Zemplar

Zemplar is a regulator of calcium and phosphorus exchange processes.

Indications Zemplar

It is indicated for the treatment and prevention of the secondary form of hyperparathyroidism, which develops with grade 3 or 4 renal pathologies (chronic form), and also with grade 5 chronic renal pathologies in patients undergoing peritoneal dialysis or hemodialysis procedures.

[ 1 ], [ 2 ]

Release form

Available in capsule form. One blister contains 7 capsules. One package contains 4 blister strips.

[ 3 ], [ 4 ]

Pharmacodynamics

Paricalcitol is an artificial analogue of bioactive calciferol – calcitrol. Its structure contains modifications of the A-type ring (19-nor), as well as the D2-type side chain, which are the cause of organ and tissue selectivity of the substance. Paricalcitol selectively activates calciferol receptors (PBD) inside the parathyroid glands, without increasing the intestinal activity of PBD, and does not actively affect the resorption process inside bone tissues.

In addition, the active ingredient activates calcium receptors inside the parathyroid glands, which subsequently reduces PTH levels (by suppressing parathyroid cell proliferation and weakening the secretion and binding of PTH). It has little effect on phosphorus and calcium levels, but directly affects cells inside bone tissue. It stabilizes calcium-phosphorus homeostasis and corrects pathological PTH levels – this allows paricalcitol to prevent the development of bone tissue diseases (which arise due to metabolic disorders that occur in chronic renal pathologies) and to treat them.

In the secondary form of hyperparathyroidism, an increase in PTH values 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 undergoes sequential hydroxylation inside the kidneys with the liver, after which it is converted into an active form that interacts with calciferol receptors. Its active form is 1,25 (OH) 2D3. It activates the function of receptors of this vitamin inside the intestine together with the parathyroid glands, and in addition to this, bone tissue with the kidneys (all this allows it to maintain the work of the parathyroid glands, as well as the processes of calcium-phosphorus homeostasis), as well as inside many other tissues, including immune cells with the endothelium and the prostate gland. Receptors must be activated so that bone tissue formation is adequate. In the event of renal pathologies, the activation of calciferol is inhibited, resulting in an increase in the PTH level, a disorder in the homeostasis of phosphorus with calcium, and the development of a secondary form of hyperparathyroidism.

A decrease in the 1,25(OH)2D3 indicator occurs at the initial stages of chronic renal pathology. This symptom, together with an increase in the activity of PTH indicators (they often become precursors to changes in phosphorus indicators together with calcium in the serum), provokes a change in the rate of bone metabolism and can cause the appearance of renal osteodystrophy.

In people with chronic renal pathologies, a decrease in PTH values has a positive effect on the functioning of bone ALP, as well as on fibrous dysplasia and bone metabolism. At the same time, treatment using active calciferol can increase phosphorus values together with calcium. The selective action of the active substance relative to calciferol receptors allows for an effective decrease in PTH values and stabilization of bone metabolism. As a result, the consequences of insufficient activation of calciferol receptor function are prevented, without significantly affecting phosphorus and calcium values.

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

Pharmacokinetics

Paricalcitol is well absorbed: when healthy volunteers took the drug orally at a dose of 0.24 mcg/kg, the mean absolute bioavailability was approximately 72%, and the peak plasma concentration was 0.63 ng/mL, which occurred after 3 hours. The AUC0-∞ value is 5.25 ng h/mL.

The average absolute bioavailability of the active component in patients undergoing peritoneal dialysis or hemodialysis is 86% and 79%, respectively. The effect of food on the above indicators was also studied in volunteers - it was noted that they remain unchanged, which allows the drug to be taken regardless of meals.

The peak concentration and AUC0-∞ values in volunteers increased proportionally in cases of drug use in dosages of 0.06-0.48 μg/kg. As a result of repeated use every day or three times a week, the equilibrium concentration value is reached in 7 days, and then does not change. At the same time, in the case of repeated daily use by individuals with stage 4 chronic renal pathologies, the AUC0-∞ value slightly decreases compared to a single dose of the drug.

The active component is actively synthesized with plasma protein (>99%). After taking a dose of 0.24 mcg/kg, the distribution volume in the tested volunteers was 34 liters. The average value in people with chronic renal disease when taking the drug in the amount of 4 mcg (stage 3) and 3 mcg (stage 4 of the disease) is approximately 44-46 liters.

After oral administration of a dose of 0.48 mcg/kg, most of the substance is metabolized, and only 2% is excreted unchanged through the intestines. No drug residues are observed in the urine. About 70% of the breakdown products are excreted through the intestines, and another 18% through the kidneys.

The systemic effect is largely due to the parent drug. Two minor breakdown products of paricalcitol (24(R)-hydroxyparicalcitol and another that could not be identified) are found in plasma. The 24(R)-hydroxyparicalcitol component is not as active in PTH suppression as paricalcitol.

In vitro testing demonstrates that paricalcitol is metabolized by numerous extrahepatic and hepatic enzymes, including mitochondrial CYP24, and also elements of CYP3A4 with UGT1A4. The identified degradation products are substances formed after 24(R)-hydroxylation, as well as direct glucuronidation and 24,26- and 24,28-dihydroxylation.

Excretion of the active component is usually carried out by the hepatobiliary excretion method. The average half-life in volunteers was 5-7 hours when using the drug at a dosage of 0.06-0.48 mcg/kg.

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

Dosing and administration

Take orally, regardless of food intake.

In case of chronic kidney pathologies at stage 3 or 4.

The medicine should be taken once daily or three times a week.

When using the drug three times a week, it is required to drink it no more than every other day. On average, the sizes of weekly dosages when using the drug daily or three times a week will be the same. Although the regimens of administration are very similar in their profile of drug action, the daily regimen is still preferable, as it is more suitable for patients - it reduces the risk of accidentally violating the doctor's prescribed regimen.

For renal pathologies (chronic form) stage 5.

Prescription: three times a day for 7 days – 1 capsule every day.

Use Zemplar during pregnancy

There are no tests regarding the use of the drug by pregnant women. There is also no information on the passage of the active substance into breast milk.

During pregnancy, the use of drugs is permitted only in situations where the potential benefit from treatment outweighs the possibility of developing adverse reactions in the fetus.

If it is necessary to take the medication during the lactation period, breastfeeding should be discontinued for the duration of treatment.

Contraindications

Among the contraindications of the drug:

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

Caution is required when combined with cardiac glycosides.

[ 13 ]

Side effects Zemplar

The most common adverse drug reaction in patients with stage 3 or 4 chronic kidney disease is a skin rash.

Clinical trials have shown that the above group of patients may also experience the following adverse effects:

• General: Allergies rarely develop;
• nervous system organs: dizziness occurs infrequently;
• digestive system organs: dry mouth, gastritis, and also dyspeptic symptoms, constipation, imbalance in liver transaminase levels rarely appear;
• skin: rashes often occur, more rarely – urticaria and itching;
• Muscle and bone system: leg muscle cramps rarely occur;
• sensory organs: taste bud disorders rarely develop.

Phase 3 clinical testing has shown that people with stage 5 chronic kidney disease may experience the following side effects:

• digestive system organs: diarrhea, anorexia, and in addition gastrointestinal disorders often develop;
• nutritional and metabolic disorders: hypo- or hypercalcemia often occurs;
• skin: acne often appears;
• nervous system organs: dizziness often occurs;
• others: breast pain often develops.

Overdose

In case of drug overdose, hypercalciuria, hypercalcemia or hyperphosphatemia may develop, and in addition, a significant decrease in PTH secretion. When consuming phosphorus and calcium in high doses together with the use of paricalcitol, similar disorders may develop.

In case of accidental acute overdose, emergency care is required. If a large dose of the drug is taken within a short period of time, vomiting may be induced or gastric lavage may be performed - this will prevent further absorption of the active component of the drug. If the drug passes through the stomach, it can be quickly excreted from the intestines using Vaseline oil. In addition, it is necessary to determine the concentration of electrolytes in the serum (especially calcium), as well as the rate of calcium excretion with urine, and at the same time monitor changes in ECG readings, because they may be due to hypercalcemia. Such monitoring is extremely necessary for people taking digitalis drugs.

Also in such situations it is necessary to stop using calcium-containing food supplements and follow a diet with the consumption of products with a low percentage of calcium. Since paricalcitol has a rather short-term effect, the above methods may be enough to get rid of the disorder. But to eliminate a severe form of hypercalcemia, drugs such as GCS and salts of orthophosphoric acids may be needed, and in addition - a forced diuresis procedure.

[ 14 ]

Interactions with other drugs

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

A cross-over test was conducted in healthy volunteers to identify interactions between Zemplar (16 mcg) and omeprazole (40 mg orally). No changes in the pharmacokinetics of the drug were observed with this combination.

When used in combination with ketoconazole, volunteers show minimal changes in the peak concentration of paricalcitol, and the AUC0-∞ increases approximately 2-fold. The average half-life of paricalcitol is 9.8 hours, and in the case of combination with ketoconazole - 17 hours. Zemplar should be combined with caution with this drug and other inhibitors of the CYP3A4 element.

[ 15 ]

Storage conditions

The medicine is kept in standard conditions for medicines, inaccessible to small children. Freezing is prohibited. Temperature – within 15-25°C.

Shelf life

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