Paricalcitol

Paricalcitol is a synthetic, biologically active vitamin D analog 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 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 normalisation of calcium and phosphorus homeostasis, may prevent or treat the metabolic bone disease associated with chronic kidney disease.

Absorption

Paricalcitol is well absorbed. In healthy adult subjects, following oral administration of paricalcitol at 0.24 micrograms/kg, the mean absolute bioavailability was approximately 72%; the maximum plasma concentration (C_max) was 0.630 ng/ml (1.512 pmol/ml) at 3 hours and area under the concentration time curve (AUC_0-∞) was 5.25 ng·h/ml (12.60 pmol•h/ml). The mean absolute bioavailability of paricalcitol in haemodialysis (HD) and peritoneal dialysis (PD) patients is 79% and 86%, respectively, with the upper bound of 95% confidence interval of 93% and 112%, respectively. A food interaction study in healthy subjects indicated that the C_max and AUC_0-∞ were unchanged when paricalcitol was administered with a high fat meal compared to fasting. Therefore, paricalcitol capsules may be taken without regard to food.

The C_max and AUC_0-∞ of paricalcitol increased proportionally over the dose range of 0.06 to 0.48 micrograms/kg in healthy subjects. Following multiple dosing, either as daily or three times a week in healthy subjects, steady-state exposure was reached within seven days.

Distribution

Paricalcitol is extensively bound to plasma proteins (>99%). The ratio of blood paricalcitol to plasma paricalcitol concentration averaged 0.54 over the concentration range of 0.01 to 10 ng/ml (0.024 to 24 pmol/ml) indicating that very little drug associated with blood cells. The mean apparent volume of distribution following a 0.24 micrograms/kg dose of paricalcitol in healthy adult subjects was 34 litres.

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.

Biotransformation

After oral administration of a 0.48 micrograms/kg dose of ³H-paricalcitol, parent drug was extensively metabolised, with only about 2% of the dose eliminated unchanged in the faeces, and no parent drug found in the urine. Approximately 70% of the radioactivity was eliminated in the faeces and 18% was recovered in the urine. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24®-hydroxy paricalcitol, while the other metabolite was unidentified. The 24®-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression.

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):

In vitro data suggest that paricalcitol is metabolised by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24®hydroxylation, as well as 24,26 and 24,28-dihydroxylation and direct glucuronidation.

Elimination

Paricalcitol is eliminated primarily via hepatobiliary excretion.

In healthy subjects, the mean elimination half-life of paricalcitol is five to seven hours over the studied dose range of 0.06 to 0.48 micrograms/kg. The degree of accumulation was consistent with the half-life and dosing frequency. Haemodialysis procedure has essentially no effect on paricalcitol elimination.

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.

Special Populations

Elderly

The pharmacokinetics of paricalcitol have not been investigated in patients greater than 65 years.

Paediatric

The pharmacokinetics of a single 3 microgram dose of paricalcitol was characterized in paediatric CKD Stage 3 (n=6) and Stage 4 (n=6) patients 10 to 16 years of age. In CKD Stage 3 paediatric patients, the C_max was 0.12 ± 0.06 ng/ml and the AUC_0-∞ was 2.63 ± 0.76 ng·h/ml. In CKD Stage 4 paediatric patients, the C_max was 0.14 ± 0.05 ng/ml and the AUC_0-∞ was 3.12 ± 0.91 ng·h/ml. The t_1/2 of paricalcitol in CKD Stage 3 and 4 paediatric patients was 13.3 ± 4.3 hour and 15.2 ± 4.4 hours, respectively.

Paricalcitol C_max, AUC, and t_1/2 values were similar between Stage 3 and Stage 4 CKD paediatric patients 10-16 years of age.

Gender

The pharmacokinetics of paricalcitol following single doses over 0.06 to 0.48 micrograms/kg dose range were gender independent.

Hepatic Impairment

In a study performed with paricalcitol intravenous, the disposition of paricalcitol (0.24 micrograms/kg) was compared in patients with mild (n=5) and moderate (n=5) hepatic impairment (in accordance with the Child-Pugh method) and subjects with normal hepatic function (n=10). The pharmacokinetics of unbound paricalcitol was similar across the range of hepatic function evaluated in this study. No dosing adjustment is required in patients with mild to moderate hepatic impairment. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.

Renal Impairment

Paricalcitol pharmacokinetics following single dose administration were characterised in patients with CKD Stage 3 or moderate renal impairment (n=15, GFR=36.9 to 59.1 ml/min/1.73 m²), CKD Stage 4 or severe renal impairment (n=14, GFR=13.1 to 29.4 ml/min/1.73 m²), and CKD 5 or end-stage renal disease [n=14 in haemodialysis (HD) and n=8 in peritoneal dialysis (PD)]. Similar to endogenous 1,25(OH)2 D3, the pharmacokinetics of paricalcitol following oral administration were affected significantly by renal impairment, as shown in Table 5. Compared to healthy subjects' results obtained, CKD Stage 3, 4, and 5 patients showed decreased CL/F and increased half-life.

Table 5. Comparison of Mean ± SD Pharmacokinetic Parameters in Different Stages of Renal Impairment versus Healthy Subjects:

* Measured at 15 nM paricalcitol concentration.

Following oral administration of paricalcitol capsules, the pharmacokinetic profile of paricalcitol for chronic kidney disease, Stages 3 to 5 was comparable. Therefore, no special dosing adjustments are required other than those recommended.

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.