Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: AbbVie Ltd., Maidenhead, SL6 4UB, UK
Pharmacotherapeutic group: Anti-parathyroid agents
ATC code: H05BX02
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.
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.
The safety and efficacy of paricalcitol capsules were evaluated in a 12-week, double-blind, placebo-controlled, randomized, multicentre study in paediatric patients ages 10 to 16 years with CKD Stages 3 and 4. A total of 18 patients received paricalcitol capsules and 18 patients received placebo during the blinded phase of the study. The mean age of the patients was 13.6 years, 69% were male, 86% were Caucasian, and 8% were Asian. Seventy-two percent (72%) of the paricalcitol-treated patients and 89% of the placebo patients completed the 12 week blinded treatment period.
The initial dose of paricalcitol capsules was 1 microgram three times a week. iPTH, calcium, and phosphorus levels were monitored every 2-4 weeks with a goal to maintain levels within KDOQI target ranges for CKD Stages 3 and 4. Starting at Treatment Week 4, doses may have been increased in 1 microgram increments every 4 weeks based upon safety observations and blood chemistry evaluations. The dose could be decreased by 1 microgram or held if the patient was receiving a 1 microgram dose as appropriate at any time. The maximum allowable dose was 3 micrograms three times a week.
Following the 12-week blinded phase, 13 paricalcitol patients and 16 placebo patients were treated with open-label paricalcitol capsules. Although the maximum allowable dose was 16 micrograms three times a week, the highest dose administered was 7 micrograms three times a week.
The primary efficacy endpoint was proportion of Stage 3 and 4 patients achieving two consecutive ≥ 30% reductions from baseline in iPTH levels. Final iPTH within KDOQI target ranges also was evaluated. Results are shown in Table 4.
Table 4. Changes in iPTH from Baseline in the CKD Stages 3 and 4 Paediatric Study:
| Phase/Treatment | Two Consecutive ≥30% Reductions From Baseline in iPTH Levels | Final iPTH Within KDOQI Target Ranges* |
|---|---|---|
| Blinded Phase | ||
| Placebo | 0/18 (0%) | 2/18 (11.1%) |
| Paricalcitol | 5/18 (27.8%)** | 6/18 (33.3%)*** |
| Open-label Phase | ||
| Placebo to Paricalcitol | 7/16 (43.8%) | 6/16 (37.5%) |
| Paricalcitol to Paricalcitol | 5/13 (38.5%) | 2/13 (15.4%) |
* CKD Stage 3: 35 to 69pg/ml; CKD Stage 4: 70 to 110pg/ml.
** p<0.05 compared to placebo
*** p=0.128 compared to placebo
During the blinded phase, the between-group difference in mean change from baseline iPTH to each post-baseline visit was statistically significant (p<0.05). Similarly, the between-group difference in mean percent change from baseline to each post-baseline visit was statistically significant (p<0.05). None of the other secondary efficacy analyses had a statistically significant between-group difference.
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).
The safety and effectiveness of Zemplar IV were examined in a 12-week randomised, double-blind, placebo-controlled study of 29 paediatric patients, aged 5-19 years, with end-stage renal disease on haemodialysis. The six youngest Zemplar IV-treated patients in the study were 5-12 years old. The initial dose of Zemplar IV was 0.04 micrograms/kg 3 times per week, based on baseline iPTH level of less than 500 pg/ml, or 0.08 micrograms/kg 3 times a week based on baseline iPTH level of ≥500 pg/ml, respectively. The dose of Zemplar IV was adjusted in 0.04 micrograms/kg increments based on the levels of serum iPTH, calcium, and Ca x P. 67% of the Zemplar IV-treated patients and 14% placebo-treated patients completed the trial. 60% of the subjects in the Zemplar IV 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 subjects in either the Zemplar IV group or placebo group developed hypercalcaemia. No data are available for patients under the age of 5.
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.
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.
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.
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.
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.
The pharmacokinetics of paricalcitol have not been investigated in patients greater than 65 years.
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 Cmax was 0.12 ± 0.06 ng/ml and the AUC0-∞ was 2.63 ± 0.76 ng·h/ml. In CKD Stage 4 paediatric patients, the Cmax was 0.14 ± 0.05 ng/ml and the AUC0-∞ was 3.12 ± 0.91 ng·h/ml. The t1/2 of paricalcitol in CKD Stage 3 and 4 paediatric patients was 13.3 ± 4.3 hour and 15.2 ± 4.4 hours, respectively.
Paricalcitol Cmax, AUC, and t1/2 values were similar between Stage 3 and Stage 4 CKD paediatric patients 10-16 years of age.
The pharmacokinetics of paricalcitol following single doses over 0.06 to 0.48 micrograms/kg dose range were gender independent.
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.
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:
| Pharmacokinetic Parameter | Healthy Subjects | CKD Stage 3 | CKD Stage 4 | CKD Stage 5 | |
|---|---|---|---|---|---|
| HD | PD | ||||
| n | 25 | 15 | 14 | 14 | 8 |
| Dose (micrograms/kg) | 0.240 | 0.047 | 0.036 | 0.240 | 0.240 |
| 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 ± 0.01 | 0.06 ± 0.01 | 0.07 ± 0.02 | 0.09 ± 0.04 | 0.13 ± 0.08 |
* 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).
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 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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