Drug Interactions
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.

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.

Ketoconazole
Although no data are available for the drug interaction between paricalcitol injection and ketoconazole, a strong inhibitor of CYP3A, the effect of multiple doses of ketoconazole administered as 200 mg BID for 5 days on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The Cmax of paricalcitol was minimally affected, but AUC0-∞ 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 PRECAUTIONS ).

CLINICAL STUDIES
In three 12-week, placebo-controlled, phase 3 studies in chronic kidney disease Stage 5 patients on dialysis, the dose of Zemplar was started at 0.04 mcg/kg 3 times per week. The dose was increased by 0.04 mcg/kg every 2 weeks until intact parathyroid hormone (iPTH) levels were decreased at least 30% from baseline or a fifth escalation brought the dose to 0.24 mcg/kg, or iPTH fell to less than 100 pg/mL, or the Ca × P product was greater than 75 within any 2 week period, or serum calcium became greater than 11.5 mg/dL at any time.

Patients treated with Zemplar achieved a mean iPTH reduction of 30% within 6 weeks. In these studies, there was no significant difference in the incidence of hypercalcemia or hyperphosphatemia between Zemplar and placebo-treated patients. The results from these studies are as follows:

  Group
(No. of Pts.) Baseline Mean
(Range) Mean (SE) Change From Baseline to Final eva luation
PTH (pg/mL) Zemplar (n = 40) 783 (291 – 2076) -379 (43.7)
  placebo (n = 38) 745 (320 –1671) -69.6 (44.8)
Alkaline Zemplar (n = 31) 150 (40 – 600) -41.5 (10.6)
Phosphatase (U/L) placebo (n = 34) 169 (56 – 911) +2.6 (10.1)
Calcium (mg/dL) Zemplar (n = 40) 9.3 (7.2 – 10.4) +0.47 (0.1)
  placebo (n = 38) 9.1 (7.8 – 10.7) +0.02 (0.1)
Phosphorus (mg/dL) Zemplar (n = 40) 5.8 (3.7 – 10.2) +0.47 (0.3)
  placebo (n = 38) 6.0 (2.8 – 8.8) -0.47 (0.3)
Calcium × Zemplar (n = 40) 54 (32 – 106) +7.9 (2.2)
Phosphorus Product placebo (n = 38) 54 (26 – 77) -3.9 (2.3)

A long-term, open-label safety study of 164 CKD Stage 5