Calcimimetics to treat hyperparathyroidism

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Pablo Ureña Torres
MD
Nephrologist
Service de Néphrologie et Dialyse
Clinique de l’Orangerie
Aubervilliers
France
E:[email protected]

Secondary hyperparathyroidism (HPTH-II) is a common complication in patients with chronic kidney disease (CKD). It affects more than 300,000 end-stage renal disease patients treated by dialysis and probably more than three million patients with CKD.(1) It is associated with an increased risk of cardiovascular calcifications and mortality.(2) Although surgical parathyroidectomy (PTX) remains the gold-standard therapy, it is not without risk. PTX exposes patients to anaesthesia risks, surgical complications and potentially permanent hypoparathyroidism.(3)

On the other hand, traditional therapies such as calcium salts and vitamin D are limited by hypercalcaemia, hyperphosphataemia and lack of long-term efficacy. Calcimimetics, a new class of drugs, amplify the sensitivity of the parathyroid calcium-sensing receptor (CaR) to calcium, thereby reducing the serum concentration of PTH.(4,5) This article briefly reviews the development of calcimimetics and the results of the principal clinical trials that have been carried out.

Principal mechanisms leading to renal HPTH-II
HPTH-II results from an abnormal regulation of calcium, phosphate and vitamin D metabolism. Several factors are involved in the development of this condition:

• Phosphate retention.(6)
• The subsequent increase in serum phosphate and in fibroblast growth factor 23 (FGF-23) inhibits 1a-hydroxylase and calcitriol synthesis.(7)
• The hyperphosphaturic effect of PTH and its stimulatory effect on the 1a-hydroxylase are compromised by a reduced renal PTH receptor expression.(8)
• The net calcium balance becomes negative and the release of PTH is stimulated.(9) The chronic overstimulation of PTH causes progressive polyclonal parathyroid gland hyperplasia, which transforms into a benign, tumour-like monoclonal growth in more than 60% of patients.(10)

Parathyroid CaR and the development of calcimimetics
The CaR of the parathyroid gland is the principal regulator of PTH secretion. When serum calcium decreases, the CaR is inhibited and PTH-containing vesicles move to the cell membrane and release PTH to the circulation. When serum calcium increases, the CaR is activated and the release of PTH is inhibited.

The cloning of the CaR by Brown and colleagues in 1993 led to the development of calcimimetics.(4) Type I calcimimetics mimic the effects of calcium. They consist of polyvalent cations, such as gadolinium, calcium, magnesium and lanthanum. Type II calcimimetics change the conformation of the CaR and stereoselectively increase its sensitivity to calcium. They do not alter PTH secretion in the absence of calcium.

Several type II calcimimetics have been synthesised: a first generation, which includes NPS R-567 and NPS R-568; and a second generation, with compounds such as AMG-073 or cinacalcet HCl and calindol.(11–13) NPS R-568 is remarkably effective in reducing serum PTH; however, it was withdrawn from clinical trials because of its unpredictable pharmacokinetic profile, due to its catabolism by the variable P450 cytochrome CYP2D6.(14) Cinacalcet HCl (Sensipar) has been extensively studied and approved in the USA by the FDA for the treatment of HPTH-II in dialysis patients,(15) and for hypercalcaemia in patients with parathyroid carcinoma (see Resource).

Clinical utilisation of cinacalcet HCl

Indications
Cinacalcet HCl is formally indicated in dialysis patients with HPTH-II characterised by a serum PTH level >300 pg/ml. These patients must also have a serum albumin-corrected total calcium >2.10mM (8.4mg/dl). It is also indicated in cases of hypercalcaemia in patients with parathyroid carcinoma.

Cinacalcet HCl in the treatment of renal HPTH-II
In dialysis patients with HPTH-II, the optimal daily dose of cinacalcet HCl appears to be 60–120mg. However, severe cases may require the maximal daily doses of 180mg. Independently of the baseline value, PTH decreases by 60–70% two to four hours after its administration and remains lower for the next 24 hours. Serum total calcium follows the same trend, but delayed by two to four hours; it often decreases by 20–30% of its baseline value. The reduction in serum PTH seen during the first weeks of treatment can reach up to 90% of the baseline value, similar to a surgical PTX. A transient hypocalcaemia often occurs during this phase, which is in part due to the phenomenon of “hungry bone”,(16) and also to a decrease in the intestinal expression of the TRPV5 calcium transporter.(17) Correcting this problem requires an increase in the dietary calcium intake, or high doses of calcium salts alone or in combination with vitamin D.

Table 1 illustrates the main results obtained with cinacalcet HCl in phase III studies in dialysis patients with HPTH-II. Cinacalcet HCl at doses of 20–180mg/day reduced mean serum PTH levels by 33% and 65% after 18 weeks and three years of treatment, respectively.(15,18–22) Mean serum calcium ¥ phosphorus (Ca ¥ P) product showed a decrease of 6–15%. This treatment frequently allows achievement of the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) recommended targets values for serum calcium, phosphorus, PTH and Ca ¥ P product (see Table 2).

[[HPE21_table1_20]]

[[HPE21_table2_21]]

Cinacalcet HCl in the treatment of parathyroid carcinoma
Parathyroid carcinoma is a rare cause of hypercalcaemia due to excessive PTH secretion. Its medical treatment is a real challenge because these tumours are often resistant to chemotherapy and radiotherapy. Two recent studies in 40 patients with inoperable parathyroid carcinoma and serum calcium of 14.5–15.4mg/dl have shown that 30–90mg of cinacalcet HCl four times a day reduces mean serum calcium to 11.8mg/dl and maintains this reduction for up to three years.(23,24)

Side-effects
The most frequent side-effects of cinacalcet HCl treatment are gastrointestinal troubles: nausea, gastralgia and vomiting. The incidence of other side-effects is not greater in dialysis patients receiving cinacalcet HCl than in nontreated patients. The transient hypocalcaemia that often occurs during the first weeks of treatment also has to be considered as a complication, because it may lower the threshold for seizures.

Conclusions
The development of calcimimetics has changed the treatment of hyperfunctioning parathyroid glands. The results of short- and long-term studies with cinacalcet HCl in patients with uraemic HPTH-II are very promising. The safety profile of this drug, its effectiveness in controlling PTH secretion and the simultaneous reductions in serum Ca ¥ P product observed make this agent advantageous over traditional therapies. However, because of the lifelong potential duration of this treatment, its cost-effectiveness needs to be estimated.

References

1. Young EW, et al. Magnitude and impact of abnormal mineral metabolism in hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004;44 Suppl:34-8.
2. Ganesh SK, 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;12:2131-8.
3. Gagné ER, et al. Short and long-term efficacy of total parathyroidectomy with immediate autografting compared with subtotal parathyroidectomy in hemodialysis patients. J Am Soc Nephrol 1992;3:1008-17.
4. Brown EM, et al. Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature 1993;366:575-80.
5. Nemeth EF, et al. Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci USA 1998;95:4040-5.
6. Slatopolsky E, et al. The control of phosphate excretion in uremia. J Clin Invest 1966;45:672-7.
7. Shigematsu T, et al. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis 2004;44:250-6.
8. Ureña P, et al. The renal PTH/PTHrP receptor is down- regulated in rats with chronic renal failure. Kidney Int 1994;45:605-11.
9. Silver J, et al. Mechanisms of secondary hyperparathyroidism. Am J Physiol Renal Physiol 2002;283:F367-76.
10. Arnold A, et al. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 1995;95:2047-54.
11. Kessler A, et al. N(2)-benzyl-N(1)-(1-(1-naphthyl)ethyl)-3-phenylpropane-1,2-diamines and conformationally restrained indole analogues: development of calindol as a new calcimimetic acting at the calcium sensing receptor. Bioorg Med Chem Lett 2004;14:3345-9.
12. Petrel C, et al. Positive and negative allosteric modulators of the Ca2+-sensing receptor interact within overlapping but not identical binding sites in the transmembrane domain. J Biol Chem 2004;279:18990-7.
13. Antonsen JE, et al. A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Kidney Int 1998;53:223-7.
14. Goodman WG, et al. A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int 2000;58:436-45.
15. Block GA, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004;350:1516-25.
16. Ureña P, et al. Short-term effects of parathyroidectomy on plasma biochemistry in chronic uremia:a prospective study. Kidney Int 1989;36:120-6.
17. Van Abel M, et al. Down-regulation of Ca2+ transporters in kidney and duodenum by the calcimimetic compound NPS R-467 (abstract). J Am Soc Nephrol 2003;14:SA-P073.
18. Urena P, et al. Sustained control of uraemic secondary hyperparathyroidism (SHPT) after three years of treatment with the calcimimetic cinacalcet HCl : a single centre experience. 40th ERA-EDTA World Congress of Nephrology, Berlin, Germany; 2003 (poster).
19. Quarles LD, et al. The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 2003;14:575-83.
20. Lindberg JS, et al. The calcimimetic AMG 073 reduces parathyroid hormone and calcium ¥ phosphorus in secondary hyperparathyroidism. Kidney Int 2003;63:248-54.
21. Mittman N, et al. Cinacalcet HCl (Sensipar) for the management of secondary hyperparathyroidism in study patients receiving peritoneal dialysis. J Am Soc Nephrol 2004;15:280A.
22. Bushinsky DA. Cinacalcet HCl in secondary hyperparathyroidism. Official Evening Symposium 2004:ASN 2004.
23. Silverberg SJ, et al. Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism. N Engl J Med 1997;337:1506-10.
24. Rubin MR, et al. Clinical course of 10 patients with inoperable parathyroid carcinoma treated with the calcimimetic cinacalcet HCl. J Bone Min Res 2004:F497 (Abstract).

Resource
Sensipar
W:www.sensipar.com