Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Anti-parathyroid agents, ATC code: H05BX02.
Mechanism of Action

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 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.

Clinical Efficacy

Chronic Kidney Disease, Stages 3-4
Adult Pivotal Studies

The primary efficacy endpoint of at least two consecutive ≥ 30 % reductions from baseline iPTH was achieved by 91% of paricalcitol capsules-treated patients and 13% of the placebo patients (p<0.001). Serum bone specific alkaline phosphatase like serum osteocalcin were significantly reduced (p<0.001) in patients treated with paricalcitol capsules compared to placebo, which is associated with a correction of the high bone turnover due to secondary hyperparathyroidism. No deterioration in the kidney function parameters of estimated glomerular filtration rate (via MDRD formula) and serum creatinine was detected in paricalcitol capsules treated patients in comparison to placebo treated patients. Significantly more of paricalcitol capsules treated patients experienced a reduction in urinary protein, as measured by semi quantitative dipstick, compared to placebo treated patients.

Chronic kidney disease, Stage 5

Adult Pivotal Study
The primary efficacy endpoint of at least two consecutive ≥ 30 % reductions from baseline iPTH was achieved by 88% of paricalcitol capsules treated patients and 13% of the placebo patients (p < 0.001).

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

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 (Cmax) was 0.630 ng/ml (1.512 pmol/ml) at 3 hours and area under the concentration time curve (AUC0-∞) 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 Cmax and AUC0- were unchanged when paricalcitol was administered with a high fat meal compared to fasting. Therefore, Zemplar capsules may be taken without regard to food.

The Cmax and AUC0-∞ 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.

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(R)-hydroxy paricalcitol, while the other metabolite was 
unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression.

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(R)-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.

Special Populations

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

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 Zemplar 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 4. Compared to healthy subjects’ results obtained, CKD Stage 3, 4, and 5 patients showed decreased CL/F and increased half-life.

Table 4. Comparison of Mean ± SD Pharmacokinetic Parameters in Different Stages of Renal Impairment versus Healthy Subjects

Pharmacokinetic         Healthy       CKD Stage       CKD Stage              CKD Stage 5 Parameter           Subjects          3               4                HD          PD n                          25             15              14                14            8 Dose                      0.240          0.047           0.036             0.240       0.240 (micrograms/kg)
CL/F (l/h)           3.6 ± 1.0       1.8 ± 0.5            1.5 ± 0.4      1.8 ± 0.8         1.8 ± 0.8 t½(h)                5.9 ± 2.8      16.8 ± 2.6           19.7 ± 7.2      13.9 ± 5.1       17.7 ± 9.6 fu* (%)                0.06 ±      0.06 ± 0.01          0.07 ± 0.02     0.09 ± 0.04      0.13 ± 0.08 0.01
* 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 (see section 4.2).