Pharmacological action Zemplar 1 mcg
Zemplar The drug, which regulates calcium and phosphorus. Parikaltsitol – a synthetic analogue of a biologically active vitamin D (calcitriol), whose structure has the side-chain modifications (D2) and of A (19 holes). Parikaltsitol selectively activates the vitamin D receptors in parathyroid gland without increasing the activity of vitamin D receptors in the gut and less potent effect on bone resorption. Parikaltsitol also activates receptors that are sensitive to calcium in the parathyroid glands, resulting in reduced levels of parathyroid hormone (PTH) by inhibiting parathyroid proliferation and decreasing PTH synthesis and secretion. Has minimal impact on the levels of calcium and phosphorus, can directly affect bone cells. Correcting the abnormal levels of PTH and normalizing the homeostasis of calcium and phosphorus, can prevent and treat bone diseases associated with the violation of its metabolism due to chronic kidney disease.
Secondary hyperparathyroidism is characterized by increased content of PTH, which is associated with inadequate levels of active vitamin D. This vitamin is synthesized in the skin and enters the body through food. Vitamin D is hydroxylated in series in the liver and kidneys and converted into an active form which interacts with receptors of vitamin D.
Calcitriol [1,25 (OH) 2 D3], as well as parikaltsitol – is an endogenous hormone that activates the vitamin D receptors in the parathyroid glands, intestine, kidney, and bone (thus it supports the function of parathyroid glands and calcium and phosphorus homeostasis ), as well as in many other tissues, including prostate, endothelium and immune cells. Activation of receptors is required for adequate bone formation. When kidney disease is suppressed by the activation of vitamin D, which leads to increased levels of PTH, the development of secondary hyperparathyroidism (diagnosis is established when intact PTH> 70 pg / ml), and disruption of homeostasis of calcium and phosphorus. Reduced calcitriol was observed in the early stages of chronic kidney disease. Reduced calcitriol and elevated PTH levels, which often precede changes in serum levels of calcium and phosphorus, cause changes in the rate of metabolic processes in bone tissue and can lead to renal osteodystrophy. In patients with chronic kidney disease, reduction of PTH has a beneficial effect on bone alkaline phosphatase activity and metabolism in bone tissue and bone fibrosis. Active vitamin D therapy not only reduces the level of PTH and improves metabolic processes in bone, but also helps to prevent or eliminate other effects of vitamin D.
Pharmacokinetics Zemplar 1 mcg
Absorption
Parikaltsitol well absorbed. In healthy volunteers, while taking an oral dose of parikaltsitola 0.24 mg / kg, the absolute bioavailability is on average about 72%, Cmax in blood plasma – 0.63 ng / ml, Tmax – 3 hours, and AUC – 5.25 ng × h / ml. The average absolute bioavailability parikaltsitola in patients on hemodialysis and peritoneal dialysis, 79% and 86%, respectively. Investigation of the effect of food in healthy volunteers showed that Cmax and AUC did not change when taking parikaltsitola with fatty food, compared with its intake on an empty stomach. Thus, the reception parikaltsitola capsules can be carried out regardless of the meal.
In healthy volunteers, Cmax and AUC increased in proportion to the use of the drug in doses ranging from 0.06 to 0.48 mg / kg. After receiving repeated daily or 3 times a week, a constant concentration parikaltsitola reached within seven days, unchanged in the future. Furthermore, with repeated daily dosing of the drug in patients with chronic kidney disease stage 4, the level of AUC was slightly lower than after a single dose.
Distribution
Parikaltsitol avidly binds to plasma proteins (> 99%). In healthy volunteers, after taking the drug at a dose of 0.24 mg / kg, Vd is 34 liters. The average Vd parikaltsitola in patients with chronic kidney disease stage 3, after receiving 4 mg of the drug, and patients with chronic kidney disease stage 4 after administration of 3 mg of the drug is about 44-46 liters.
Metabolism
After oral administration at a dose of 0.48 mg / kg parent drug is largely metabolized by only 2% of the dose is excreted unchanged through the intestines, urinary parent drug is not detected. Approximately 70% of the metabolites are excreted through the intestines and 18% – by the kidneys. Systemic impact is caused, basically, the original drug. In the plasma are determined by two minor metabolite parikaltsitola. One of them is defined as 24 (R)-gidroksiparikaltsitol, while the other is not identified. 24 (R)-gidroksiparikaltsitol less active than parikaltsitol, for the suppression of PTH. These in vitro studies confirm that parikaltsitol metabolized by numerous hepatic and extrahepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product 24 (R)-hydroxylation, and the products 24.26 – 24.28 and-digidroksilirovaniya and direct glucuronidation.
Breeding
Parikaltsitol derived mainly by hepatobiliary excretion. In healthy volunteers, mean T1 / 2 parikaltsitola from 5 to 7 hours when using the drug in doses ranging from 0.06 to 0.48 mg / kg. Pharmacokinetics parikaltsitola capsules was investigated in patients with chronic kidney disease stages 3 and 4. After receiving 4 mg parikaltsitola capsules in patients with chronic kidney disease stage 3 average T1 / 2 of the drug at 17 h. The average T1 / 2 parikaltsitola in patients with chronic kidney disease stage 4 when used in doses of 3 mg at 20 h. The degree of accumulation consistent with T1 / 2 and the multiplicity of the drug. Hemodialysis does not affect the rate of excretion parikaltsitola.
Pharmacokinetics in special clinical situations
The pharmacokinetics of single dose parikaltsitola at a dose of 0.06 to 0.48 mg / kg did not depend on gender.
Pharmacokinetics parikaltsitola (0.24 mg / kg) in patients with mild and moderate hepatic impairment (according to Child-Pugh classification) compared to healthy volunteers does not change. Dose adjustment in patients with mild or moderate hepatic impairment is not required. Pharmacokinetics parikaltsitola in patients with severe hepatic impairment has not been studied.
The pharmacokinetic profile while taking parikaltsitola capsules in patients with chronic kidney disease stage 5 on hemodialysis or peritoneal dialysis is comparable to that in patients with chronic kidney disease stages 3 and 4. Thus, no special dose adjustment is required.
Indications for use of the drug Zemplar 1 mcg
- Prevention and treatment of secondary hyperparathyroidism developing chronic kidney disease stages 3 and 4, as well as in patients with chronic kidney disease stage 5 on hemodialysis or peritoneal dialysis.
Dosage regimen Zemplar 1 mcg
The drug is administered orally, with or without food.
Chronic kidney disease stages 3 and 4
The drug is administered 1 time / day. Daily or 3 times a week. In the case of the drug 3 times a week it should take no more than a day. Average weekly dose of the drug when used every day and three times a week do not differ. Despite the fact that dosing regimens are similar to the profile of therapeutic action, we recommend a daily intake of the drug, because it contributes to greater patient adherence to treatment and reduces the risk of inadvertently dosing regimen.
The starting dose
The starting dose is determined parikaltsitola baseline PTH (IPTG)
| Baseline IPTG | Dose daily intake |
Dose when taking 3 times a week * |
| ≤ 500 pg / ml | 1 mg | 2 mg |
| > 500 pg / ml | 2 mg | 4 mg |
| * Accept no more than a day | ||
Titration of dose
The dose should be adjusted individually depending on the level of IPTG in the plasma or serum, based on the data monitoring of serum levels of calcium and phosphorus.
| The level of IPTG compared to the original | Zemplara dose (in caps). | Changing the dose at intervals of 2-4 weeks | |
| With daily admission |
When administered 3 times per week 1 | ||
| Same or increased | Enlarge | 1 mg | 2 mg |
| Decreased by <30% | |||
| Decreased by ≥ 30% but ≤ 60% | Leave the old | ||
| Decreased by> 60% | Reduce 2 | 1 mg | 2 mg |
| IPTG <60 pg / ml | Reduce 2 | 1 mg | 2 mg |
| 1 – take no more than a day. 2 – if the patient receives the drug at the minimum dose daily or 3 times a week, and required dose reduction may decrease the frequency of ingestion. |
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We must carefully monitor serum levels of calcium and phosphorus after the start of parikaltsitola, during dose titration and a joint appointment with potent inhibitors of CYP3A. If hypercalcemia is detected or a stable increase of calcium and phosphorus product (Ca × P), calcium phosphate dose of drugs should be reduced or required removal of the drug. As an alternative method may reduce the dose or temporary interruption parikaltsitola treatment. In case of interruption of treatment, the drug should resume with a lower dose when serum calcium and Ca × P product reached the target values.
Chronic kidney disease stage 5
The drug is administered three times a week, no more than a day.
The starting dose
The starting dose (mg) is determined from the calculation: the starting level of IPTG (in pg / ml) / 60.
Titration of dose
The dose should be adjusted individually depending on the level of IPTG, serum levels of calcium and phosphorus. Proposed to titrate the dose parikaltsitola capsules to the following formula:
Titrated dose (mg) = IPTG level (pg / ml) according to the latest measurements (in pg / ml) / 60.
Serum levels of calcium and phosphorus should be carefully monitored after starting treatment, during dose titration and concomitant appointment of a potent inhibitor of CYP3A. If there is an increase in serum calcium and Ca × P product, and calcium phosphate patient receives the medication, the dose of the latter can be reduced, or they need to be lifting. Perhaps the use of calcium phosphate containing no drugs. If serum calcium> 11 mg / dl or Ca × P product> 70 mg2/dl2, the dose should be reduced and should be 2-4 g less than that calculated for the last time the formula iPTG/60. If you still need a dosage adjustment parikaltsitola, it can be reduced or the drug may be interrupted for as long as these parameters are not normalized.
When PTH levels approaching the desired, you may need a little dose of self-correction to achieve a stable level of PTH. In situations where control over the level of PTH, calcium or phosphorus is less common than 1 time per week, you can use a lower starting dose and smaller dose change during its titration.
The average dose of the drug when it is used 3 times a week during the first week of treatment in clinical trials was 11.2 micrograms. The average dose of the drug when used in clinical trials, 3 times per week was 6.3 micrograms. The maximum safe dose in clinical studies was 32 mcg.
Side effect Zemplar 1 mcg
Among the side effects in patients with chronic kidney disease stages 3 and 4, treated parikaltsitolom, the most frequently reported skin rashes (2% of patients).
All adverse events, both clinical and laboratory, whose connection with the admission parikaltsitola could be characterized, at least as possible, are presented by organ systems and the frequency of development. The incidence of, they are divided into the following groups: very common (≥ 1 / 10), common (≥ 1 / 100, <1 / 10), uncommon (≥ 1 / 1000, <1 / 100), rare (≥ 1 / 10 000, <1 / 1000), very rare (<1 / 10, 000), including individual cases.
Adverse reactions in patients with chronic kidney disease stages 3 and 4, described in clinical studies
Central nervous system: infrequent – dizziness.
From the digestive system: Infrequent – a perversion of taste, constipation, dry mouth, dyspepsia, gastritis, abnormal liver test results.
For the skin: Frequent – skin rash, rarely pruritus, urticaria.
With the Musculoskeletal System: Infrequent – muscle spasms of the lower extremities.
Other: rare – allergic reactions.
Adverse reactions in patients with chronic kidney disease stage 5 described in the clinical phase III study
From the digestive system: common – anorexia, diarrhea, gastro-intestinal disorders.
Central nervous system: often – dizziness.
For the skin: common – acne.
Other: often – a pain in the breast, hypercalcemia, hypocalcemia.
Adverse events reported during postmarketing observations: angioedema and laryngeal edema.
Contraindications to the use of the drug Zemplar 1 mcg
- Giipervitaminoz D;
- Hypercalcemia;
- A joint reception with phosphates or derivatives of vitamin D;
- Children up to age 18 years (clinical studies were not conducted);
- Lactation;
- Hypersensitivity to any component of the drug.
Precautions should be prescribed the drug in conjunction with cardiac glycosides.
Use of the drug ZEMPLAR in pregnancy and breastfeeding
Studies in pregnant women has not been conducted. Parikaltsitol can be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Information on breeding parikaltsitola with breast milk in females. If necessary, use during lactation, breast-feeding should be discontinued.
Cautions
Excessive suppression of PTH secretion may increase serum calcium levels and reduced metabolism in the bone. To achieve the necessary control of the physiological characteristics of the patient and the individual selection of doses.
In the event of clinically significant hypercalcemia in patients taking calcium-phosphate products, the last dose should be reduced or interrupted reception.
For the initial selection of doses, or any change in her, you should determine serum levels of calcium, phosphorus, serum or plasma levels of IPTG, at least every 2 weeks to 3 months after starting treatment parikaltsitolom in capsules or after changing the dose parikaltsitola, then – on a monthly basis for 3 months, then – every 3 months.
There were no differences in the effectiveness or safety in patients aged 65 years and older.
Use in Pediatrics
Efficacy and safety of children parikaltsitola not been studied.
Overdose Zemplar 1 mcg
Symptoms: possible hypercalcemia, hypercalciuria and hyperphosphatemia, as well as marked reduction in PTH secretion. Consumption of large amounts of calcium and phosphorus simultaneously hosting parikaltsitola may lead to similar disorders.
Treating acute accidental overdose parikaltsitola requires emergency care. If overdose is revealed through the fact of a relatively short time, can cause vomiting or perform gastric lavage, which will help prevent further absorption parikaltsitola. If the drug has already passed through the stomach, its rapid excretion from the gut may contribute to acceptance of vaseline oil. It is necessary to determine serum concentrations of electrolytes (especially calcium), rate of excretion of calcium in the urine and to evaluate the changes on the ECG, which may be associated with hypercalcemia. Such monitoring is very important for patients receiving digitalis preparations. Termination of dietary supplements containing calcium and adherence to a diet low in calcium, are also shown in a random drug overdose. Given the relatively short duration of action parikaltsitola mentioned measures may be sufficient. For the treatment of severe hypercalcemia may use drugs such as salts of phosphoric acid and corticosteroids, as well as forced diuresis.
Drug Interactions Zemplar 1 mcg
Results of in vitro studies suggest that parikaltsitol at concentrations up to 50 nM (21 ng / ml) (approximately 20 times higher than concentrations observed after administration of the maximum dose studied) have no inhibitory effect on CYP3A, CYP1A2, CYP2A6, CYP2B6 , CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1. In experiments with fresh hepatocyte culture parikaltsitol at concentrations up to 50 nM caused an increase in the activity of CYP2B6, CYP2C9, or CYP3A in less than 2 times, while under the influence of inducers of these isoenzymes (positive control), it increased to 6-19 times. Consequently, parikaltsitol should not inhibit or induce the clearance of drugs metabolized by the action of these enzymes.
Pharmacokinetic interaction between parikaltsitolom capsules (16 mg) and omeprazole (40 mg orally) was studied in cross-sectional study in healthy volunteers. Pharmacokinetics parikaltsitola with his co-administered with omeprazole does not change.
In healthy volunteers, Cmax parikaltsitola by coadministration with ketoconazole changed minimally, AUC increased approximately twofold. The average T1 / 2 of 9.8 h parikaltsitola, with concomitant ketoconazole – 17 hours should be taken while appointing parikaltsitola and ketoconazole or other known inhibitors of CYP3A4.
