Zemplar

Zemplar is a regulator of the processes of calcium exchange with phosphorus.

Indications Zemplar

It is indicated for treatment, but in addition to prevention of the secondary form of hyperparathyroidism, which develops at the 3rd or 4th degree of renal pathologies (chronic form), and in addition, at the 5th degree of chronic renal pathologies in patients undergoing peritoneal dialysis or hemodialysis .

[1], [2]

Release form

Produced in the form of capsules. One blister contains 7 capsules. One package contains 4 blister plates.

[3], [4]

Pharmacodynamics

Paricalcitol is an artificial analogue of bioactive calciferol - calcitrol. In its structure there are modifications of ring type A (19-nor), and also side chain type D2, which are the cause of organ, as well as tissue selectivity of the substance. Paricalcitol selectively activates the calciferol (PBD) receptors inside the parathyroid glands, without increasing the intestinal activity of PBD, nor does it actively influence the resorption process inside bone tissues.

In addition, the active ingredient activates receptors that are susceptible to calcium within the parathyroid glands, which subsequently decreases PTH (by suppressing parathyroid cell multiplication and weakening PTH secretion and binding). Weakly affects the parameters of phosphorus with calcium, and with it directly affects the cells inside the bone tissue. It stabilizes the calcium-phosphorus homeostasis, and also corrects the pathological parameters of PTH - this allows the paricalcitol to prevent the development of bone tissue diseases (which arise from the disorders of their metabolism that appear in chronic kidney pathologies) and to treat them.

In the secondary form of hyperparathyroidism, an increase in PTH is observed - due to an inadequate level of the active form of calciferol. This vitamin is synthesized inside the skin and enters the body with food. Calciferol is sequentially hydroxylated inside the kidneys with the liver, and then converted into an active form interacting with the calciferol receptors. Its active form is 1.25 (OH) 2D3. It activates the function of the receptors of this vitamin inside the intestine along with the parathyroid glands, and in addition to this bone tissue with the kidneys (all this allows it to support parathyroid gland activity, as well as the calcium-phosphorus homeostasis processes), as well as a variety of other tissues, including immune cells with endothelium and prostate. The receptors need to be activated in order for the formation of bone tissue to be adequate. In the case of the appearance of renal pathologies, the activation of calciferol is inhibited, as a result of which the index of PTH increases, the homeostasis of phosphorus with calcium develops, and the secondary form of hyperparathyroidism develops.

Decrease in the index 1.25 (OH) 2D3 occurs at the initial stages of the chronic form of renal pathology. This sign, together with an increase in the activity of PTH indices (they often become precursors of changes in phosphorus levels along with calcium in the serum), provokes a change in the rate of bone metabolism and can cause osteodystrophy of the kidneys.

In people with chronic renal pathologies, the decrease in PTH indices has a positive effect on the functioning of the bone gland, and also on fibrotic dysplasia and bone metabolism. In this treatment with active calciferol can increase the phosphorus levels together with calcium. The selective action of the active substance with respect to the calciferol receptors makes it possible to effectively reduce the PTH index and stabilize the bone metabolism. As a result, the effects of insufficient activation of the function of the calciferol receptor are prevented, without significantly affecting the phosphorus and calcium values.

[5], [6], [7], [8]

Pharmacokinetics

Paricycitol has a good absorption - when oral medication was used by healthy volunteers in the amount of 0.24 μg / kg, the average absolute bioavailability was approximately 72%, and the peak concentration of plasma was 0.63 ng / ml, which came after 3 hours. The value of AUC0-∞ is 5.25 ng · h / ml.

The average absolute bioavailability of the active component in patients on peritoneal dialysis or hemodialysis is 86% and 79%, respectively. Also, volunteers examined the effect of food on the above indicators - it was noted that they remain unchanged, which allows you to take the medicine regardless of meals.

The peak concentration and AUC0-∞ in volunteers increased proportionally in cases of drug use at dosages of 0.06-0.48 μg / kg. As a result of repeated use every day or three times a week, the achievement of the equilibrium concentration index occurs within 7 days, then does not change. Along with this, in case of repeated daily use by persons with chronic renal pathologies of the 4th stage, the AUC0-∞ index decreases slightly as compared with a one-time drug intake.

The active ingredient is actively synthesized with a plasma protein (> 99%). After using a dosage of 0.24 μg / kg, the distribution volume of the volunteers tested was 34 liters. The average in people with chronic stage of renal pathology when taking drugs at a rate of 4 μg (3rd stage) and 3 μg (stage 4 of the disease) is approximately 44-46 liters.

After oral administration of a dosage of 0.48 μg / kg, most of the substance is metabolized, and only 2% are excreted unchanged through the intestine. Remains of the drug are not observed in the urine. About 70% of the decay products are excreted by the intestine, and another 18% by the kidneys.

The systemic effect is largely due to the original drug. Inside the plasma, two secondary products of the decomposition of paricylcytol (24 (R) - hydroxyparicalcitol, and another one that could not be identified) are detected. Component 24 (R) -hydroxyparacarcitol is not as active with respect to PTH suppression processes as paricalcitol.

In vitro tests demonstrate that the metabolism of paricalcitol is carried out with the participation of numerous extrahepatic and hepatic enzymes, including mitochondrial CYP24, and in addition elements of CYP3A4 with UGT1A4. Identified decay products are substances formed after 24 (R) -hydroxylation, and in addition to direct glucuronization and 24.26-, as well as 24,28-dihydroxylation.

Excretion of the active component, as a rule, is carried out by the hepatobiliary elimination method. The average half-life of volunteers was 5-7 hours with drug use at a dosage of 0.06-0.48 μg / kg.

[9], [10], [11], [12]

Dosing and administration

Apply orally, regardless of eating.

In renal pathologies in chronic form at the 3rd or 4th stage.

The medicine should be drunk once every day or three times a week.

When using drugs three times a week, you need to drink it no more than a day. On average, the sizes of weekly dosages with the use of the medicine will be the same daily or three times in 7 days. Although the regimens are very similar in their medical profile, the daily regimen is preferable, since it is more suitable for patients - it reduces the risk of an accidental disruption of the prescribing regimen prescribed by the doctor.

With renal pathologies (chronic form) of the 5th stage.

The appointment in the regime three times for 7 days - one capsule every day.

Use Zemplar during pregnancy

There were no tests of the use of the drug by pregnant women. There is also no information on the passage of the active substance into the mother's milk.

In pregnancy, use of drugs is allowed only in situations where the potential benefit of treatment exceeds the possibility of developing fetal adverse reactions.

If you need to take the medication during the lactation period, you should stop breastfeeding during the treatment.

Contraindications

Among the contraindications of drugs:

• intolerance to any of the components of the drug;
• presence of hypervitaminosis type D in the patient;
• hypercalcemia;
• combined use with phosphates or derivatives of vitamin D group;
• Children under 18 years of age (because there is no experience of use in the above category of patients).

Caution is required when combined with cardiac glycosides.

[13],

Side effects Zemplar

The most frequent adverse reaction to a drug in patients with stage 3 or stage 4 chronic renal disease is a rash on the skin.

Clinical trials have demonstrated that the above group of patients can also have such negative effects:

• general: infrequently allergies develop;
• organs of the National Assembly: infrequent dizziness appears;
• organs of the digestive system: infrequently there is dryness in the oral cavity, gastritis, and in addition dyspepsia, constipation, imbalance in the parameters of hepatic transaminases;
• skin: often there are rashes, more rarely - hives and itching;
• system of muscles and bones: infrequent cramps appear in the musculature of the legs;
• sensory organs: the disorder of taste receptors is rarely developed.

Clinical testing of the 3rd phase showed that in people with the 5th degree of chronic renal pathology such side effects are possible:

• organs of the digestive system: often develop diarrhea, anorexia, and in addition to this disorder of the gastrointestinal tract;
• malnutrition, and metabolism: often manifests hypo- or hypercalcemia;
• skin: often there is acne;
• organs of the National Assembly: dizziness often occurs;
• others: often develop pain in the mammary glands.

Overdose

In case of drug overdose, it is possible to develop hypercalciuria, hypercalcemia or hyperphosphataemia, and in addition a significant decrease in PTH secretion. When using phosphorus and calcium in high dosages together with the use of paricalcitol, similar disorders can develop.

In case of a sudden acute overdose, emergency care is necessary. If a large dose of drugs is detected after a short period of time, it is allowed to induce vomiting or perform gastric lavage - this will prevent further absorption of the active drug component. In the case of passing the drug through the stomach, it is possible to excrete it quickly from the intestine with the help of vaseline oil. In addition, it is necessary to find out the concentration of electrolytes in the serum (especially calcium), as well as the rate of calcium excretion along with the urine, and at the same time monitor the change in ECG readings, because they can be caused by hypercalcemia. Such monitoring is extremely necessary for people who take digitalis medicines.

Also in such situations it is necessary to abolish the use of calcium-containing food additives and to follow a diet with consumption of products with a low percentage of calcium. Since paricalcitol has a relatively short duration, the above methods may be sufficient to get rid of the disorder. But to eliminate the severe form of hypercalcemia, you may need drugs such as GCS and orthophosphoric acid salts, and in addition, a forced diuresis procedure.

[14]

Interactions with other drugs

According to in vitro testimony it is clear that with the concentration of the active drug component to 50 nM (21 ng / ml) (which is almost 20 times higher than the values observed after the drug was consumed as much as possible dosed), it does not slow down the activity of elements CYP3A and CYP1A2, and in addition CYP2A6 with CYP2B6 and CYP2C8, as well as CYP2C9, CYP2C19 and CYP2D6 or CYP2E1. Tests on fresh hepatocyte culture (up to 50 nM) increased the activity of CYP2B6 cells with CYP2C9 and CYP3A approximately twice, and under the influence of inducers of these isoenzymes, it was increased 6-19 times. Thus, the active component of drugs should not cause or suppress the clearance of drugs metabolized by the above enzymes.

Cross-sectional testing was conducted on healthy volunteers to identify the interaction between Zemplar (16 μg) and omeprazole (40 mg orally). Changes in the pharmacokinetics of medication with this combination are not observed.

When combined with ketonazole, the volunteers have minimal changes in the peak concentration of paricalcitol, and the AUC0-∞ index is approximately 2-fold higher. The average indicator of the half-life of paricalcitol is 9.8 hours, and in the case of combination with ketoconazole - 17 hours. It is necessary to carefully combine Zemplar with this medicine and other inhibitors of the element CYP3A4.

[15],

Storage conditions

The drug is contained in standard for medicines conditions, not available for young children. Do not freeze. The temperature is within 15-25 ° C.

Shelf life

Zemplar is suitable for use for 2 years from the date of release of the medicine.