CLINICAL PHARMACOLOGY
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 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.
Pharmacokinetics
Within two hours after administering Zemplar intravenous doses ranging from 0.04 to 0.24 mcg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly. No accumulation of paricalcitol was observed with multiple dosing.
Distribution
Paricalcitol is extensively bound to plasma proteins (≥99.8%). In healthy subjects, the steady state volume of distribution is approximately 23.8 L. The mean apparent volume of distribution following a 0.24 mcg/kg dose of paricalcitol in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD) is between 31 and 35 L.
Metabolism
After IV 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 (present at low levels in plasma), as well as 24,26- and 24,28-dihydroxylation and direct glucuronidation.
Elimination
Paricalcitol is excreted primarily by hepatobiliary excretion. Approximately 63% of the radioactivity was eliminated in the feces and 19% was recovered in the urine in healthy subjects. In healthy subjects, the mean elimination half-life of paricalcitol is about five to seven hours over the studied dose range of 0.04 to 0.16 mcg/kg. The pharmacokinetics of paricalcitol has been studied in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD). The mean elimination half-life of paricalcitol after administration of 0.24 mcg/kg paricalcitol IV bolus dose in CKD Stage 5 HD and PD patients is 13.9 and 15.4 hours, respectively (Table 1).
Table 1 Mean ± SD Paricalcitol Pharmacokinetic Parameters in CKD Stage 5 Subjects Following Single 0.24 mcg/kg IV Bolus Dose | CKD Stage 5-HD
(n=14) | CKD Stage 5-PD
(n=8) |
|
† harmonic mean ± pseudo standard deviation, HD: hemodialysis, PD: peritoneal dialysis
|
| Cmax (ng/mL) | 1.680 ± 0.511 | 1.832 ± 0.315 |
| AUC0-∞ (ng·h/mL) | 14.51 ± 4.12 | 16.01 ± 5.98 |
| β (1/h) | 0.050 ± 0.023 | 0.045 ± 0.026 |
| t1/2 (h) † | 13.9 ± 7.3 | 15.4 ± 10.5 |
| CL (L/h) | 1.49 ± 0.60 | 1.54 ± 0.95 |
| Vdβ (L) | 30.8 ± 7.5 | 34.9 ± 9.5 |
The degree of accumulation was consistent with the half-life and dosing frequency.
Special Populations
Geriatric
The pharmacokinetics of paricalcitol have not been investigated in geriatric patients greater than 65 years.
Pediatrics
The pharmacokinetics of paricalcitol have not been investigated in patients less than 18 years of age.
Gender
The pharmacokinetics of paricalcitol were gender independent.
Hepatic Impairment
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.
Renal Impairment
The pharmacokinetics of paricalcitol have been studied in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD). Hemodialysis procedure has essentially no effect on paricalcitol elimination. However, compared to healthy subjects, CKD Stage 5 subjects showed a decreased CL and increased half-life (see Pharmacokinetics - Elimination).
Drug Interactions
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.
Drug interactions with paricalcitol injection have not been studied.
Omeprazole
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 administrated approximately 2 hours prior to the paricalcitol dose.
Ketoconazole
Although no data are available for the drug interaction between paricalcitol injection and ketoconazole, 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).
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