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Calcimimetic agents for the treatment of secondary hyperparathyroidism.

This article was first published in CANNT Journal (2002), 12(2), 27-29.

Calcimimetic agents are currently being studied as a novel strategy for the management of secondary hyperparathyroidism in patients with renal insufficiency. Calcimimetic agents are activators of calcium-sensing receptors throughout the body including those located in the parathyroid glands. They imitate calcium and, therefore, they lower the threshold for the activation of extracellular calcium ions and decrease the secretion of parathyroid hormone (PTH) (Goodman, 2002). Preliminary short-term studies in humans have shown positive, reproducible results (Antonsen, Sherrard, & Andress, 1998; Goodman et al., 2000; Silverberg et al., 1997).

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In normal circumstances, a feedback loop controls the level of calcium in the blood. As calcium levels fall, calcium receptors on the parathyroid cells detect the decrease in calcium and stimulate PTH secretion. PTH acts on the bone to cause release of calcium, on the kidney to increase calcium retention and stimulate synthesis of vitamin D3 in the kidney. Vitamin D3 increases calcium absorption from the gastrointestinal tract. As a result, calcium increases. As calcium levels in the blood rise, calcium receptors sense this and there is a decrease in the secretion of PTH. Calcimimetic agents imitate calcium and trick the parathyroid hormone into perceiving that serum calcium levels are higher than they are. Calcimimetic agents directly control PTH secretion without increasing serum calcium levels.

Calcimimetic agents produce rapid reductions in PTH levels within a few hours, as much as 50% to 70% of pretreatment levels (Goodman, 2002). However, levels increase towards pretreatment levels after 18 to 24 hours (Goodman, 2002). These effects are very different than current management with vitamin D analogs that have much smaller fluctuations over a longer period of time. Calcimimetics are still being studied in humans to see if the observed rapid suppression of PTH leads to an improvement in signs of renal osteodystrophy. Rapid variations in PTH compared to more continuous PTH levels, as in vitamin D3 treatment, could result in potentially unexpected metabolic bone activity. Potential adverse effects of this treatment have yet to be clearly defined, although the agents appear to be well-tolerated in small studies (Antonsen et al., 1998; Goodman et al., 2000; Silverberg et al., 1997).

Long-acting anemia management

Erythropoietin is a glycoprotein hormone that regulates erythropoiesis, or the production of red blood cells. In normal circumstances, erythropoietin is synthesized in the kidney and secreted into the blood in response to a decrease in tissue oxygenation. The hormone binds to specific receptors on the surface of red blood cell precursors in the bone marrow, leading to the survival, proliferation, and differentiation of new red blood cells. The end result is an increase in hemoglobin and hematocrit.

In renal insufficiency, erythropoietin synthesis is inadequate to maintain a red blood cell supply. As a result, recombinant human erythropoietin has become the gold standard in treating anemia of chronic renal insufficiency. Recombinant human erythropoietin has been well established in its role in correcting anemia, improving patient well-being, enhancing physical, cognitive, and sexual function, improving some cardiovascular indicators and decreasing the need for transfusions (Canaud et al., 1990; Eschbach et al., 1989; Eschbach, Aquiling, Haley, Fan, & Blagg, 1992; Eschbach, Egrie, Downing, Browne, & Adamson, 1987; Harnett, Kent, Foley, & Parfrey, 1995; Levin, Lazarus, & Nissenson, 1993; Lim, Kirchner, Fangman, Richmond, & DeGowin, 1989; Macdougall et al., 1990; Sundal & Kaeser, 1989; Temple, Langan, Deary, & Winney, 1992; Winearls, et al., 1986). Recombinant human erythropoietin (epoetin alpha or Eprex[R] in Canada) is normally dosed subcutaneously one to three times per week. Once-weekly dosing is effective at maintaining target hemoglobin in most patients, however may require a slightly higher weekly dose to do so when compared to three times weekly dosing (Canaud et al., 1995; Frifelt et al., 1996).

Anemia management may change somewhat in the near future, as a new erythropoietin analogue is introduced into the Canadian market. Darbepoetin alfa (novel erythropoiesis stimulating protein, NESP) is expected to receive its notice of compliance for the treatment of anemia in chronic renal insufficiency shortly. To create NESP, two extra N-linked carbohydrate addition sites were added to the current epoetin alfa structure (Egrie & Browne, 2001). The new product was designed to have a longer half-life than the current epoetin alfa product.

Based on the available data, the two agents appear to be comparable in terms of mean change in hemoglobin, percentage of patients who will achieve their target hemoglobin and the time required to reach the target hemoglobin (Graf, Lancombe, Braun, & Gomes da Costa, 2000; Locatelli, Olivares, Walker, & Wilkie, 2001; Nissenson et al., 2000; Vanrenterghem, Barany, & Mann, 1999). In terms of other endpoints such as improved well-being, physical, sexual, and cognitive improvements and cardiovascular indicators as discussed previously, we can only infer that the new product will show these same benefits. It is very likely that these benefits occur secondary to the correction of anemia alone, regardless of the product used. However, these benefits were demonstrated secondary to recombinant erythropoietin therapy and similar studies have not been conducted with the NESP product.

The greatest advantage of the new product is less-frequent administration. Although NESP is at this moment still investigational, it is expected that most patients will be managed on once-weekly dosing. For patients who are currently controlled on once-weekly epoetin alfa, they may be able to be managed with a dose of NESP every two weeks (Joy, 2001). Another advantage is that it appears that no dose adjustment is required when switching from IV to SC administration with NESP (personal communication with Amgen, Canada). This suggests that the two routes may be interchangeable, allowing for IV administration during hemodialysis.

It is important to note that the two products are expressed in different units, which could potentially lead to confusion. It has been defined that 200 U of epoetin alfa is equivalent to 1 ug of NESP on a peptide mass basis (Graf et al., 2000). Starting doses of NESP will likely be 0.45 ug/kg weekly, compared to 150 U/kg of epoetin alfa divided three times weekly (50 U/kg three times weekly) as currently recommended. This will increase the complexity of monitoring anemia indices. Recommendations for adjusting doses based on hemoglobin with the new product are similar to those current recommendations for adjusting epoetin alfa doses.

It will be interesting to see the role this new product will play in the management of anemia of chronic renal insufficiency. The agent's pricing is anxiously awaited.

References

Antonsen, J.E., Sherrard, D.J., & Andress, D.L. (1998). A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Kidney International, 53, 223-227.

Canaud, B., Bennhold, I., & Delons, S. (1995). What is the optimum frequency of administration of r-HuEPO for correcting anemia in hemodialysis patients? Dialysis & Transplantation, 24, 286-289.

Canaud, B., Polito-Bouloux, C., Garred, L.J., Rivory, J.D., Donnadieu, P., Taib, J., Florence, P., & Mion, C. (1990). Recombinant human erythropoietin: 18 months' experience in hemodialysis patients. The American Journal of Kidney Diseases, 15, 169-175.

Egrie, J.C., & Browne, J.K. (2001). Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrology Dialysis, Transplantation, 16(Suppl. 3), 3-13.

Eschbach, J.W., Egrie, J.C., Downing, M.R., Browne, J.K., & Adamson, J.W. (1987). Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. The New England Journal of Medicine, 316, 73-78.

Eschbach, J.W., Abduladhi, M.H., Browne, J.K., Delano, B.G., Downing, M.R., Ergie, J.C., et al. (1989). Recombinant human erythropoietin in anemic patients with end-stage renal disease: Results of a phase III multicenter clinical trial. The Annals of Internal Medicine, 111, 992-1000.

Eschbach, J.W., Aquiling, T., Haley, N.R., Fan, M.H., & Blagg, C.R. (1992). The long-term effects of recombinant human erythropoietin on the cardiovascular system. Clinical Nephrology, 38(Suppl. 1), S98-S103.

Frifelt, J.J., Tvedagaard, E., Bruun, K., Steffensen, G., Cintin, C., Breddam, M., et al. (1996). Efficacy of recombinant human erythropoietin administered subcutaneously to CAPD patients once weekly. Peritoneal Dialysis International, 16, 594-598.

Goodman, W.G., Frazao, J.M., Goodkin, D.A, Turner, S.A., Liu, W., & Coburn, J.W. (2000). A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney International, 58, 436-445.

Goodman, W. (2002). Calcimimetic agents and secondary hyperparathyroidism: treatment and prevention. Nephrology Dialysis, Transplantation, 17, 204-207.

Graf, H., Lancombe, J-L., Braun, J., Gomes da Costa, A.A., & the European/Australian NESP 980140/194 Study Group. (2000). Novel erythropoiesis stimulating protein (NESP) effectively maintains hemoglobin (Hgb) when administered at reduced dose frequency compared with recombinant human erythropoietin (r-HuEPO) in ESRD patients (Abstract). Journal of the American Society of Nephrology, 11(Suppl.), 1317A.

Harnett, J.D., Kent, G.M., Foley, R.N., & Parfrey, P.S. (1995). Cardiac function and hematocrit level. The American Journal of Kidney Diseases, 25(Suppl. 1), S3-S7.

Joy, M.S. (2001). Novel erythropoiesis-stimulating protein: An erythropoietin analogue with an extended half-life and less frequent dosing. Formulary 36, 19-25.

Levin, N.W., Lazarus, J.M., & Nissenson, A.R. (1993). National Cooperative rHu Erythropoietin Study in patients with chronic renal failure: An interim report. The National Cooperative rHu Erythropoietin Study Group. The American Journal of Kidney Diseases, 22(Suppl. 1), 3-12.

Lim, V.S., Kirchner, P.T., Fangman, J., Richmond, J., & DeGowin, R.L. (1989). The safety and efficacy of maintenance therapy of recombinant human erythropoietin in patients with renal insufficiency. American Journal of Kidney Diseases, 14(6), 496-506.

Locatelli, F., Olivares, J., Walker, R., Wilkie, M., and the European/Australian NESP 980202 Study Group. (2001). Novel erythropoiesis stimulating protein (NESP) administered subcutaneously corrects anemia in subjects with chronic renal insufficiency (CRI) when administered at a reduced dose frequency compared with recombinant-human erythropoietin (r-HuEPO) (Abstract). Journal of the American Society of Nephrology, 11(Suppl.), 1486A.

Macdougall, I.C., Lewis, N.P., Saunders, M.J., Cochlin, D.L., Davies, M.E., & Hutton, R.D. (1990). Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. The Lancet, 335, 489-493.

Nissenson, A.R., Swan, S.K., Lindberg, J.S., Soroka, S.D., McDermott-Vitak, A.D., & Wang, C. (2000). Novel erythropoiesis stimulating protein (NESP) safely maintains hemoglobin concentrations in hemodialysis patients as effectively as r-HuEPO when administered once weekly (Abstract). Journal of the American Society of Nephrology, 11(Suppl.), 1326A.

Silverberg, S.J., Bone, H.G. III, Marriott, T.B, Locker, F.G., Thys-Jacobs, S., Dziem, G., et al. (1997). Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism. The New England Journal of Medicine, 337, 1506-1510.

Sundal, E., & Kaeser, U. (1989). Correction of anemia of chronic renal failure with recombinant human erythropoietin: Safety and efficacy of one year's treatment in a European multicenter study of 150 heamodialysis-dependant patients. Nephrology Dialysis, Transplantation, 4, 979-987.

Temple, R.M., Langan, S.J., Deary, I.J., & Winney, R.J. (1992). Recombinant erythropoietin improves cognitive function in chronic hemodialysis patients. Nephrology, Dialysis, Transplantation, 7, 240-245.

Vanrenterghem, Y., Barany, P., & Mann J., on behalf of European/Australian NESP 970290 Study Group. (1999). Novel erythropoiesis stimulating protein (NESP) maintains hemoglobin (Hgb) in ESRD patients when administered once weekly or once every other week (Abstract). Journal of the American Society of Nephrology, 10(Suppl.), 1365A.

Winearls, C.G., Oliver, D.O., Pippard, M.J., Reid, C., Downing, M.R., & Cotes, P.M. (1986). Effect of human erythropoietin derived from recombinant DNA on the anemia of patients maintained by chronic hemodialysis. The Lancet, 2(8517), 1175-1178.

By Jennifer Dykeman, BScPharm, Renal Pharmacist, Clinical Coordinator, Pharmacy Services, Atlantic Health Sciences Corporation, Saint John, NB
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Title Annotation:Pharmacy news and reviews
Author:Dykeman, Jennifer
Publication:CANNT Journal
Geographic Code:1CANA
Date:Jul 1, 2008
Words:1910
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