Cinacalcet

Pharmaceuticals -> Systemic hormonal preparations, excluding sex hormones and insulins -> Calcium homeostasis

Pharmaceuticals -> Listed in ZINC15

log Kow = 6.8 /Estimated/

6.5

Slightly soluble (in HCl salt form)

In water, 9.2X10-2 mg/L at 25 °C /Estimated/

5.59e-05 g/L

Breast Feeding; Lactation; Milk, Human; Calcium-Regulating Hormones and Agents; Calcimimetic Agents

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

White to off white crystalline solid. Soluble in methanol. Soluble in 95% ethanol. Slightly soluble in water. /Hydrochloride/

Hydroxyl radical reaction rate constant = 8.3X10-11 cu cm/molec-sec at 25 °C /Estimated/

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P264, P264+P265, P270, P280, P301+P317, P302+P352, P305+P351+P338, P318, P321, P330, P332+P317, P337+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl cinacalcet hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Cinacalcet Hydrochloride/

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Potential pharmacokinetic interaction (increased plasma concentrations of drugs metabolized principally by cytochrome P450 (CYP) isoenzyme 2D6). In patients receiving cinacalcet 25 or 100 mg concurrently with amitriptyline hydrochloride 50 mg, exposure to amitriptyline and its active metabolite, norrtiptyline, was increased by 20%. Dosage adjustment maybe required if cinacalcet is administered concomitantly with ta drug that has a narrow therapeutic index and is metabolized principally by CYP2D6 (e.g., flecainide, vinblastine, thioridazine, most tricyclic antidepressants).

Potential pharmacokinetic interaction (increased plasma cinacalcet concentrations) with potent CYP3A4 inhibitors (e.g. ketoconazole, erythromycin, itraconazole). Approximate 2.3-fold increase in cinacalcet exposure reported following concomitant administration of a single 90-mg dose of cinacalcet with ketoconazole (200 mg twice daily for 7 days). Cinacalcet dosage adjustment may be required and PTH and serum calcium concentrations should be closely monitored if a potent CYP3A4 inhibitor is initiated or discontinued.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 9.9X10+6(SRC), determined from a structure estimation method(2), indicates that cinacalcet is expected to be immobile in soil(SRC). Volatilization of cinacalcet from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.2X10-7 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Cinacalcet is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.6X10-7 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 9.9X10+6(SRC), determined from a structure estimation method(2), indicates that cinacalcet is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.2X10-7 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). The estimated pKa of the amine of cinacalcet is 8.4(5), indicating that this compound will partially exist in cation form in the environment and cations generally adsorb more strongly to suspended solids and sediment than their neutral counterparts(6). According to a classification scheme(7), an estimated BCF of 3.3X10+4(SRC), from an estimated log Kow of 6.8(8) and a regression-derived equation(9), suggests the potential for bioconcentration in aquatic organisms is very high(SRC). Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), cinacalcet, which has an estimated vapor pressure of 1.6X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase cinacalcet is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4.6 hours (SRC), calculated from its rate constant of 8.3X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase cinacalcet may be removed from the air by wet and dry deposition(SRC). Cinacalcet may contain chromophores that would be expected to absorb light at wavelengths >290 nm and may be susceptible to direct photolysis by sunlight however the rate of this reaction is not known(SRC).

The common adverse drug reactions of cinacalcet are nausea and vomiting. In some cases, up to one-third of patients who take cinacalcet may experience this adverse drug reaction. Dizziness, diarrhea, and decreased appetite are other adverse effects of this medication. Cinacalcet can cause hypocalcemia. The patients on this medication need to be closely followed for common symptoms associated with hypocalcemia, including tingling, muscle twitching, cramps, changes in mood, or irritability. On the electrocardiogram (ECG), a prolonged QT interval may be present. Patients with a history of congenital long QT syndrome, family history of long QT syndrome, and other conditions that predispose patients to QT interval prolongation may be at increased risk. Oversuppresion of PTH can cause adynamic bone disease.

Using a structure estimation method based on molecular connectivity indices(1), the Koc for cinacalcet can be estimated to be 9.9X10+6(SRC). According to a classification scheme(2), this estimated Koc value suggests that cinacalcet is expected to be immobile in soil. The estimated pKa of the amino group of cinacalcet is 8.4(3), indicating that this compound will partially exist in cation form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(4).

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

cinacalcet

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 3.3X10+4 was calculated for cinacalcet(SRC), using an estimated log Kow of 6.8(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC).

The Henry's Law constant for cinacalcet is estimated as 2.2X10-7 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that cinacalcet is expected to be essentially nonvolatile from water surfaces(2). Cinacalcet is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.6X10-7 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In mice and rat studies with cinacalcet exposures of up to 2 times those resulting with a human oral dose of 180 mg per day based on AUC comparison, no increased incidence of tumors was observed .

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No effects were observed in male or female rat fertility with exposures up to 3 times those resulting with a human oral dose of 180 mg per day based on AUC comparison when given to female rats beginning two weeks before mating and continuing through gestation day 7 and when given to male rats 4 weeks prior to mating, during mating (three weeks) and 2 weeks postmating. However, at 75 mg per kg of body weight per day, there were slight adverse effects of slight decreases in body weight and food consumption in male and female rats .

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In pregnant female rats, decreased fetal body weights were observed at all doses (less than one to four times a human oral dose of 180 mg per day based on AUC comparison in conjunction with maternal toxicity (decreased food consumption and baby weight gain)). In pregnant rats given doses with exposures less than with a human therapeutic dose of 180 mg per day based on AUC comparison, no adverse fetal or pup (post-weaning) effects were observed. Higher doses with exposures two to three times a human oral dose of 180 mg per day based on AUC comparisons were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body weight gain .

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In pregnant female rabbits given oral doses with exposures less than with a human oral dose of 180mg per day based on AVC comparisons, no fetal adverse effects were observed. Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg per kg of body weight per day. Cinacalcet has been shown to cross the placental barrier in rabbits .

For more Non-Human Toxicity Excerpts (Complete) data for CINACALCET (6 total), please visit the HSDB record page.

In 3 clinical studies of chronic kidney disease (CKD) patients on dialysis, 5% of the patients in the cinacalcet and placebo groups reported a history of seizure disorder at baseline. During the trials, seizures (primarily generalized or tonic-clonic) were observed in 1.4% of cinacalcet-treated patients and 0.4% of placebo-treated patients. Five of the 9 cinacalcet-treated patients had a history of seizure disorder and 2 were receiving antiseizure medication at the time of their seizure. Both placebo-treated patients had a history of seizure disorder and were receiving antiseizure medication at the time of their seizure. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Therefore, closely monitor serum calcium levels in patients receiving cinacalcet, particularly in patients with a history of a seizure disorder.

The rate constant for the vapor-phase reaction of cinacalcet with photochemically-produced hydroxyl radicals has been estimated as 8.3X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4.6 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Cinacalcet is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). Cinacalcet may contain chromophores that would be expected to absorb light at wavelengths >290 nm and may be susceptible to direct photolysis by sunlight however the rate of this reaction is not known(SRC).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl cinacalcet hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Cinacalcet Hydrochloride/

H05BX01

H - Systemic hormonal preparations, excl. sex hormones and insulins

QH - Systemic hormonal preparations, excl. sex hormones and insulin

Cinacalcet is a drug that acts as a calcimimetic (i.e. it mimics the action of calcium on tissues). Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis. Cinacalcet reduces calcium levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium.

Cinacalcet directly lowers parathyroid hormone levels by increasing the sensitivity of the calcium sensing receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.

Calcimimetics are positive allosteric modulators that activate the parathyroid calcium receptor (CaR) and thereby immediately suppress parathyroid hormone (PTH) secretion. Preclinical studies have demonstrated that calcimimetics inhibit PTH secretion and parathyroid gland hyperplasia and ameliorates bone qualities in rats with chronic renal insufficiency. Clinical trials with cinacalcet hydrochloride, a calcimimetic compound, have shown that calcimimetics possess lowering effects not only on serum PTH levels but also on serum phosphorus levels in dialysis patients with secondary hyperparathyroidism (2HPT). Thus, calcimimetics have considerable potential as an innovative medical approach to manage 2HPT. In this review, the similarities are extrapolated between the pharmacological effect of calcimimetics on the set point of Ca-regulated PTH secretion and clinical observations in affected subjects with activating CaR mutations.

Cinacalcet is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in PTH levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity, resulting in cortical bone resorption and bone marrow fibrosis. The goals of treatment of secondary HPT are to lower levels of PTH, calcium, and phosphorus in the blood in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone specific alkaline phosphatase, bone turnover, and bone fibrosis. The calcium sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Cinacalcet 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.

Oral cinacalcet hydrochloride (HCl) is the first in a new class of therapeutic agents, the calcimimetics, and has a novel mechanism of action. It directly modulates the principal regulator of parathyroid hormone (PTH) secretion, namely the calcium-sensing receptor (CaR) on the chief cells in the parathyroid gland. Cinacalcet HCl reduces circulating PTH levels by increasing the sensitivity of the CaR to extracellular calcium. In three pivotal phase III, 26-week, randomised, double-blind, multicentre trials in chronic kidney disease (CKD) patients (n = 1136) on dialysis with uncontrolled secondary hyperparathyroidism (HPT), a significantly higher proportion of oral cinacalcet HCl 30-180 mg/day than placebo recipients achieved a reduction in intact PTH levels to < or =250 pg/mL. Cinacalcet HCl treatment also simultaneously lowered serum calcium and phosphorus, and calcium-phosphorous product levels. Notably, cinacalcet HCl proved effective in a broad range of CKD patients on dialysis with uncontrolled secondary HPT, regardless of disease severity, duration of dialysis treatment, dialysis modality, race, age, gender, or concurrent phosphate binder or vitamin D sterol use. Cinacalcet HCl (60-360 mg/day) also reduced elevated serum calcium levels by > or =1 mg/dL in 15 of 21 (71%) patients with parathyroid carcinoma in an open-label, multicentre, dose-titration trial. Cinacalcet HCl was generally well tolerated in clinical trials. Most treatment-emergent adverse events were mild to moderate in severity. /Cinacalcet hydrochloride/

Terminal half-life is 30 to 40 hours. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively.

The mean half life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively.

terminal half-life: 30 to 40 hours

Metabolism is hepatic by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via &szlig;-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are further conjugated with glucuronic acid.

The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after a single oral administration to mice, rats, monkeys, and human volunteers. ... The primary routes of metabolism of cinacalcet were N-dealkylation leading to carboxylic acid derivatives (excreted in urine as glycine conjugates) and oxidation of naphthalene ring to form dihydrodiols (excreted in urine and bile as glucuronide conjugates). The plasma radioactivity in both animals and humans was primarily composed of carboxylic acid metabolites and dihydrodiol glucuronides, with <1% circulating radioactivity accounting for the unchanged cinacalcet. Overall, the circulating and excreted metabolite profile of cinacalcet in humans was qualitatively similar to that observed in preclinical animal models.

Cinacalcet is metabolized by multiple cytochrome P-450 (CYP) isoenzymes, mainly CYP3A4, CYP2D6, and CYP1A2, and is a potent inhibitor of CYP2D6 in vitro.

Rapidly and extensively metabolized hepatically by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2 via oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid which are further metabolized via beta-oxidation and glycine conjugations; the oxidative N-dealkylation process also generates metabolites that contains the naphthalene ring; and oxidation of the naphthalene ring on the parent drug to form dihydrodiols which are further conjugated with glucuronic aicd. The hydrocinnamic acid metabolite was shown to be inactive at concentrations up to 10 uM in a cell-based assay measuring calcium-receptor activation. The glucuronide conjugates formed after oxidation were shown to have a potency approximately 0.003 times that of cinacalcet in a cell-based assay measuring a calcimimetic response.

UAZ6V7728S

CINACALCET

Established Pharmacologic Class [EPC] - Calcium-sensing Receptor Agonist

Mechanisms of Action [MoA] - Increased Calcium-sensing Receptor Sensitivity

Cinacalcet is a Calcium-sensing Receptor Agonist. The mechanism of action of cinacalcet is as an Increased Calcium-sensing Receptor Sensitivity.

CINACALCET

Hormones and molecules with calcium-regulating hormone-like actions that modulate OSTEOLYSIS and other extra-skeletal activities to maintain calcium homeostasis.

Small organic molecules that act as allosteric activators of the calcium sensing receptor (CaSR) in the PARATHYROID GLANDS and other tissues. They lower the threshold for CaSR activation by extracellular calcium ions and diminish PARATHYROID HORMONE (PTH) release from parathyroid cells.

Rapidly absorbed following oral administration.

Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. Renal excretion of metabolites was the primary route of elimination of radioactivity.

1000 L

The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after a single oral administration to mice, rats, monkeys, and human volunteers. In all species examined, cinacalcet was well absorbed, with greater than 74% oral bioavailability of cinacalcet-derived radioactivity in monkeys and humans. In rats, cinacalcet-derived radioactivity was widely distributed into most tissues, with no marked gender-related differences. In all animal models examined, radioactivity was excreted rapidly via both hepatobiliary and urinary routes. In humans, radioactivity was cleared primarily via the urinary route (80%), with 17% excreted in the feces. Cinacalcet was not detected in the urine in humans. ...

After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half life of 30 to 40 hours. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.

Steady-state drug levels are achieved within 7 days. The mean accumulation ratio is approximately 2 with once-daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice-daily oral administration. The AUC and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once-daily dosing of 30 to 180 mg. The volume of distribution is high (approximately 1000 L), indicating extensive distribution. Cinacalcet is approximately 93% to 97% bound to plasma proteins. The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.8 at a blood cinacalcet concentration of 10 ng/mL.

Cinacalcet is indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma. /Included in US product labeling/

MEDICATION

Cinacalcet is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. /Included in US product labeling/

Use (kg; approx.) in Germany (2009): >100