Brands, Medical Use, Clinical Data
Brands / Synonyms
For treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 3 and 4
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)2 D3 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. 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).
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 andin 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.
Biotrnasformation / Drug Metabolism
Metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4
Zemplar Capsules should not be given to patients with evidence of vitamin D toxicity, hypercalcemia, or
hypersensitivity to any ingredient in this product .
Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2,
CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by
CYP2B6, CYP2C9 or CYP3A.
A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol
Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of
cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A
inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir,
saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum
calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong
CYP3A4 inhibitor such as ketoconazole.
Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the
absorption of Zemplar Capsules.