Cinacalcet
When ATH: H05BX01
Pharmacological action
Antiparatireoidnoe means.
Kaltsiychuvstvitelnye receptors, located on the top surface of parathyroid cells, They are the main regulator secretion of parathyroid hormone (PTG). Tsinakaltset has calcimimetic action, directly reduces the level of PTH, increasing the sensitivity of the receptor to extracellular calcium. Reduction of PTH associated with reduced calcium content in serum.
Reduction in PTH levels correlate with the concentration tsinakaltseta. Shortly after receiving tsinakaltseta PTH level begins to drop: wherein the maximum decrease occurs approximately 2-6 hr postdose, corresponding to Cmax cinacalcet. Thereafter, the concentration starts to decrease tsinakaltseta, and the level increased during PTH 12 hr postdose, and then PTH suppression remains approximately at the same level until the end of the day interval when dosing regimen 1 time / day. PTH levels in clinical studies Tsinakaltseta measured at the end of the dosing interval.
After reaching a stable phase in the serum calcium concentration remains at a constant level throughout the dosing interval of the drug.
Pharmacokinetics
Absorption
After oral administration, Cmax tsinakaltseta plasma levels achieved approximately 2-6 no. The absolute bioavailability in the fasting tsinakaltseta, established by comparing the results of different studies, It was approximately 20-25%. Admission Tsinakaltseta with food increases the bioavailability tsinakaltseta about 50-80%. Such an increase in concentration in blood plasma tsinakaltseta observed regardless of the content of fat in food.
Увеличение AUC и Cmax tsinakaltseta occurs essentially linearly in a dosage range 30-180 mg 1 time / day. At doses above 200 mg observed absorption saturation, probably due to poor solubility. Pharmacokinetic parameters tsinakaltseta not change with time.
Distribution
Css tsinakaltseta achieved within 7 days with a minimum of cumulation. There big Vd about 1000 l, indicating a broad distribution. Tsinakaltset about 97% bound to plasma proteins and is distributed at the minimum level in erythrocytes.
Metabolism
Tsinakaltset metabolised mainly with the participation isozymes CYP3A4 and CYP1A2 (the role of CYP1A2 has not been confirmed by clinical methods). The main metabolites, detected in blood, inactive. According to studies in vitro, tsinakaltset is a potent inhibitor of CYP2D6. However, at concentrations, is achieved in the clinical setting, tsinakaltset does not inhibit the activity of other isoenzymes (in t. no. CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4) and not an inducer of CYP1A2, CYP2C19 и CYP3A4. After the introduction of healthy volunteers 75 mg labeled dose radioisotope method, tsinakaltset undergoes rapid and extensive oxidative metabolism, followed by conjugation.
Deduction
T1/2 the initial phase is about 6 no, in the final phase – from 30 to 40 no.
The metabolites are mainly excreted by the kidneys: about 80% the dose found in the urine and 15% Calais.
Testimony
Secondary hyperparathyroidism in patients with end-stage renal disease, dialysis.
Hypercalcemia in patients with parathyroid carcinoma.
In a combination therapy with medications, связывающими фосфаты и/или витамин D.
Dosage regimen
The drug is recommended to be taken orally with meals or soon after meals, tsinakaltseta since bioavailability is increased by taking the drug with food. Tablets should be taken as a whole.
Secondary hyperparathyroidism
Adults and elderly patients (> 65 years)
The recommended starting dose is Tsinakaltseta 30 mg 1 time / day.
Dose adjustment should be carried out every 2-4 weeks to a maximum of 180 mg 1 time / day, whereby patients, dialysis achieved the required level of PTG range 150-300 pg / ml (15.9-31.8 mmol / l), defined by content iPTH. Determination of PTH levels should be carried out not earlier, than 12 h after dosing. In assessing the level of PTH must adhere to current guidelines.
Measurement of PTH levels should be carried out 1-4 weeks after initiation of therapy or correction dose. When you receive a maintenance dose of PTH level monitoring should be conducted about once a 1-3 of the month. To measure PTH levels can use the content of iPTH or biointaktnogo PTH (biPTG). Tsinakaltset drug therapy does not alter the relationship between the iPTH and biPTG.
During titration often necessary to monitor the level of calcium in blood serum, in t. no. through 1 week after initiation of therapy or correction dose. Upon reaching a maintenance dose level of serum calcium should be determined approximately 1 once a month. If calcium levels in the serum decreased below the normal range, you must take appropriate measures.
Concomitant therapy using drugs phosphate binders and / or vitamin D, You need to be adjusted as required.
Paraŝitovidnyh cancer glands
Adults and elderly patients (> 65 years)
The recommended starting dose is Tsinakaltseta 30 mg 2 times / day.
Dose adjustment should be carried out every 2-4 weeks following sequence changes dosage: 30 mg 2 times / day, 60 mg 2 times / day, 90 mg 2 times / day and 90 mg 3-4 times / day as needed to reduce the concentration of calcium in blood serum to ULN or below this level. The maximum dose, is used in clinical trials, was 90 mg 4 times / day.
Determining the level of serum calcium should be carried out 1 week after initiation of therapy or correction dose. Upon reaching the maintenance dose of calcium levels in the blood serum is determined every 2-3 months. After adjusting doses up to the maximum dose of the drug should be periodic monitoring of serum calcium. If it is not possible to maintain a clinically significant reduction in serum calcium, should decide on the termination of therapy.
In the treatment of patients with hepatic failure initial dose is not required to change. With care prescribe a drug to patients with hepatic failure secondary to severe. It should be carefully monitored during treatment for dose titration and long-term therapy.
Side effect
From the digestive system: Often – nausea, vomiting, anorexia; sometimes – dyspepsia, diarrhea.
From the central and peripheral nervous system: often – dizziness, paresthesia; sometimes – convulsions.
On the part of the musculoskeletal system: often – myalgia.
On the part of the endocrine system: often – a decrease in testosterone levels.
Dermatological reactions: often – rash.
Allergic reactions: sometimes – hypersensitivity reactions.
Other: often – asthenia, hypocalcemia.
Contraindications
Children and teens under 18 years;
Hypersensitivity to the drug.
Pregnancy and lactation
Clinical data on the use in pregnancy tsinakaltseta. Use of the drug during pregnancy is possible only in case, when the intended benefits to the mother outweighs the potential risk to the fetus.
Drug Interactions
Tsinakaltset is a potent inhibitor of CYP2D6. If drugs, метаболизирующиеся CYP2D6, They have a narrow therapeutic index and require individual selection of doses (flekainid, propafenone, metoprolol, desipramine, nortryptylyn, clomipramine), may require correction of the dose while taking a drug Tsinakaltset.
At the same time taking a dose tsinakaltseta 90 mg 1 time / day with desipramine (tricyclic antidepressant, метаболизирующийся CYP2D6) dose 50 mg increases the level of exposure to desipramine 3.6 times (90% CI3.0, 4.4) patients with active CYP2D6 metabolism.
Multiple oral tsinakaltseta did not affect the pharmacokinetics or pharmacodynamics of warfarin (measured by prothrombin time and factor VII).
No effect on the pharmacokinetics of R tsinakaltseta- and S-warfarin and absence autoinduction enzymes in patients following multiple dose indicates, that tsinakaltset not an inducer of CYP3A4, CYP1A2 или CYP2C9 у человека.
