placebo group. The mean maximum daily dose of cinacalcet was 1.0 mg/kg/day.
The percentage of patients who achieved the primary endpoint (≥30% reduction from baseline in mean plasma iPTH during the EAP; weeks 25 to 30) was 55% in the cinacalcet group and 19.0% in the placebo group (p = 0.02). The mean serum calcium levels during the EAP were within the normal range for the cinacalcet treatment group. This study was terminated early due to a fatality with severe hypocalcaemia in the cinacalcet group (see section 4.8).
Study 2 was an open-label study in which 55 patients aged 6 to <18 years (mean 13 years) were randomised to receive either cinacalcet in addition to standard of care (SOC, n=27) or SOC alone (n=28). The majority of patients (75%) were using vitamin D sterols at baseline. The mean (SD) iPTH concentrations at baseline were 946 (635) pg/mL for the cinacalcet + SOC group and 1228 (732) pg/mL for the SOC group. The mean (SD) corrected total serum calcium concentrations at baseline were 9.8 (0.6) mg/dL for the cinacalcet + SOC group and 9.8 (0.6) mg/dL for the SOC group. 25 subjects received at least one dose of cinacalcet and the mean maximum daily dose of cinacalcet was 0.55 mg/kg/day. The study did not meet its primary endpoint (≥30% reduction from baseline in mean plasma iPTH during the EAP; weeks 17 to 20). Reduction of ≥30% from baseline in mean plasma iPTH during the EAP was achieved by 22% of patients in the cinacalcet + SOC group and 32% of patients in the SOC group.
Study 3 was a 26-week, open-label, single-arm safety study in patients aged 8 months to <6 years (mean age 3 years). Patients receiving concomitant medications known to prolong the corrected QT interval were excluded from the study. The mean dry weight at baseline was 12 kg. The starting dose of cinacalcet was 0.20 mg/kg. The majority of patients (89%) were using vitamin D sterols at baseline.
Seventeen patients received at least one dose of cinacalcet and 11 completed at least 12 weeks of treatment. None had corrected serum calcium <8.4 mg/dL (2.1 mmol/L) for ages 2-5 years. iPTH concentrations from baseline were reduced by ≥30% in 71% (12 out of 17) of patients in the study.
In one study, 46 adult patients (29 with parathyroid carcinoma and 17 with primary HPT and severe hypercalcaemia who had failed or had contraindications to parathyroidectomy) received cinacalcet for up to 3 years (mean of 328 days for patients with parathyroid carcinoma and mean of 347 days for patients with primary HPT). Cinacalcet was administered at doses ranging from 30 mg twice daily to 90 mg four times daily. The primary endpoint of the study was a reduction of serum calcium of ≥1 mg/dL (≥0.25 mmol/L). In patients with parathyroid carcinoma, mean serum calcium declined from 14.1 mg/dL to 12.4 mg/dL (3.5 mmol/L to 3.1 mmol/L), while in patients with primary HPT, serum calcium levels declined from 12.7 mg/dL to 10.4 mg/dL (3.2 mmol/L to 2.6 mmol/L). Eighteen (18) of 29 patients (62%) with parathyroid carcinoma and 15 of 17 subjects (88%) with primary HPT achieved a reduction in serum calcium of ≥1 mg/dL (≥0.25 mmol/L).
In a 28 week placebo-controlled study, 67 adult patients with primary HPT who met criteria for parathyroidectomy on the basis of corrected total serum calcium (>11.3 mg/dL (2.82 mmol/L) but ≤12.5 mg/dL (3.12 mmol/L), but who were unable to undergo parathyroidectomy were included. Cinacalcet was initiated at a dose of 30 mg twice daily and titrated to maintain a corrected total serum calcium concentration within the normal range. A significantly higher percentage of cinacalcet-treated patients achieved mean corrected total serum calcium concentration ≤10.3 mg/dL (2.57 mmol/L) and ≥1 mg/dL (0.25 mmol/L) decrease from baseline in mean corrected total serum calcium concentration, when compared with the placebo-treated patients (75.8% versus 0% and 84.8% versus 5.9% respectively).
After oral administration of Mimpara, maximum plasma cinacalcet concentration is achieved in approximately 2 to 6 hours. Based on between-study comparisons, the absolute bioavailability of cinacalcet in fasted subjects has been estimated to be about 20-25%. Administration of Mimpara with food results in an approximate 50–80% increase in cinacalcet bioavailability. Increases in plasma cinacalcet concentration are similar, regardless of the fat content of the meal.
At doses above 200 mg, the absorption was saturated probably due to poor solubility.
The volume of distribution is high (approximately 1,000 litres), indicating extensive distribution. Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into red blood cells.
After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours and a terminal half-life of 30 to 40 hours. Steady state levels of cinacalcet are achieved within 7 days with minimal accumulation. The pharmacokinetics of cinacalcet does not change over time.
Cinacalcet is metabolised by multiple enzymes, predominantly CYP3A4 and CYP1A2 (the contribution of CYP1A2 has not been characterised clinically). The major circulating metabolites are inactive.
Based on in vitro data, cinacalcet is a strong inhibitor of CYP2D6, but is neither an inhibitor of other CYP enzymes at concentrations achieved clinically, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 nor an inducer of CYP1A2, CYP2C19 and CYP3A4.
After administration of a 75 mg radiolabelled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolised by oxidation followed by conjugation. Renal excretion of metabolites was the prevalent route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the faeces.
The AUC and Cmax of cinacalcet increase approximately linearly over the dose range of 30 to 180 mg once daily.
Soon after dosing, PTH begins to decrease until a nadir at approximately 2 to 6 hours post-dose, corresponding with cinacalcet Cmax. Thereafter, as cinacalcet levels begin to decline, PTH levels increase until 12 hours post-dose, and then PTH suppression remains approximately constant to the end of the once daily dosing interval. PTH levels in Mimpara clinical trials were measured at the end of the dosing interval.
There are no clinically relevant differences due to age in the pharmacokinetics of cinacalcet.
The pharmacokinetic profile of cinacalcet in patients with mild, moderate, and severe renal insufficiency, and those on haemodialysis or peritoneal dialysis is comparable to that in healthy volunteers.
Mild hepatic impairment did not notably affect the pharmacokinetics of cinacalcet. Compared to subjects with normal liver function, average AUC of cinacalcet was approximately 2-fold higher in subjects with moderate impairment and approximately 4-fold higher in subjects with severe impairment. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function. Because doses are titrated for each subject based on safety and efficacy parameters, no additional dose adjustment is necessary for subjects with hepatic impairment (see sections 4.2 and 4.4).
Clearance of cinacalcet may be lower in women than in men. Because doses are titrated for each subject, no additional dose adjustment is necessary based on gender.
The pharmacokinetics of cinacalcet was studied in paediatric patients with ESRD receiving dialysis aged 3 to 17 years of age. After single and multiple once daily oral doses of cinacalcet, plasma cinacalcet concentrations (Cmax and AUC values after normalisation by dose and weight) were similar to those observed in adult patients.
A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no significant impact of age, sex, race, body surface area, and body weight on cinacalcet pharmacokinetics.
Clearance of cinacalcet is higher in smokers than in non-smokers, likely due to induction of CYP1A2-mediated metabolism. If a patient stops or starts smoking, cinacalcet plasma levels may change and dose adjustment may be necessary.
Cinacalcet was not teratogenic in rabbits when given at a dose of 0.4 times, on an AUC basis, the maximum human dose for secondary HPT (180 mg daily). The non-teratogenic dose in rats was 4.4 times, on an AUC basis, the maximum dose for secondary HPT. There were no effects on fertility in males or females at exposures up to 4 times a human dose of 180 mg/day (safety margins in the small population of patients administered a maximum clinical dose of 360 mg daily would be approximately half those given above).
In pregnant rats, there were slight decreases in body weight and food consumption at the highest dose. Decreased foetal weights were seen in rats at doses where dams had severe hypocalcaemia. Cinacalcet has been shown to cross the placental barrier in rabbits.
Cinacalcet did not show any genotoxic or carcinogenic potential. Safety margins from the toxicology studies are small due to the dose-limiting hypocalcaemia observed in the animal models. Cataracts and lens opacities were observed in the repeat dose rodent toxicology and carcinogenicity studies, but were not observed in dogs or monkeys or in clinical studies where cataract formation was monitored. Cataracts are known to occur in rodents as a result of hypocalcaemia.
In in vitro studies, IC50 values for the serotonin transporter and KATP channels were found to be 7 and 12-fold greater, respectively, than the EC50 for the calcium-sensing receptor obtained under the same experimental conditions. The clinical relevance is unknown, however, the potential for cinacalcet to act on these secondary targets cannot be fully excluded.
In toxicity studies in juvenile dogs, tremors secondary to decreased serum calcium, emesis, decreased body weight and body weight gain, decreased red cell mass, slight decreases in bone densitometry parameters, reversible widening of the growth plates of long bones, and histological lymphoid changes (restricted to the thoracic cavity and attributed to chronic emesis) were observed. All of these effects were seen at a systemic exposure, on an AUC basis, approximately equivalent to the exposure in patients at the maximum dose for secondary HPT.
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