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.

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.

Pharmacokinetics

Absorption

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 (C_max), time to C_max (T_max), and area under the concentration time curve (AUC_0-¥) were 0.630 ng/mL, 3 hours and 5.25 ng·h/mL, respectively. A food effect study in healthy subjects indicated that the C_max and AUC_0-¥ were unchanged when paricalcitol was administered with a high fat meal compared to fasting. Food delays Tmax about 2 hours. The AUC_0-¥ 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.

Distribution

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.

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