Summary
Abstract
Paricalcitol (Zemplar®) is a synthetic vitamin D2 analogue that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is approved in the US and in most European nations for intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult, and in the US paediatric, patients.
Paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcaemia and/or elevated calcium-phosphorus product (Ca × P). Thus, paricalcitol is a useful option for the management of secondary hyperparathyroidism in adults and children with chronic renal failure.
Pharmacological Properties
Paricalcitol (19-nor-1,25-dihyroxyvitamin D2) mimics the actions of 1,25-dihydroxyvitamin D3 (calcitriol), at the vitamin D receptor. This receptor heterodimerises the retinoid X receptor to regulate transcriptional activity of vitamin D-responsive genes.
In rats, paricalcitol inhibits the secretion of PTH in a dose-dependent manner, and suppresses parathyroid hyperplasia. Paricalcitol stimulates less osteoclastic activity than calcitriol and induces similar inhibition of osteoblast maturation in vitro. In rodent models, paricalcitol stimulates less intestinal calcium uptake and is 10-fold less active in the mobilisation of skeletal calcium and phosphorus in vivo than calcitriol.
Intravenous paricalcitol absorption is dose proportional, with little evidence of accumulation of the drug after repeated doses in healthy volunteers or in haemodialysis patients. Mean maximum plasma concentration and area under the plasma concentration-time curve from 0 to 44 hours were 4566 pg/mL and 18 232 pg · h/mL after 4 weeks’ treatment with paricalcitol 0.16 μg/kg three times weekly in haemodialysis patients. The drug is extensively bound to plasma proteins (>99.9%).
Paricalcitol elimination, primarily by biliary excretion, is biphasic. Paricalcitol was metabolised by the cytochrome P450 enzyme 24-hydroxylase in vitro, and only 5.7% of an intravenous dose of the drug was excreted unchanged in healthy volunteers. In patients undergoing haemodialysis, paricalcitol clearance was 0.58–0.91 L/h, and the terminal elimination half-life was 11–32 hours; clearance did not appear to be altered by haemodialysis, indicating that paricalcitol may be administered at any time during haemodialysis.
Therapeutic Efficacy
Intravenous paricalcitol is effective in the treatment of secondary hyperparathyroidism associated with chronic renal failure. In patients undergoing maintenance haemodialysis, paricalcitol reduced mean serum intact PTH (iPTH) levels from ≥650 pg/mL to <300 pg/mL in 18–19 weeks and these reductions were proportionally similar to those evoked by calcitriol therapy.
In calcitriol-resistant patients on maintenance haemodialysis, a switch to paricalcitol therapy elicited a sustained reduction in serum iPTH levels, while in children and young adults, paricalcitol reduced serum iPTH levels without increasing the incidence of elevated serum calcium or phosphorus levels.
Both paricalcitol and calcitriol evoked reductions in serum alkaline phosphatase levels, indicating reductions in bone turnover.
Tolerability
Morbidity and mortality data from analysis of a historical cohort indicate that, over a 36-month period in patients undergoing haemodialysis, paricalcitol provided a 16% survival advantage over calcitriol. Therapy with paricalcitol had little effect on serum calcium and phosphorus levels, and differences in the effect of paricalcitol compared with calcitriol on the induction of single episodes or prolonged periods of hypercalcaemia and/or elevated Ca × P were equivocal.
In calcitriol-resistant patients switched to paricalcitol therapy, use of a calcitriol: paricalcitol dose conversion ratio of 1: 3 minimised increases in serum calcium levels. In children and young adults receiving maintenance haemodialysis, paricalcitol use did not cause increases in serum calcium or phosphorus levels.
Other adverse events reported by patients treated with paricalcitol included nausea, vomiting and oedema.
Similar content being viewed by others
Notes
The use of trade names is for identification purposes only and does not imply endorsement.
References
Dobrez DG, Mathes A, Amdahl M, et al. Paricalcitol-treated patients experience improved hospitalization outcomes compared with calcitriol-treated patients in real-world clinical settings. Nephrol Dial Transplant 2004 May; 19(5): 1174–81
U.S. Renal Data System. 2004 annual data report: atlas of end-stage renal disease in the United States [online]. Available from URL: http://www.usrds.org/ [Accessed 2004 Sep 9]
Stein MS, Wark JD. An update on the therapeutic potential of vitamin D analogues. Expert Opin Invest Drugs 2003; 12(5): 825–40
Brown AJ, Coyne DW. Vitamin D analogs: new therapeutic agents for secondary hyperparathyroidism. Treat Endocrinol 2002; 1(5): 313–27
Brown AJ. Vitamin D analogues. Am J Kidney Dis 1998 Oct; 32 (4 Suppl. 2 Suppl. 2): 25–39
Cunningham J. What is the optimal regimen for vitamin D? Kidney Int Suppl 1999 Dec; 56 Suppl. 73: S59–64
Martin KJ, Gonzalez EA. Strategies to minimize bone disease in renal failure. Am J Kidney Dis 2001 Dec; 38(6): 1430–6
Schroeder NJ, Cunningham J. What’s new in vitamin D for the nephrologist? Nephrol Dial Transplant 2000; 15(4): 460–6
National Kidney Foundation. Kidney Disease Outcomes Quality Initiative [online]. Available from URL: http://www.kidney.org/professionals/kdoqi [Accessed 2004 Sep 30]
Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000 May 18; 342(20): 1478–83
Noms KC. Avoiding the risks of secondary hyperparathyroidism in chronic renal failure: A new approach, and a review. Dial Transplant 2001; 30(6): 355–67
Salusky IB, Goodman WG. Managing phosphate retention: is a change necessary? Nephrol Dial Transplant 2000; 15(11): 1738–42
Ganesh SK, Stack AG, Levin NW, et al. Association of elevated serum PO4, Ca × PO4 product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001 Oct; 12(10): 2131–8
Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004 Aug; 15(8): 2208–18
Sanchez CP. Secondary hyperparathyroidism in children with chronic renal failure: pathogenesis and treatment. Paediatr Drugs 2003; 5(11): 763–76
Carbajo E, Lopez JM, Santos F, et al. Histologic and dynamic changes induced by chronic metabolic acidosis in the rat growth plate. J Am Soc Nephrol 2001 Jun; 12(6): 1228–34
Thadhani R, Wolf M, Ofsthun N, et al. Hemodialysis survival and vitamin D injections: a historical cohort study [abstract no. F-PO553]. Proceedings of the American Society of Nephrology; 2004 Oct 27–Nov 1; St Louis
Graul A, Leeson PA, Castaner J. Paricalcitol: vitamin D analog, treatment for hyperparathyroidism. Drugs Future 1998; 23(6): 602–6
Abbott Laboratories. Zemplar® paricalcitol injection [online]. Available from URL: http://www.fda.gov [Accessed 2004 Sep 29]
Dusso AS, Thadhani R, Slatopolsky E. Vitamin D receptor and analogs. Semin Nephrol 2004; 24(1): 10–6
Schroeder NJ, Burrin JM, Noonan K, et al. Effects of ‘non-calcaemic’ vitamin D analogues on 24-hydroxylase expression in MG-63 osteoblast-like cells. Nephron Physiol 2003; 94(4): 62–73
Tocchini-Valentini G, Rochel N, Wurtz JM, et al. Crystal structures of the vitamin D receptor complexed to superagonist 20-epi ligands. Proc Natl Acad Sci U S A 2001 May 8; 98(10): 5491–6
Adams JS, Chen H, Chun R, et al. Response element binding proteins and intracellular vitamin D binding proteins: novel regulators of vitamin D trafficking, action and metabolism. J Steroid Biochem Mol Biol 2004 May; 89-90(1–5): 461–5
Leong GM, Subramaniam N, Issa LL, et al. Ski-interacting protein, a bifunctional nuclear receptor coregulator that interacts with N-CoR/SMRT and p 300. Biochem Biophys Res Commun 2004 Mar 19; 315(4): 1070–6
Slatopolsky E, Finch J, Ritter C, et al. A new analog of calcitriol, 19-nor-1,25-(OH)2D2, suppresses parathyroid hormone secretion in uremic rats in the absence of hypercalcemia. Am J Kidney Dis 1995 Nov; 26(5): 852–60
Slatopolsky E, Cozzolino M, Lu Y, et al. Efficacy of 19-Nor-1,25-(OH)2D2 in the prevention and treatment of hyperparathyroid bone disease in experimental uremia. Kidney Int 2003 Jun; 63(6): 2020–7
Takahashi F, Finch JL, Denda M, et al. A new analog of 1,25-(OH)2D3, 19-NOR-1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content. Am J Kidney Dis 1997 Jul; 30(1): 105–12
Cozzolino M, Lu Y, Finch J, et al. p21WAF1 and TGF-α mediate parathyroid growth arrest by vitamin D and high calcium. Kidney Int 2001 Dec; 60(6): 2109–17
Slatopolsky E, Cozzolino M, Finch JL. Differential effects of 19-nor-1,25-(OH)2D2 and 1α-hydroxyvitamin D2 on calcium and phosphorus in normal and uremic rats. Kidney Int 2002 Oct; 62(4): 1277–84
Brown AJ, Finch J, Slatopolsky E. Differential effects of 19-nor-1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 on intestinal calcium and phosphate transport. J Lab Clin Med 2002 May; 139(5): 279–84
Brown AJ, Finch J, Takahashi F, et al. Calcemic activity of 19-Nor-1,25(OH)2D2 decreases with duration of treatment. J Am Soc Nephrol 2000 Nov; 11(11): 2088–94
Balint E, Marshall CF, Sprague SM. Effect of the vitamin D analogues paricalcitol and calcitriol on bone mineral in vitro. Am J Kidney Dis 2000 Oct; 36(4): 789–96
Holliday LS, Gluck SL, Slatopolsky E, et al. 1,25-Dihydroxy-19-nor-vitamin D2, a vitamin D analog with reduced bone resorbing activity in vitro. J Am Soc Nephrol 2000 Oct; 11(10): 1857–64
Finch JL, Brown AJ, Slatopolsky E. Differential effects of 1,25-dihydroxy-vitamin D3 and 19-nor-1,25-dihydroxy-vitamin D2 on calcium and phosphorus resorption in bone. J Am Soc Nephrol 1999 May; 10(5): 980–5
Zager RA. Calcitriol directly sensitizes renal tubular cells to ATP-depletion- and iron-mediated attack. Am J Pathol 1999 Jun; 154(6): 1899–909
Panda DK, Miao D, Bolivar I, et al. Inactivation of the 25-hydroxyvitamin D 1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem 2004 Apr 16; 279(16): 16754–66
Nakane M, Fey TA, Dixon DB. Effect of vitamin D receptor activators on bone formation and resorption [abstract no. SA PO611 plus poster]. Proceedings of the American Society of Nephrology; 2004 Oct 27–Nov 1; St Louis
Finch JL, Dusso AS, Pavlopoulos T, et al. Relative potencies of 1,25-(OH)2D3 and 19-Nor-1,25-(OH)2D2 on inducing differentiation and markers of bone formation in MG-63 cells. J Am Soc Nephrol 2001 Jul; 12(7): 1468–74
Durakovic C, Ray S, Holick MF. Topical paricalcitol (19-nor-1 α,25-dihydroxyvitamin D2) is a novel, safe and effective treatment for plaque psoriasis: a pilot study. Br J Dermatol 2004 Jul; 151(1): 190–5
Lee RD, Grabowski B, Johnson MK, et al. Disposition and excretion of [3H]19-nor-1α,25-dihyroxyvitamin D2 in humans [abstract no. S402]. J Bone Miner Res 1997; 12 Suppl.: S453
Lutwak L. Medical Officer’s review. Paricalcitol injection [online]. Available from URL: http://www.fda.gov/cder/foi/nda/98/20819_Zemplar.htm [Accessed 2004 Sep 20]
Cato A, Cady WW, Soltanek C, et al. Effect of hemodialysis on the pharmacokinetics of 19-nor-1-α,25-dihydroxyvitamin D2. Am J Kidney Dis 1998 Oct; 32 (4 Suppl. 2 Suppl. 2): 55–60
Slatopolsky E, Cavanaugh J, Cato A. Pharmacokinetics of para-calcin (19-nor-1-α,25-dihydroxyvitamin D2) in healthy subjects [abstract no. p428]. Nephrology (Carlton) 1997 May; 3 Suppl. 1: S182
Cato A, Buschen C, Ahmed A, et al. The pharmacokinetics of paracalcin [abstract no. PIII-95]. 98th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics; 1997 Mar 5–8; San Diego, 218
Sprague SM, Llach F, Amdahl M, et al. Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int 2003 Apr; 63(4): 1483–90
Llach F, Keshav G, Goldblat MV, et al. Suppression of parathyroid hormone secretion in hemodialysis patients by a novel vitamin D analogue: 19-nor-1,25-dihydroxyvitamin D2. Am J Kidney Dis 1998 Oct; 32 (4 Suppl. 2): S48–54
Martin KJ, Gonzalez EA, Gellens M, et al. 19-Nor-1-α-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol 1998 Aug; 9(8): 1427–32
Elashof B, Lutwak L. Statistical review. Capthrol (tradename) paricalcin injection/paricalcitol injection (generic name) [online]. Available from URL: http://www.fda.gov/cder/foi/nda/98/20819_Zemplar.htm [Accessed 2004 Sep 20]
Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003 Jul 31; 349: 446–56
Lindberg J, Martin KJ, Gonzalez EA, et al. A long-term, multicenter study of the efficacy and safety of paricalcitol in end-stage renal disease. Clin Nephrol 2001 Oct; 56(4): 315–23
Llach F, Yudd M. Paricalcitol in dialysis patients with calcitriol-resistant secondary hyperparathyroidism. Am J Kidney Dis 2001 Nov; 38 (5 Suppl. 5): S45–50
Martin KJ, Gonzalez EA, Gellens ME, et al. Therapy of secondary hyperparathyroidism with 19-nor-l-cc,25-dihydroxyvitamin D2. Am J Kidney Dis 1998 Oct; 32 (4 Suppl. 2 Suppl. 2): S61–6
Mittman N, Khanna. R., Rani S, et al. Comparison of paricalcitol and calcitriol therapy for the treatment of secondary hyperparathyroidism in patients on maintenance hemodialysis [abstract no. PUB253]. Proceedings of the American Society of Nephrology; 2004 Oct 27–Nov 1; St Louis
Melnick JZ, Kommala D, Mattingly S, et al. Paricalcitol and calcitriol in treating SHPT in children-a comparison of 2 studies [abstract no. SU-P0930]. Proceedings of the American Society of Nephrology; 2004 Oct 27-Nov 1; St Louis
Zemplar. Clinical review: executive summary. Summaries of medical and clinical pharmacology reviews of pediatric studies [online]. Available from URL: http://www.fda.gov/cder/foi/esum/2004/20819se5-014_zemplar_clinical_bpca.pdf [Accessed 2004 Sep 15]
Colussi G. Paricalcitol, calcitriol, and survival of patients undergoing hemodialysis [letter]. N Engl J Med 2003 Nov 13; 349(20): 1971–2; author reply 1971-2
Llach F. Paricalcitol: an updated review and guidelines for use. Dial Transplant 2001; 30(10): 654–64
Martin KJ, Gonzalez E, Lindberg JS, et al. Paricalcitol dosing according to body weight or severity of hyperparathyroidism: a double-blind, multicenter, randomized study. Am J Kidney Dis 2001 Nov; 38 (5 Suppl. 5): S57–63
Agencia Espanola del Medicamento. Resolucion de autorizacion de comercializacion de la especialidad farmaceutica “Zemplar 5 g/mL solucion inyectable”. Madrid: Minsterio de Sanidad y Consumo, 2002 Aug
Medicine and Healthcare products Regulatory Agency. Grant of marketing authorisation. Zemplar 5 microgram/ml solution for injection. London: Department of Health, 2003 Jul
Block GA, Port FK. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management. Am J Kidney Dis 2000; 35(6): 1226–37
Kratz A, Lewandrowski KB. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Normal reference laboratory values [published erratum appears in N Engl J Med 1999 Apr 22; 340 (16): 1300]. N Engl J Med 1998 Oct 8; 339(15): 1063–72
Moe SM, Drueke TB. Management of secondary hyperparathyroidism: the importance and the challenge of controlling parathyroid hormone levels without elevating calcium, phosphorus, and calcium-phosphorus product. Am J Nephrol 2003; 23(6): 369–79
Hruska KA, Teitelbaum SL. Renal osteodystrophy. N Engl J Med 1995 Jul 20; 333(3): 166–74
Fukuda N, Tanaka H, Tominaga Y, et al. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 1993 Sep; 92(3): 1436–43
Wang M, Hercz G, Sherrard DJ, et al. Relationship between intact 1-84 parathyroid hormone and bone histomorphonietric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis 1995 Nov; 26(5): 836–44
Brancaccio D, Cozzolino M, Gorio A, et al. Bone disease in uremic patients: advances in PTH suppression. J Nephrol 2002 Nov–Dec; 15 Suppl. 6: S86–93
Llach F, Fernandez E. Overview of renal bone disease: Causes of treatment failure, clinical observations, the changing pattern of bone lesions, and future therapeutic approach. Kidney Int 2003; 64 Suppl. 87: S113–9
Portale AA, Booth BE, Halloran BP, et al. Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxy vitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 1984 Jun; 73(6): 1580–9
Malluche HH, Monier-Faugere MC. Understanding and managing hyperphosphatemia in patients with chronic renal disease. Clin Nephrol 1999; 52(5): 267–77
Amgen. European Commission approves innovative first-in-class treatment for a serious complication of chronic kidney disease [online]. Available from URL: http://www.amgen.com/news/viewPR.jsp?id=637355 [Accessed 2004 Nov 22]
Joy MS, Kshirsagar AV, Franceschini N. Calcimimetics and the treatment of primary and secondary hyperparathyroidism. Ann Pharmacother 2004 Nov; 38(11): 1871–80
Quarles LD, Sherrard DJ, Adler S, et al. The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 2003 Mar; 14(3): 575–83
Barman Balfour JA, Scott LJ. Cinacalcet hydrochloride. Drugs 2005; 65(2): 271–81
Maung HM, Elangovan L, Frazao JM, et al. Efficacy and side effects of intermittent intravenous and oral doxercalciferol (1α-hydroxyvitamin D2) in dialysis patients with secondary hyperparathyroidism: a sequential comparison. Am J Kidney Dis 2001 Mar; 37(3): 532–43
Coburn JW, Maung HM, Elangovan L, et al. Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis 2004 May; 43(5): 877–90
Acharya M, Andress D, Lunde N. Safety experience of paricalcitol (Zemplar®) capsule in phase 3 trials in CKD stages 3 and 4 patients with secondary hyperparathyroidism (SHPT) [abstract no. SA PO935 plus poster]. Proceedings of the American Society of Nephrology; 2004 Oct 27–Nov 1; St Louis
Abbott Laboratories. Abbott laboratories submits new drug application to U.S. FDA for Zemplar® (Paricalcitol) capsules [online]. Available from URL: http://abbott.com/news/press_release.cfm?id=802 [Accessed 2005 Feb 1]
Author information
Authors and Affiliations
Corresponding author
Additional information
Various sections of the manuscript reviewed by: A.J. Brown, Renal Division, Washington University School of Medicine, St Louis, Missouri, USA; J. Cunningham, University College London, The Middlesex Hospital, London, UK; A.S. Dusso, Renal Division, Washington University School of Medicine, St Louis, Missouri, USA; K.J. Martin, Division of Nephrology, Saint Louis University School of Medicine, St Louis, Missouri, USA; C.W. McIntyre, Department of Renal Medicine, Derby City General Hospital, Derby, UK; K.C. Norris, School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA; C.P. Sanchez, Department of Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin, USA.
Data Selection
Sources: Medical literature published in any language since 1980 on paricalcitol, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘paricalcitol’. EMBASE search terms were ‘paricalcitol’. AdisBase search terms were ‘paricalcitol’. Searches were last updated 18 January 2005.
Selection: Studies in patients with secondary hyperSimpleParathyroidism who received paricalcitol. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Paricalcitol, secondary hyperSimpleParathyroidism, renal failure, paediatric, pharmacodynamics, pharmacokinetics, therapeutic use.
Rights and permissions
About this article
Cite this article
Robinson, D.M., Scott, L.J. Paricalcitol. Drugs 65, 559–576 (2005). https://doi.org/10.2165/00003495-200565040-00008
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-200565040-00008