ely 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)
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
† harmonic mean ± pseudo standard deviation, HD: hemodialysis, PD: peritoneal dialysis
No accumulation of paricalcitol was observed with three times a week dosing which is consistent with the observed half-life.
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 eva luated in this study. No dose 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 eva luated.
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 pari
