Paricalcitol (Page 4 of 6)

8.4 Pediatric Use

The safety and efficacy of Paricalcitol Injection for the prevention and treatment of secondary hyperparathyroidism associated with CKD have been established in pediatric patients 5 years of age and older with CKD on dialysis. Use of Paricalcitol Injection for this indication is supported by evidence from an adequate and well-controlled study of another paricalcitol injection product in 29 patients, 5 to 19 years of age, with CKD on hemodialysis [see Clinical Studies (14)] .

The safety and efficacy of Paricalcitol Injection have not been established in pediatric patients less than 5 years old.

8.5 Geriatric Use

Clinical studies of paricalcitol injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

The pharmacokinetics of paricalcitol were studied in patients with mild and moderate hepatic impairment and were similar to that of patients with normal hepatic function. No dose adjustment is required in patients with mild or moderate hepatic function.

Paricalcitol Injection has not been studied in patients with severe hepatic impairment.

10 OVERDOSAGE

Overdosage of Paricalcitol Injection may lead to hypercalcemia, hypercalciuria, and hyperphosphatemia [see Warnings and Precautions (5.1)] .

The treatment of acute overdosage should consist of supportive measures and discontinuation of drug administration. Serum calcium levels should be measured until normal.

Paricalcitol is not significantly removed by dialysis.

11 DESCRIPTION

Paricalcitol, USP, is a synthetically manufactured active vitamin D analog. It is a white powder chemically designated as 19-nor-1α,3β,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)-triene and has the following structural formula:

1
(click image for full-size original)

Molecular formula is C 27 H 44 O 3 .

Molecular weight is 416.64.

Paricalcitol Injection is a sterile, clear, colorless, aqueous solution for intravenous use. Each mL contains paricalcitol, 2 mcg or 5 mcg and the following inactive ingredients: alcohol, 35% (v/v) and propylene glycol, 30% (v/v).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Paricalcitol is a synthetic, biologically active vitamin D 2 analog. Preclinical and in vitro studies have demonstrated that paricalcitol’s biological actions are mediated through binding of the vitamin D receptor (VDR), which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce PTH levels by inhibiting PTH synthesis and secretion.

12.3 Pharmacokinetics

Within two hours after administering paricalcitol injection 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 three times a week 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 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.

Elimination

Metabolism

After intravenous administration of a 0.48 mcg/kg dose of 3 H-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.

Excretion

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 patients 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 HD and PD patients is 13.9 and 15.4 hours, respectively (Table 5).

Table 5: Mean ± SD Paricalcitol Pharmacokinetic Parameters in CKD Patients on Dialysis Following Single 0.24 mcg/kg Intravenous Bolus Dose

CKD –HD (n=14)

CKD –PD (n=8)

C max (ng/mL)

1.680 ± 0.511

1.832 ± 0.315

AUC 0-∞ (ng·h/mL)

14.51 ± 4.12

16.01 ± 5.98

β (1/h)

0.050 ± 0.023

0.045 ± 0.026

t 1/2 (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. The degree of accumulation was consistent with the half-life and dosing frequency.

Specific Populations

The pharmacokinetics of paricalcitol has not been investigated in geriatric and pediatric patients.

Male and Female Patients

The pharmacokinetics of paricalcitol were gender independent.

Patients with 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. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.

Patients with Renal Impairment

The pharmacokinetics of paricalcitol have been studied in CKD patients requiring hemodialysis (HD) and peritoneal dialysis (PD). Hemodialysis procedure has essentially no effect on paricalcitol elimination. However, compared to healthy subjects, CKD patients on dialysis showed a decreased CL and increased half-life.

Drug Interaction Studies

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. The following studies have been performed with oral paricalcitol capsules.

Omeprazole

The pharmacokinetic interaction between paricalcitol capsule (16 mcg) and omeprazole (40 mg; oral), a strong inhibitor of CYP2C19, 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.

Strong CYP3A Inhibitors

Ketoconazole

The effect of multiple doses of ketoconazole, a strong inhibitor of CYP3A administered as 200 mg BID for 5 days, on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The C max of paricalcitol was minimally affected, but AUC 0-∞ 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 Drug Interactions (7)] .

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