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Calcimimetics: a New Tool for Management of Hyperparathyroidism and Renal Osteodystrophy in Patients with Chronic Kidney Disease

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Calcimimetics: a New Tool for Management of Hyperparathyroidism and Renal Osteodystrophy in Patients with Chronic Kidney Disease View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 67, Supplement 95 (2005), pp. S33–S36 Calcimimetics: A new tool for management of hyperparathyroidism and renal osteodystrophy in patients with chronic kidney disease JILL S. LINDBERG New Orleans Nephrology Associates, New Orleans, Louisiana Calcimimetics: A new tool for management of hyperparathy- serum calcium, phosphorus, calcium-phosphorus (Ca × roidism and renal osteodystrophy in patients with chronic kid- P) product, and parathyroid hormone (PTH) levels have ney disease. Epidemiologic, clinical, and basic scientific studies often been difficult to attain with the previously available led to an explosion in our understanding of disorders of min- eral metabolism in the chronic kidney disease (CKD) patient. treatment options, namely, dietary phosphorus restric- These advances are not always translated into improved care tion, various dietary phosphate binders, and vitamin D of renal osteodystrophy in CKD-5 patients. The introduction of preparations. Unfortunately, the therapeutic options for a new class of drugs, calcimimetics, allows improved control of secondary hyperparathyroidism that were available over abnormal calcium/phosphorus metabolism. The calcimimetics the last decade have all too often led to vexing clinical compliment, rather than replace, current treatment options for secondary hyperparathyroidism in the chronic disease patient. problems, including hypercalcemia, inadequate control of hyperphosphatemia, increased Ca × P product, and refractory hyperparathyroidism or oversuppression of Basic scientific studies have led to an explosion in PTH [3]. Paradoxically, efforts to attain the NKF DOQI our understanding of disorders of mineral metabolism goals for management of second hyperparathyroidism in chronic renal failure. These advances have been trans- have often exacerbated these abnormalities of mineral lated into new therapeutic options that have improved metabolism, making it more difficult to attain the treat- × the care of the patients with stage 5 chronic kidney dis- ment goals for serum calcium and phosphorus and Ca ease (CKD). The introduction of a new class of drugs P product. called calcimimetics has allowed for improved control of abnormal calcium and phosphorus metabolism. The cal- cimimetic drugs compliment, rather than replace, current RESULTS treatment options for secondary hyperparathyroidism in The cloning of the calcium sensing receptor has led to the patient with CKD. The understanding of basic sci- the development of new pharmacologic agents that have ence and its application to clinical management of sec- added strength and definition to our current armamen- ondary hyperparathyroidism in chronic kidney disease tarium of therapies for secondary hyperparathyroidism. patients has led to a shift in our thought process in man- These new pharmacologic agents are called calcimimetic agement of this difficult problem. In recent years, in- agents. Calcimimetic agents are small organic molecules creased emphasis has been placed on controlling serum that act as allosterse activators of the calcium sensing phosphorus and normalizing (as opposed to increasing) receptors (CaSR) in the parathyroid gland and other serum calcium. Moreover, among practitioners there is tissues. Calcimimetics increase the threshold sensitivity now a greater appreciation of the potential toxicities of of the CaSR to extracellular calcium leading to activa- calcium overload with regard to the risk for develop- tion of the CaSR at lower than normal levels of serum ment of vascular calcification. All of these issues form the calcium (Fig. 1). As a result, in the presence of these basis of the National Kidney Foundation Dialysis Out- agents, even the low levels of ionized calcium typically comes Quality Initiative (K/DOQI) guidelines [1, 2]. The present in patients with chronic kidney disease exert a K/DOQI recommendations for optimal management of suppressive effect on PTH secretion [5]. Moreover, in several short-term and long-term studies in experimental animals with chronic kidney disease, calcimimetics have Keywords: cinacalcet HCl, calcimimetics, secondary hyperparathy- been shown to lead to regression of advanced parathyroid roidism, PTH, serum calcium, serum phosphorus, Ca × P product. hyperplasia [6, 7] and reversal of osteitis fibrosa cystica [8] C 2005 by the International Society of Nephrology (Fig. 1). Clinical trials of cinacalcet HCl, the first agent S-33 S-34 Lindberg: Calcimimetics and hyperparathyroidism and renal osteodystrophy Parathyroid gland size PTH gene transcription/ (tissue hyperplasia) PTH synthesis iPTH Ca x P Ca iPTH Ca x P Ca iPTH Ca x P Ca 0 Phosphorus Vitamin D receptors Production Calcium Calcitriol 10 7% 6% 7% 6% 10%8% 13% 13% 20 17% Intracellular PTH 30 Secretion 40 38% Calcium 40% (CaR) 50 48% Reduction from baseline, % Reduction from baseline, Plasma PTH US/Can phase 3 EU/Aus phase 3 US/Can/Aus phase 3 Fig. 2. Vitamin D and calcium affect different components of parathy- roid gland function. Vitamin D sterols inhibit PTH gene transcrip- Fig. 1. Percentage change in PTH and Ca × Plevels at 12 weeks tion and, thus, reduce the amount of hormone that is synthesized and of treatment with cinacalcet HCl (50 or 100 mg/day) or placebo. Re- stored in parathyroid tissues. Vitamin D sterols do not, however, affect produced with permission from Torres PU: Nephrol Dial Transplant calcium-regulated PTH secretion directly. In contrast, changes in blood, 17:723–731, 2002 [5]. ionized calcium concentration, modulate PTH release directly by affect- ing the level of activation of the CaSR. Signaling through the CaSR also appears to be critically important in the prevention of parathyroid gland in this new class of drugs to be developed and marketed, hyperplasia. Reproduced with permission from Goodman WG: Semin Nephrol 24:17–24, 2004 [21]. are ongoing. In this paper, these clinical trials will be re- viewed, and the role of calcimimetics used in conjunction with phosphate binders and vitamin D steroids for attain- Gland size/tissue Gene transcription/hormone ment K/DOQI treatment goals will be discussed. hyperplasia synthesis Vitamin D Early clinical trials in secondary hyperparathyroidism Production VDR (−) VDRE The calcimimetic R-568 was the first drug of this class (−) to be evaluated in patients with stage 5 CKD and sec- CaSR Storage (−) (+) CaSR ondary hyperparathyroidism. Two separate R-568 stud- activation inactivation ies in CKD-5 patients revealed dramatic dose-dependent Secretion decreases in PTH levels within 2 hours of single oral doses High iCa+2 Low iCa+2 of R-568 [9–11]. When given repeatedly or in single large doses to humans or experimental animals, calcimimetic Plasma PTH agents not only lower PTH but also decrease calcium lev- Fig. 3. Calcimimetics increase CaSR sensitivity to extracellular cal- els [9–11]. As PTH levels are lowered, there is a simulta- cium, thus stimulating activation of the CaSR at lower serum calcium neous temporal decline in blood calcium concentrations levels than normal. [9–11]. In the early single dose study of Amg-073 [12], daily doses of 50 mg over 8 days were administered to CKD-5 × patients, with secondary hyperparathyroidism. PTH val- there was an 8% reduction in Ca P products. In con- × ues were reduced by 39% [12]. Importantly, decreases in tract, both Ca P product and PTH levels increased in serum calcium and phosphorus levels and Ca × P product the placebo group. were observed even in this early single dose study [12]. These findings became a recurrent theme as the results of Lessons learned from phase III placebo all subsequent international phase II and phase III stud- controlled studies ies in both hemodialysis and peritoneal dialysis patients Results from studies of 1100 hemodialysis and peri- were reported. toneal dialysis patients in phase III studies are similar to those from phase II studies. However, these placebo- Clinical results from phase II and phase III studies controlled phase III studies were 26 weeks in duration Data combined from 3 phase II studies conducted and cinacalcet HCl doses ranged from 30 to 180 mg per in 142 hemodialysis patients from the United States, day. Patients included in these studies had intact PTH Canada, and Europe, who received cinacalcet HCl doses levels (iPTH) >300 pg/mL. The primary end point was of 50 or 100 mg per day for 12 weeks are shown in achievement of a mean PTH level ≤200 pg/mL during a Figure 2 [13–15]. Overall, a 25% reduction in PTH levels 14- to 16-week efficacy assessment period. The results of was observed in the active treatment group. Furthermore, these studies are summarized in Figure 3 [16–18]. Lindberg: Calcimimetics and hyperparathyroidism and renal osteodystrophy S-35 groups. The only side effects that occurred more fre- = 25 N 68 Ca x P quently in the cinacalcet treatment groups were nausea N = 66 20 Parathyroid hormone and vomiting. In the largest phase III study, which in- 15 cluded over 400 patients, nausea occurred in 33% of pa- 10 tients in the cinacalcet HCl treatment group compared 5 to 19% of patients in the placebo group [17]. However, SE throughout these phase III studies, the number of patients + 0 withdrawn from treatment was equivalent in the placebo −5 and active treatment groups [16–18]. Transient hypocal- mean −10 N = 119 cemia was a frequent occurrence (21% of cinacalcet- −15 treated patients) during the first 4 weeks of these studies. −20 It should be noted that all of these studies allowed for −25 the addition or increase in dose of vitamin D sterols, or = −30 N 127 an increase in calcium-containing phosphate binders for % Change in serum PTH and Ca x P levels, Placebo Cinacalcet HCL treatment of hypocalcemia. Fig. 4. Percentage change in PTH and Ca × Plevels at 28 weeks of treatment with cinacalcet HCl (30-180 mg/day) in 3 phase III placebo- Phosphate binders and vitamin D therapy in phase II and controlled, double-blind randomized titration studies performed in North America, Europe, and Australia in hemodialysis and peritoneal III studies dialysis patients at centers in North America, Europe, and Australia.
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