Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: AbbVie Ltd., Maidenhead, SL6 4UB, UK
Pharmaco-therapeutic group: Anti-parathyroid agents
ATC code: H05BX02
Paricalcitol is a synthetic, biologically active vitamin D analogue of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Unlike calcitriol, paricalcitol is a selective vitamin D receptor (VDR) activator. Paricalcitol selectively upregulates the VDR in the parathyroid glands without increasing VDR in the intestine and is less active on bone resorption. Paricalcitol also upregulates the calcium sensing receptor (CaSR) in the parathyroid glands. As a result, paricalcitol reduces parathyroid hormone (PTH) levels by inhibiting parathyroid proliferation and decreasing PTH synthesis and secretion, with minimal impact on calcium and phosphorus levels, and can act directly on bone cells to maintain bone volume and improve mineralization surfaces. Correcting abnormal PTH levels, with normalization of calcium and phosphorus homeostasis, may prevent or treat the metabolic bone disease associated with chronic kidney disease.
The safety and effectiveness of paricalcitol injection were examined in a 12-week randomised, double-blind, placebo-controlled study of 29 pediatric patients, aged 5-19 years, with end-stage renal disease on hemodialysis. The six youngest paricalcitol-treated patients in the study were 5-12 years old. The initial dose of paricalcitol was 0.04 microgram/kg 3 times per week, based on baseline iPTH level of less than 500 pg/ml, or 0.08 microgram/kg 3 times a week based on baseline iPTH level of ≥500 pg/ml, respectively. The dose of paricalcitol was adjusted in 0.04 microgram/kg increments based on the levels of serum iPTH, calcium, and Ca x P. 67% of the paricalcitol -treated patients and 14% placebo-treated patients completed the trial. 60% of the subjects in the paricalcitol group had 2 consecutive 30% decreases from baseline iPTH compared with 21% patients in the placebo group. 71% of the placebo patients were discontinued due to excessive elevations in iPTH levels. No patients in either the paricalcitol group or placebo group developed hypercalcaemia. No data are available for patients under the age of 5.
The pharmacokinetics of paricalcitol have been studied in patients with chronic renal failure (CRF) requiring haemodialysis. Paricalcitol is administered as an intravenous bolus injection. Within two hours after administering doses ranging from 0.04 to 0.24 microgram/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly with a mean half-life of about 15 hours. No accumulation of paricalcitol was observed with multiple dosing. In vitro plasma protein binding of paricalcitol was extensive (>99.9%) and nonsaturable over the concentration range of 1 to 100 ng/ml.
Several unknown metabolites were detected in both the urine and faeces, with no detectable paricalcitol in the urine. These metabolites have not been characterised and have not been identified. Together, these metabolites contributed 51% of the urinary radioactivity and 59% of the faecal radioactivity.
Paricalcitol Pharmacokinetic Characteristics in CRF Patients (0.24 μg/kg dose):
| Parameter | N | Values (Mean ± SD) |
|---|---|---|
| Cmax (5 minutes after bolus) | 6 | 1850 ± 664 (pg/ml) |
| AUCo-∞ | 5 | 27382 ± 8230 (pg•hr/ml) |
| CL | 5 | 0.72 ± 0.24 (l/hr) |
| Vss | 5 | 6 ± 2 (l) |
In healthy subjects, a study was conducted with a single 0.16 microgram/kg intravenous bolus dose of 3H-paricalcitol (n=4), plasma radioactivity was attributed to parent substance. Paricalcitol was eliminated primarily by hepatobiliary excretion, as 74% of the radioactive dose was recovered in faeces and only 16% was found in urine.
No age or gender related pharmacokinetic differences have been observed in adult patients studied. Pharmacokinetic differences due to race have not been identified.
Unbound concentrations of paricalcitol in patients with mild to moderate hepatic impairment is similar to healthy subjects and dose adjustment is not necessary in this patient population. There is no experience in patients with severe hepatic impairment.
Salient findings in the repeat dose toxicology studies in rodents and dogs were generally attributed to paricalcitol’s calcaemic activity. Effects not clearly related to hypercalcaemia included decreased white blood cell counts and thymic atrophy in dogs, and altered APTT values (increased in dogs, decreased in rats). WBC changes were not observed in clinical trials of paricalcitol.
Paricalcitol did not affect fertility in male or female rats and there was no evidence of teratogenic activity in rats or rabbits. High doses of other vitamin D preparations applied during pregnancy in animals lead to teratogenesis. Paricalcitol was shown to affect foetal viability, as well as to promote a significant increase of peri-natal and post-natal mortality of newborn rats, when administered at maternally toxic doses.
Paricalcitol did not exhibit genotoxic potential in a set of in-vitro and in-vivo genotoxicity assays.
Carcinogenicity studies in rodents did not indicate any special risks for human use.
Doses administered and/or systemic exposures to paricalcitol were slightly higher than therapeutic doses/systemic exposures.
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