Parikalьcitol

When ATH: A11CC07

Pharmacological action

Means, regulates calcium and phosphorus metabolism, a synthetic analogue of calcitriol (biologically active vitamin D). Paricalcitol has biological action by interacting with receptors of vitamin D, which leads to selective activation response, mediated in this vitamin. Vitamin D and paricalcitol reduce parathyroid hormone levels by inhibiting its synthesis and secretion. In the early stages of chronic kidney disease is observed reduction of calcitriol.

Secondary hyperparathyroidism is characterized by an increase in the content of parathyroid hormone (PTG), It is associated with inadequate levels of active vitamin D. This vitamin is synthesized in the skin and enters the body with food. Vitamin D is sequentially hydroxylated in the liver and kidneys and is converted to the active form, which interacts with the vitamin D receptor.

Calcitriol [1,25(IT)2 D3] – endogenous hormones, which activates vitamin D receptors in the parathyroid glands, intestine, kidney and bone (thanks to this feature it supports the parathyroid glands and calcium and phosphorus homeostasis), as well as in many other tissues, including prostate, endothelium and immune cells. Receptor activation is necessary for normal bone formation. When kidney disease inhibits the activation of vitamin D, resulting in increased levels of PTH, the development of secondary hyperparathyroidism and disturbance of homeostasis of calcium and phosphorus. Reduced levels of calcitriol and elevated PTH, which often precede changes in plasma levels of calcium and phosphorus, cause changes in bone turnover rate, and may lead to the development of renal osteodystrophy. In patients with chronic kidney disease reduction in PTH has a beneficial effect on the activity of bone alkaline phosphatase, metabolism in bone and bone fibrosis. The active vitamin D therapy not only reduces the PTH level and improves metabolic processes in bone, but also helps to prevent or eliminate other consequences of vitamin D deficiency.

Pharmacokinetics

After the on / in bolus doses of paricalcitol 0.04 ug / kg to 0.24 ug / kg drug concentration decreases rapidly during 2 no, subsequently drug concentration decreases linearly, with an average T1 / 2 of about 15 no. Repeated use of paricalcitol signs of accumulation were observed.

Plasma protein binding is high – more 99%. In healthy people, Vd at steady state is approximately 23.8 l. In patients with chronic kidney disease in the terminal stage, receiving hemodialysis or peritoneal dialysis, Vd at a dose of paricalcitol 0.24 ug / kg averages 31-35 l.

Urine and feces are determined by several metabolites paricalcitol. In urine, unchanged paricalcitol was not found. Paricalcitol is metabolized by the action of enzymes in liver and extrahepatic, including mitochondrial CYP24, а также CYP3A4 и UGT1A4. Identified metabolites include products 24(R)-hydroxylation (plasma is in low concentrations), and 24,26- and 24,28-dihydroxylation and direct glyukuronirovaniya. Paricalcitol has no inhibitory effect on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 или CYP3A в концентрациях до 50 nM (21 ng / ml). At similar concentrations of paricalcitol Activity CYP2B6, CYP2C9 and CYP3A4 increases less than 2 times.

Paricalcitol derived by biliary excretion. In healthy people, about 63% active compound through the intestine and output 19% kidney. When used in doses from 0.04 to 0.16 ug / kg T1 / 2 paricalcitol healthy volunteers averaging 5-7 no. In patients with chronic kidney disease showed a reduction in end-stage clearance and increased T1 / 2 compared with healthy people.

Testimony

Prevention and treatment of secondary hyperparathyroidism, developing chronic renal failure (chronic kidney disease in the terminal stage).

Dosage regimen

Enter the I / O through a catheter for hemodialysis. In the absence of a hemodialysis catheter paricalcitol can be administered slowly in / for at least 30 sec, to minimize pain on infusion.

The starting dose is determined individually by a special scheme based on body weight or PTH levels.

Side effect

Cardio-vascular system: often – tachycardia.

From the digestive system: dry mouth, gastrointestinal bleeding, nausea, vomiting, dysgeusia.

CNS: dizziness, headache.

The respiratory system: pneumonia.

Allergic reactions: rarely – hives, angioedema, laryngeal edema.

Dermatological reactions: rash, itch.

Other: swelling, chills, malaise, fever, flu, sepsis.

Contraindications

Гипервитаминоз D; co-administration with phosphates or derivatives of vitamin D; hypercalcemia; Children up to age 18 years (clinical studies have not been conducted); lactation (breast-feeding); Hypersensitivity to paricalcitol.

Pregnancy and lactation

Adequate and well-controlled clinical studies on the safety of drugs in pregnancy has not been. Paricalcitol can be used during pregnancy only when, if the potential benefit to the mother outweighs the potential risk to the fetus.

Unknown, whether paricalcitol is allocated with breast milk in humans. If necessary, use during lactation, Breastfeeding should be discontinued.

Cautions

Caution should be used in conjunction with cardiac glycosides.

During dose titration paricalcitol may require more frequent laboratory tests. When the dose is chosen, serum levels of calcium and phosphorus to be measured, at least, 1 once a month. PTH levels in serum or plasma is recommended to control every 3 Months. For reliable analysis of biologically active PTH in patients with chronic kidney disease 5 stage it is recommended to use the method of the second or subsequent generation.

There were no differences in efficacy or safety of the drug in patients under the age of 65 and older 65 years.

Experience in the use of paricalcitol in children and adolescents under the age of 18 years limited.

Drug Interactions

In the study of the interaction of ketoconazole and paricalcitol ingestion has been shown, which causes an increase in ketoconazole AUC paricalcitol about 2 times. Paricalcitol is partially metabolized by the action of isoenzyme CYP3A, Ketoconazole is a potent inhibitor of isozyme, therefore caution is required with concomitant use of paricalcitol with ketoconazole or other potent inhibitors of CYP3A isoenzyme.

Hypercalcemia of any origin enhances intoxication cardiac glycosides (In a joint application requires caution).