Paricalcitol

Paricalcitol
Systematic (IUPAC) name
(1R,3R,7E,17β)-17-[(1R,2E,4S)-5-hydroxy-1,4,5-trimethylhex-2-en-1-yl]-9,10-secoestra-5,7-diene-1,3-diol
Clinical data
Trade names Zemplar
AHFS/Drugs.com monograph
MedlinePlus a682335
  • AU: C
  • US: C (Risk not ruled out)
Oral, Intravenous
Pharmacokinetic data
Bioavailability 72%[1]
Protein binding 99.8%[1]
Metabolism Hepatic[1]
Half-life 14-20 hours[1]
Excretion Faeces (74%), urine (16%)[1]
Identifiers
131918-61-1 Yes
H05BX02
PubChem CID 5281104
IUPHAR ligand 2791
DrugBank DB00910 
ChemSpider 4444552 Yes
UNII 6702D36OG5 Yes
KEGG D00930 
ChEBI CHEBI:7931 
ChEMBL CHEMBL1200622 Yes
Synonyms (1R,3S)-5-[2-[(1R,3aR,7aS)-1-[(2R,5S)-6-hydroxy-5,6-dimethyl-3E-hepten-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-cyclohexane-1,3-diol
Chemical data
Formula C27H44O3
416.636 g/mol
  (what is this?)  (verify)

Paricalcitol (chemically it is 19-nor-1,25-(OH)2-vitamin D2. Marketed by Abbott Laboratories under the trade name Zemplar) is a drug used for the prevention and treatment of secondary hyperparathyroidism (excessive secretion of parathyroid hormone) associated with chronic renal failure. It is an analog of 1,25-dihydroxyergocalciferol, the active form of vitamin D2 (Ergocalciferol).

Medical uses

Its primary use in medicine is in the treatment of secondary hyperparathyroidism associated with chronic kidney disease.[2] In three placebo-controlled studies, chronic renal failure patients treated with paricalcitol achieved a mean parathyroid hormone (PTH) reduction of 30% in six weeks. Additionally there was no difference in incidence of hypercalcemia or hyperphosphatemia when compared to placebo.[3] A double-blind randomised study with 263 dialysis patients showed a significant advantage over calcitriol (also known as activated vitamin D3; a similar molecule to 1,25-dihydroxyergocalciferol, adding a methyl group on C24 and lacking a double-bond in the C22 position). After 18 weeks, all patients in the paricalcitol group had reached the target parathormone level of 100 to 300 pg/ml, versus none in the calcitriol group.[4] Combination therapy with paricalcitol and trandolapril has been found to reduce fibrosis in obstructive uropathy.[5] Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in 227 patients with chronic kidney disease.[6]

Adverse effects

Adverse effects by frequency:[1][2][7][8]
Very common (>10% frequency):

Common (1-10% frequency):

Uncommon (0.1-1% frequency):

‡ These are adverse effects only seen in patients with grade 3 or 4 chronic kidney disease. † These are adverse effects only seen in patients with grade 5 chronic kidney disease.

Contraindications

Contraindications include:[8]

whereas cautions include:[1]

Interactions

Drugs that may interact with paricalcitol include:[1][8]

  • Ketoconazole, as it may interfere with paricalcitol's metabolism in the liver.
  • Digitoxin, hypercalcaemia due to any cause can exacerbate the toxicity of digitoxin.
  • Thiazide diuretics or calcium supplements as hypercalcaemia may be induced by this combination
  • Magnesium-containing products such as antacids may increase the risk of hypermagnesemia.
  • Aluminium-containing products such as antacids may increase the risk of aluminium toxicity.
  • Drugs that interfere with the absorption of fat-soluble vitamins, such as cholestyramine may interfere with the absorption of paricalcitol.

Overdose

Electrolyte abnormalities (e.g. hypercalcaemia and hyperphosphataemia) are common overdose symptoms.[8] Treatment is mostly supportive, with particular attention being paid to correcting electrolyte anomalies and reducing intake of calcium in both the form of supplementation and diet.[8] As it is so heavily bound to plasma proteins haemodialysis is unlikely to be helpful in cases of overdose.[8]

Early symptoms of overdose can include:[8]

  • Weakness
  • Headache
  • Somnolence
  • Nausea
  • Vomiting
  • Dry mouth
  • Constipation
  • Muscle pain
  • Bone pain
  • Metallic taste in the mouth.

It is worth noting, however, that may of these symptoms are also indicative of kidney failure and hence may be masked by the patient's condition.[8]

Late symptoms of overdose include:

  • Loss of appetite
  • Weight loss
  • Conjunctivitis (calcific)
  • Pancreatitis
  • Photophobia
  • Rhinorrhoea
  • Pruritis
  • Hyperthermia
  • Decreased libido
  • Elevated BUN
  • Hypercholesterolaemia
  • Elevated AST and ALT
  • Ectopic calcification
  • Hypertension
  • Cardiac arrhythmias
  • Somnolence
  • Death
  • Psychosis (rare)

Mechanism of action

3D structure of paricalcitol

Like 1,25-dihydroxyergocalciferol, paricalcitol acts as an agonist for the vitamin D receptor and thus lowers the bloodparathyroid hormone level.[1]

Pharmacokinetics

Within two hours after administering paricalcitol intravenous doses ranging from 0.04 to 0.24 µg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly. No accumulation of paricalcitol was observed with multiple dosing.[9]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Zemplar (paricalcitol) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 26 January 2014.
  2. ↑ 2.0 2.1 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  3. ↑ "Zemplar: Drug Information"
  4. ↑ Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2005/2006 (in German).
  5. ↑ Tan, X; He, W; Liu, Y (2009). "Combination therapy with paricalcitol and trandolapril reduces renal fibrosis in obstructive nephropathy". Kidney international 76 (12): 1248–57. doi:10.1038/ki.2009.346. PMID 19759524.
  6. ↑ Thadhani, R; Appelbaum, E; Pritchett, Y; Chang, Y; Wenger, J; Tamez, H; Bhan, I; Agarwal, R et al. (2012). "Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease - The PRIMO Randomized Controlled Trial". JAMA 307 (7): 674–684. doi:10.1001/jama.2012.120. PMID 22337679.
  7. ↑ "PARICALCITOL capsule, liquid filled [Teva Pharmaceuticals USA Inc]" (PDF). DailyMed. Teva Pharmaceuticals USA Inc. September 2013. Retrieved 26 January 2014.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 "Zemplar Soft Capsules 1 mcg - Summary of Product Characteristics". electronic Medicines Compendium. AbbVie Limited. 15 April 2013. Retrieved 26 January 2014.
  9. ↑ Rxlist: Zemplar