Metabolism

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.

Elimination

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

* Four mcg paricalcitol capsule was given to CKD Stage 3 patients; three mcg paricalcitol capsule was
given to CKD Stage 4 patients.

Special Populations

Geriatric

The pharmacokinetics of paricalcitol have not been investigated in geriatric patients greater than 65 years (see PRECAUTIONS).

Pediatric

The pharmacokinetics of paricalcitol have not been investigated in patients less than 18 years of age.

Gender

The pharmacokinetics of paricalcitol following single doses over 0.06 to 0.48 mcg/kg dose range 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.

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