Paricalcitol

Paricalcitol is a prescription drug marketed as Zemplar by Abbott Laboratories. It is used for prevention and treatment of elevated parathyroid hormone levels (secondary hyperparathyroidism) in patients with kidney failure. Paricalcitol is a synthetic form of calcitriol, the metabolically active form of vitamin D. Its chemical name is 19-nor-1alpha-25-dihydroxyvitamin D2. It is the most widely used active vitamin D therapy in the United States and has been used in more than 200,000 patients since its approval by the Food and Drug Administration (FDA) in March 2005.

Uses

Paricalcitol is prescribed for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease.

Calcium In Kidney Failure

Three hormones maintain calcium levels in the blood: calcitonin, parathyroid hormone, and vitamin D. To do this, they balance processes that increase and decrease calcium levels in the blood. Calcitonin, produced by the thyroid gland, decreases blood calcium by stimulating the formation of new bone (by osteoblasts) and inhibiting bone breakdown (by osteoclasts). Too much calcitonin would result in very strong bones at the expense of low blood calcium levels. Parathyroid hormone, by contrast, acts on bone, kidney, and intestinal cells by increasing their input of calcium into the blood. Parathyroid hormone’s effects on the bone tends to decrease its mineral content and structural integrity. Parathyroid hormone also promotes absorption of calcium into the kidneys and intestines. A lack of parathyroid hormone, like an excess of calcitonin, results in low blood calcium. Vitamin D (calcitriol) is necessary for the absorption of calcium from the small intestine. Because the active form of vitamin D is generated in the kidney, patients with kidney disease often experience vitamin D deficiency, low serum calcium levels, and compensatory (secondary) high levels of parathyroid hormone. This is an early, major, and progressive complication of chronic kidney disease.

Treatment with vitamin D tends to increase blood calcium and phosphorus levels at the expense of increasing the risk of cardiovascular disease.^{[1] [2] [3]}. Vitamin D analogs, like paricalcitol, have been developed to suppress parathyroid hormone secretion without simultaneous elevations in the blood calcium or phosphorus levels.

How Paricalcitol is Taken

Paricalcitol is available as 1 µg (micrograms), 2 µg, and 4 µg capsules. It is also available in an injectable form. The drug may be administered daily or three times a week. Calcium, phosphorus and parathyroid hormone levels are closely monitored after initiation of treatment.

How Paricalcitol Works

Paricalcitol binds to and activates the vitamin D receptor (VDR) in a way similar to naturally-produced calcitriol. This results in the selective activation of downstream vitamin D pathways. Paricalcitol has been shown to reduce parathyroid hormone levels by inhibiting its synthesis and secretion.

How the Body Affects Paricalcitol

Most of paricalcitol is metabolized, or chemically-altered, by enzymes in the liver. The half-life of the drug, or time needed for the concentration in the blood to be reduced by half, is 5–7 hours in healthy volunteers. Severe kidney impairment approximately doubles this half-life. Most of the metabolized drug is eliminated in the feces.

Side Effects

Potential adverse effects of paricalcitol are similar to those encountered with excessive vitamin D intake. Below are some early symptoms of vitamin D overdose:

• weakness
• headache
• sleepiness
• nausea
• vomiting
• dry mouth
• constipation
• muscle pain
• bone pain
• metallic taste

Late symptoms of vitamin D overdose include the following:

• anorexia
• weight loss
• eye infections (conjunctivitis)
• pancreatitis
• photophobia (hypersensitivity to light)
• runny nose
• generalized itching
• hyperthermia
• decreased libido
• hypercholesteremia (high blood cholesterol)
• high blood pressure
• heartbeat problems
• sleepiness
• psychosis

Risks and Precautions

Paricalcitol has been shown to cross the placental barrier in mammals, but there are no adequate and well-controlled clinical studies in pregnant women. However, paricalcitol has been shown to cause minimal decreases in fetal survival (5%) when administered daily to rabbits at a dose 0.5 times the equivalent human dose, and when administered to rats at a dose two times the equivalent human dose (based on body surface area).

As a result, paricalcitol should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Studies in rats have shown that paricalcitol is present in the milk. It is not known whether paricalcitol is excreted in human milk. In the nursing patient, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Excessive administration of paricalcitol can cause hypercalcemia (high blood calcium levels), hypercalciuria (high urine calcium levels), and hyperphosphatemia (high blood phosphate levels), and over-suppression of parathyroid hormone.

Drug Interactions

Because of partial metabolism by liver enzymes, paricalcitol may interact with drugs that inhibit these enzymes. Some of these drugs include the following:

• ketoconazole (Nizoral)
• clarithromycin (Biaxin)
• indinavir (Crixivan)
• itraconazole (Sporanox)
• nefazodone (Serzone)
• anti-HIV drugs (e.g., nelfinavir(Viracept), ritonavir (Norvir), and atazanavir (Reyataz))
• telithromycin (Ketek)
• voriconazole (VFEND)

Side effects caused by interactions with drugs that strongly inhibit liver enzymes are minimized if parathyroid hormone and calcium levels are monitored after starting or stopping these drugs.

Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.

Clinical Trials

The effectiveness of paricalcitol was evaluated in three clinical studies of patients with chronic kidney disease. A total of 107 patients received paricalcitol and 113 patients received placebo. Effectiveness was measured by at least two consecutive ≥30% reductions from baseline parathyroid hormone levels. This result was achieved by 91% of Zemplar Capsules treated patients and 13% of the placebo treated patients.

Paricalcitol may also find clinical utility in treating hypercalcemia associated with other conditions, such as prostate cancer. ^[4] This paper notes that elevated blood levels of parathyroid hormone, a common feature of advanced prostate cancer, were reduced by paricalcitol. Because elevated parathyroid hormone is associated with increased cardiovascular and skeletal morbidity, including an increased risk for fracture, the study concludes that further evaluation of paricalcitol in the reduction of skeletal morbidity in advanced prostate cancer is warranted.

References

1. ↑ Qunibi WY, Nolan CA, Ayus JC. Cardiovascular calcification in patients with end-stage renal disease: a century-old phenomenon. Kidney Int Supplemental. 2002;82:73–80 PMID 12410860
2. ↑ Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcifications in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2003;342:1478–83. PMID 10816185 Full TextPDF
3. ↑ Goldsmith D, Ritz E, Covic A. Vascular calcification: a stiff challenge for the nephrologist; Does preventing bone disease cause arterial disease? Kidney Int. 2004;66:1315–33 PMID 15458425 Full Text PDF
4. ↑ Schwartz GG, Hall MC, Stindt D, Patton S, Lovato J, Torti FM. Phase I/II study of 19-nor-1alpha-25-dihydroxyvitamin D2 (paricalcitol) in advanced, androgen-insensitive prostate cancer. Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8680-5. PMID 16361554 Full Text PDF

External Links

Abbott Labs: Zemplar

FDA: Zemplar

Rx List: Zemplar

Drug Digest: Zemplar

Drugs.com: Zemplar