"The U.S. Food and Drug Administration today approved Procysbi (cysteamine bitartrate) for the management of nephropathic cystinosis in children and adults. Procysbi was granted orphan product designation because it is intended to treat a rare dis"...
Secondary hyperparathyroidism is characterized by an elevation in parathyroid hormone (PTH) associated with inadequate levels of active vitamin D hormone. The source of vitamin D in the body is from synthesis in the skin and from dietary intake. Vitamin D requires two sequential hydroxylations in the liver and the kidney to bind to and to activate the vitamin D receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH)2 D3], is a hormone that binds to VDRs that are present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis, and to VDRs found in many other tissues, including prostate, endothelium and immune cells. VDR activation is essential for the proper formation and maintenance of normal bone. In the diseased kidney, the activation of vitamin D is diminished, resulting in a rise of PTH, subsequently leading to secondary hyperparathyroidism and disturbances in the calcium and phosphorus homeostasis.1 Decreased levels of 1,25(OH)2D3 have been observed in early stages of chronic kidney disease. The decreased levels of 1,25(OH)2 D3 and resultant elevated PTH levels, both of which often precede abnormalities in serum calcium and phosphorus, affect bone turnover rate and may result in renal osteodystrophy.
Mechanism of Action
Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the VDR, which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.
Paricalcitol decreases serum intact parathyroid hormone (iPTH) and increases serum calcium and serum phosphorous in both hemodialysis (HD) and peritoneal dialysis (PD) patients. This observed relationship was quantified using a mathematical model for HD and PD patient populations separately. Computer-based simulations of 100 trials in HD or PD patients (N = 100) using these relationships predict slightly lower efficacy (at least two consecutive ≥ 30% reductions from baseline iPTH) with lower hypercalcemia rates (at least two consecutive serum calcium ≥ 10.5 mg/dL) for lower iPTH-based dosing regimens. Further lowering of hypercalcemia rates was predicted if the treatment with paricalcitol is initiated in patients with lower serum calcium levels at screening.
Based on these simulations, a dosing regimen of iPTH/80 with a screening serum calcium ≤ 9.5 mg/dL, approximately 76.5% (95% CI : 75.6% – 77.3%) of HD patients are predicted to achieve at least two consecutive ≥ 30% reductions from baseline iPTH over a duration of 12 weeks. The predicted incidence of hypercalcemia is 0.8% (95% CI : 0.7% – 1.0%). In PD patients, with this dosing regimen, approximately 83.3% (95% CI : 82.6 – 84.0%) of patients are predicted to achieve at least two consecutive ≥ 30% reductions from baseline iPTH. The predicted incidence of hypercalcemia is 12.4% (95% CI : 11.7% - 13.0 %:). (see Clinical Studies ; CKD Stage 5 and DOSAGE AND ADMINISTRATION; CKD Stage 5)
Paricalcitol is well absorbed. In healthy subjects, following oral administration of paricalcitol at 0.24 mcg/kg, the mean absolute bioavailability was approximately 72%; the mean maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the concentration time curve (AUC0-∞) were 0.630 ng/mL, 3 hours and 5.25 ng•h/mL, respectively. The mean absolute bioavailability of paricalcitol in CKD Stage 5 patients on hemodialysis (HD) or peritoneal dialysis (PD) was 79% or 86%, respectively. A food effect study in healthy subjects indicated that the Cmax and AUC0-∞ were unchanged when paricalcitol was administered with a high fat meal compared to fasting. Food delays Tmax about 2 hours. The AUC0-∞ of paricalcitol increased proportionally over the dose range of 0.06 to 0.48 mcg/kg in healthy subjects. Following multiple dosing, as once daily in CKD Stage 4 patients, the exposure (AUC) was slightly lower than that obtained after a single dose administration.
Paricalcitol is extensively bound to plasma proteins ( ≥ 99.8%). The mean apparent volume of distribution following a 0.24 mcg/kg dose of paricalcitol in healthy subjects was 34 L. The mean apparent volume of distribution following a 4 mcg dose of paricalcitol in CKD Stage 3 and 3 mcg dose in CKD Stage 4 patients is between 44 and 46 L.
After oral administration of a 0.48 mcg/kg dose of 3H-paricalcitol, parent drug was extensively metabolized, with only about 2% of the dose eliminated unchanged in the feces, and no parent drug found in the urine. Several metabolites were detected in both the urine and feces. 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 metabolized 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, 24,26- and 24,28-dihydroxylation and direct glucuronidation.
Paricalcitol is eliminated primarily via hepatobiliary excretion; approximately 70% of the radiolabeled dose is recovered in the feces and 18% is recovered in the urine. In healthy subjects, the mean elimination half-life of paricalcitol is 4 to 6 hours over the studied dose range of 0.06 to 0.48 mcg/kg. The pharmacokinetics of paricalcitol capsule have been studied in patients with chronic kidney disease (CKD) Stage 3 and 4 patients. After administration of 4 mcg paricalcitol capsule in CKD Stage 3 patients, the mean elimination half-life of paricalcitol is 17 hours. The mean half-life of paricalcitol is 20 hours in CKD Stage 4 patients when given 3 mcg of paricalcitol capsule.
Table 1. Paricalcitol Capsule Pharmacokinetic Characteristics
in CKD Stage 3 and 4 Patients
|Pharmacokinetic Parameters||CKD Stage 3
n = 15*
|CKD Stage 4
n = 14*
|Cmax(ng/mL)||0.11 ± 0.04||0.06 ± 0.01|
|AUC0-∞(ng•h/mL)||2.42 ± 0.61||2.13 ± 0.73|
|CL/F (L/h)||1.77 ± 0.50||1.52 ± 0.36|
|V/F (L)||43.7 ± 14.4||46.4 ± 12.4|
|t½||16.8 ± 2.65||19.7 ± 7.2|
|* Four mcg paricalcitol capsule was given to CKD Stage 3 patients; three mcg paricalcitol capsule was given to CKD Stage 4 patients.|
The pharmacokinetics of paricalcitol have not been investigated in geriatric patients greater than 65 years (see PRECAUTIONS).
The pharmacokinetics of paricalcitol have not been investigated in patients less than 18 years of age.
The pharmacokinetics of paricalcitol following single doses over 0.06 to 0.48 mcg/kg dose range were gender independent.
The disposition of paricalcitol (0.24 mcg/kg) was compared in patients with mild (n = 5) and moderate (n = 5) hepatic impairment (as indicated by the Child-Pugh method) and subjects with normal hepatic function (n = 10). The pharmacokinetics of unbound paricalcitol were similar across the range of hepatic function evaluated in this study. No dosing adjustment is required in patients with mild and moderate hepatic impairment. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.
Following administration of Zemplar Capsules, the pharmacokinetic profile of paricalcitol for CKD Stage 5 on hemodialysis (HD) or peritoneal dialysis (PD) was comparable to that in CKD 3 or 4 patients. Therefore, no special dosing adjustments are required other than those recommended in the Dosage and Administration section (see DOSAGE AND ADMINISTRATION).
An in vitro study indicates that paricalcitol is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations up to 50 nM (21 ng/mL) (approximately 20-fold greater than that obtained after highest tested dose). In fresh primary cultured hepatocytes, the induction observed at paricalcitol concentrations up to 50 nM was less than two-fold for CYP2B6, CYP2C9 or CYP3A, where the positive controls rendered a six- to nineteen-fold induction. Hence, paricalcitol is not expected to inhibit or induce the clearance of drugs metabolized by these enzymes.
The pharmacokinetic interaction between paricalcitol capsule (16 mcg) and omeprazole (40 mg; oral) was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol were unaffected when omeprazole was administered approximately 2 hours prior to the paricalcitol dose.
The effect of multiple doses of ketoconazole administered as 200 mg BID for 5 days on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The Cmax of paricalcitol was minimally affected, but AUC0-∞ approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone (see PRECAUTIONS).
CKD Stages 3 and 4
The safety and efficacy of Zemplar Capsules (paricalcitol) were evaluated in three, 24-week, double blind, placebo-controlled, randomized, multicenter, Phase 3 clinical studies in CKD Stage 3 and 4 patients. Two studies used an identical three times a week dosing design, and one study used a daily dosing design. A total of 107 patients received Zemplar Capsules (paricalcitol) and 113 patients received placebo. The mean age of the patients was 63 years, 68% were male, 71% were Caucasian, and 26% were African-American. The average baseline iPTH was 274 pg/mL (range: 145-856 pg/mL). The average duration of CKD prior to study entry was 5.7 years. At study entry 22% were receiving calcium based phosphate binders and/or calcium supplements. Baseline 25-hydroxyvitamin D levels were not measured.
The initial dose of Zemplar Capsules (paricalcitol) was based on baseline iPTH. If iPTH was ≤ 500 pg/mL, Zemplar Capsules (paricalcitol) were administered 1 mcg daily or 2 mcg three times a week, not more than every other day. If iPTH was > 500 pg/mL, Zemplar Capsules (paricalcitol) were administered 2 mcg daily or 4 mcg three times a week, not more than every other day. The dose was titrated by 1 mcg daily or 2 mcg three times a week every 2 to 4 weeks until iPTH levels were reduced by at least 30% from baseline. The overall average weekly dose of Zemplar Capsules was 9.6 mcg/week in the daily regimen and 9.5 mcg/week in the three times a week regimen.
In the clinical studies, doses were titrated for any of the following reasons: if iPTH fell to < 60 pg/mL, or decreased > 60% from baseline, the dose was reduced or temporarily withheld; if iPTH decreased < 30% from baseline and serum calcium was ≤ 10.3 mg/dL and serum phosphorus was ≤ 5.5 mg/dL, the dose was increased; and if iPTH decreased between 30 to 60% from baseline and serum calcium and phosphorus were ≤ 10.3 mg/dL and ≤ 5.5 mg/dL, respectively, the dose was maintained. Additionally, if serum calcium was between 10.4 to 11.0 mg/dL, the dose was reduced irrespective of iPTH, and the dose was withheld if serum calcium was > 11.0 mg/dL. If serum phosphorus was > 5.5 mg/dL, dietary counseling was provided, and phosphate binders could have been initiated or increased. If the elevation persisted, the Zemplar Capsules (paricalcitol) dose was decreased. Seventy-seven percent (77%) of the Zemplar Capsules (paricalcitol) treated patients and 82% of the placebo treated patients completed the 24-week treatment. The primary efficacy endpoint of at least two consecutive ≥ 30% reductions from baseline iPTH was achieved by 91% of Zemplar Capsules (paricalcitol) treated patients and 13% of the placebo treated patients (p < 0.001). The proportion of Zemplar Capsules (paricalcitol) treated patients achieving two consecutive ≥ 30% reductions was similar between the daily and the three times a week regimens (daily: 30/33, 91%; three times a week: 62/68, 91%).
The incidence of hypercalcemia (defined as two consecutive serum calcium values > 10.5 mg/dL), hyperphosphatemia and elevated Ca x P product in Zemplar Capsules (paricalcitol) treated patients was similar to placebo. There were no treatment related adverse events associated with hypercalcemia or hyperphosphatemia in the Zemplar Capsules (paricalcitol) group. No increases in urinary calcium or phosphorous were detected in Zemplar Capsules (paricalcitol) treated patients compared to placebo.
The pattern of change in the mean values for serum iPTH during the studies are shown in Figure 1.
Figure 1 : Mean Values for Serum iPTH Over Time in the Three
Double-Blind, Placebo-Controlled, Phase 3, CKD Stage 3 and 4 Studies Combined
The mean changes from baseline to final treatment visit in serum iPTH, calcium, phosphorus, calcium-phosphorus product (Ca x P), and bone-specific alkaline phosphatase are shown in Table 2.
Table 2 : Mean Changes from Baseline to Final Treatment Visit
in Serum iPTH, Bone Specific Alkaline Phosphatase, Calcium, Phosphorus, and
Calcium x Phosphorus Product in Three Double-Blind, Placebo-Controlled, Phase
3, CKD Stage 3 and 4 Studies Combined
|iPTH (pg/mL)||n = 104||n = 110|
|Mean Baseline Value||266||279|
|Mean Final Treatment Value||162||315|
|Mean Change from Baseline (SE)||-104 (9.2)||+35 (9.0)|
|Bone Specific Alkaline Phosphatase (mcg/L)||n = 101||n = 107|
|Mean Final Treatment Value||9.2||17.4|
|Mean Change from Baseline (SE)||-7.9 (0.76)||-1.4 (0.74)|
|Calcium (mg/dL)||n = 104||n = 110|
|Mean Final Treatment Value||9.5||9.3|
|Mean Change from Baseline (SE)||+0.2 (0.04)||-0.1 (0.04)|
|Phosphorus (mg/dL)||n = 104||n = 110|
|Mean Final Treatment Value||4.3||4.3|
|Mean Change from Baseline (SE)||+0.3 (0.08)||+0.3 (0.08)|
|Calcium x Phosphorus Product (mg²/dL²)||n = 104||n = 110|
|Mean Final Treatment Value||40.7||39.7|
|Mean Change from Baseline (SE)||+4.0 (0.74)||+2.9 (0.72)|
CKD Stage 5
The safety and efficacy of Zemplar Capsules (paricalcitol) were evaluated in a Phase 3, 12-week, double blind, placebo-controlled, randomized, multicenter study in patients with CKD Stage 5 on HD or PD. The study used a three times a week dosing design. A total of 61 patients received Zemplar Capsules and 27 patients received placebo. The mean age of the patients was 57 years, 67% were male, 50% were Caucasian, 45% were African-American, and 53% were diabetic. The average baseline iPTH was 701 pg/mL (range: 216-1933 pg/mL). The average time since first dialysis across all subjects was 3.3 years.
The initial dose of Zemplar Capsules (paricalcitol) was based on baseline iPTH/60. Subsequent dose adjustments were based on iPTH/60 as well as primary chemistry results that were measured once a week. Starting at Treatment Week 2, study drug was maintained, increased or decreased weekly based on the results of the previous week's calculation of iPTH/60. Zemplar Capsules (paricalcitol) were administered three times a week, not more than every other day.
The proportion of patients achieving at least two consecutive ≥ 30% reductions from baseline iPTH was achieved by 88% of Zemplar Capsules (paricalcitol) treated patients and 13% of the placebo treated patients. The proportion of patients achieving at least two consecutive ≥ 30% reductions from baseline iPTH was similar for HD and PD patients.
The incidences of hypercalcemia (defined as two consecutive serum calcium values > 10.5 mg/dL) in patients treated with Zemplar Capsules (paricalcitol) was 6.6% as compared to 0% for patients given placebo. In PD patients the incidences of hypercalcemia in patients treated with Zemplar Capsules (paricalcitol) was 21% as compared to 0% for patients given placebo. The pattern of change in the mean values for serum iPTH during the studies are shown in Figure 2. The rate of hypercalcemia with Zemplar Capsules (paricalcitol) may be reduced with a lower dosing regimen based on the iPTH/80 formula as shown by computer simulations. The hypercalcemia rate can be further predicted to decrease, if the treatment is initiated in only those with baseline serum calcium ≤ 9.5 mg/dL. (see CLINICAL PHARMACOLOGY; Pharmacodynamics and DOSAGE AND ADMINISTRATION; CKD Stage 5)
Figure 2 : Mean Values for Serum iPTH Over Time in a Phase
3, Double-Blind, Placebo-Controlled CKD Stage 5 Study
1. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003; Volume 42(4): Supplement 3.
Last reviewed on RxList: 7/20/2009
This monograph has been modified to include the generic and brand name in many instances.
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