Kidney International, Vol. 61, Supplement 80 (2002), pp. S149–S154

The calcimimetic agents: Perspectives for treatment

JOAO M. FRAZAO, PATRICIA MARTINS, and JACK W. COBURN

Department of Nephrology, Hospital Sao Joao, Porto, Porto School of Medicine, University of Porto, Porto, Portugal;and Medical and Research Services, Veterans Affairs, West Los Angeles Healthcare Center Department of Medicine,UCLA School of Medicine, Los Angeles, California, USA

The calcimimetic agents: Perspectives for treatment. Recogni- face of parathyroid cells, on calcitonin-secreting C-cellstion of the role of the extracellular calcium sensing receptor of the thyroid, at various sites along the nephron, in cer-(CaR) in mineral metabolism has greatly improved our under- tain areas of the brain, on bone cells, and in other tissues.standing of calcium homeostasis. The biology of the low affinity,

The activation of this receptor by small changes in extra-G-protein-coupled CaR and the effects of its activation in vari-cellular ionized Ca (Ca��) accounts for both the steepous tissues are reviewed. Physiological roles include regulation

of parathyroid hormone (PTH) secretion by small changes in inverse relationship between parathyroid hormone (PTH)ionized calcium (Ca��), and control of urinary calcium excre- levels and small changes of blood Ca�� [1], and the sharption with small changes in blood Ca��. The CaR also affects rise in urinary Ca that occurs as serum Ca rises slightlythe renal handling of sodium, magnesium, and water. Mutations

above a “threshold” value. This provides the mechanismaffecting the CaR that make it either less or more sensitive towhereby the body controls calcium homeostasis and tightlyCa�� cause various clinical disorders. Disorders, such as pri-

mary and secondary hyperparathyroidism, may exhibit ac- regulates the blood Ca��. Alterations of this receptor arequired abnormalities of the CaR. Calcimimetic drugs, which responsible for certain disease states, including familialamplify the sensitivity of the CaR to Ca��, can suppress PTH hypocalciuric hypercalcemia [3], severe infantile hyper-levels with a resultant fall in blood Ca��. Experiences with

parathyroidism [4, 5], and hereditary forms of hypopara-R-568 in patients with secondary and primary hyperparathy-thyroidism [6, 7]. Acquired alterations in the CaR mayroidism and parathyroid carcinoma are summarized. In humans

with hyperparathyroidism, these agents produce a dose-depen- play a role in the pathogenesis of secondary and pri-dent fall in PTH and blood Ca��, with larger doses causing mary hyperparathyroidism. This receptor became an idealmore sustained effects. The second generation calcimimetic, target for the development of compounds that enhancesAMG 073, with a better pharmacokinetic profile appears to

the affinity of the CaR for Ca�� and reduces PTH secre-be an effective and safe treatment for secondary hyperparathy-tion [8]. These compounds, the calcimimetic agents, haveroidism, producing suppression of PTH levels with a simultane-

ous reduction in serum phosphorus levels and the calcium X been explored as potential therapy for primary and sec-phosphorus product. The advantage of controlling PTH secre- ondary hyperparathyroidism. This review describes thetion without the complications related to hypercalcemia, hyper- data on the clinical use of the calcimimetic agents.phosphatemia, and increased calcium X phosphorus productis very promising. Treatment trials have been relatively short-term except for one patient treated with R-568 for more than CHARACTERISTICS OF THE600 days for parathyroid carcinoma; nonetheless the drug had

CALCIUM-RECEPTORno major side effects and appeared to be safe. Further long-term controlled studies are underway to further confirm the The features of the CaR, a member of the superfamilyeffectiveness and safety of these compounds. of G-protein-coupled receptors, are reviewed in detail

elsewhere [9–11]. It has a large extracellular domain com-prised of approximately 700 amino acids, seven mem-

The discovery and cloning of the extracellular calcium brane-spanning segments, and a cytoplasmic carboxyl ter-sensing receptor (CaR) and its molecular role in mineral minal segment consisting of approximately 200 aminometabolism represents a major scientific advance during acids. Unique in comparison to many hormone re-the last decade [1, 2]. This low affinity, G-protein-cou- ceptors, which are activated by nanomolar quantities ofpled receptor is found in high concentrations on the sur- agonist, the CaR is sensitive to relatively small changes

in Ca�� in extracellular fluid having a very high concen-tration of extracellular Ca�� (over one millimole/liter).

Key words: calcium-sensing receptor, calcimimetics, secondary hyper- The CaR is a G-protein coupled receptor which on ac-parathyroidism, primary hyperparathyroidism, parathyroid carcinoma,tivation stimulates phospholipase C that results in in-blood ionized calcium, phosphorus levels, calcium X phosphorus prod-

uct, review. creased levels of inositol 1,3,5-triphosphate, which in turnelevates the cytosolic Ca�� activity by mobilizing Ca 2002 by the International Society of Nephrology

S-149

Frazao, Martins, and Coburn: Calcimimetic agentsS-150

from various intracellular sites. Activation of the CaR reduction in transluminal voltage, leading to reducedparacellular transport of Ca and Mg. Activation of thealso inhibits the accumulation of hormone-stimulated

intracellular cAMP [1]. CaR also inhibits the PTH stimulated adenylate cyclase,reducing the cAMP-mediated transport of Ca and Mg.Another feature of the CaR is its lack of specificity;

thus, it is stimulated by other divalent cations, such as In the IMCD, increased Ca�� inhibits the generationof cAMP by vasopressin through its effect on the CaRmagnesium (Mg), by the trivalent elements gadolinium

and lanthanum, and by polycationic compounds such as at the basolateral surface, causing less concentrated urineand polyuria. Also, increased tubular fluid Ca�� acti-neomycin and spermine. It is likely that the affinity of

magnesium for the CaR is responsible for the effects of vates the luminal CaR which specifically reduces ADH-stimulated osmotic H2O permeability via the aquaporinacute hypermagnesemia to suppress PTH secretion [12].

Also, many effects of an elevated serum magnesium lev- channels, and lowers the urinary concentrating ability[17]. The action of increased extracellular fluid Ca�� toels on the renal handling of calcium, sodium, and chloride

[13, 14] probably arise because of the activation of the inhibit the Na�K�2Cl� cotransporter located in the thickascending limb reduces the medullary hypertonicity andrenal tubular CaR by Mg��. The activation of the CaR

by the polyvalent cations, neomycin and gentamicin, may the effectiveness of the countercurrent mechanism and,therefore, further reduces the maximum urinary concen-account for certain effects of these agents on the kidney,

including the development of nonoliguric renal failure, trating ability.Thus, the effect of hypercalcemia to lower GFR, toperhaps due to impairment of the vasopressin-sensitive

renal concentrating mechanism via activation of the CaR reduce the renal cortical synthesis of calcitriol [18], tocause increased urinary excretion of both Ca and Mg,of the collecting duct.and to lead to increased volumes of dilute urine mayarise, in whole or in part, through activation of the CaR

ROLE OF CaR IN PARATHYROID CELLS within various parts of the nephron.The secretory response of the parathyroid cell to changes

in blood Ca�� occurs within seconds, an observationCaR IN OTHER TISSUESthat suggested that Ca�� acts directly on the plasma

membrane [1]. The presence of CaR in very high concen- The role of the CaR that are found in the intestine[19], parts of the brain [20], the lungs, and bone remainstrations on the parathyroid cell membrane provides the

extracellular Ca��-sensing mechanism for these cells. to be clarified. It is probable that Ca�� activation of aCa��-sensitive receptor acts to stimulate bone formationThe extracellular domain of the CaR contains several

clusters of acidic amino acids that are involved in Ca�� and to inhibit bone resorption; moreover, the G-proteincoupled CaR has been identified in bone cell precursorsbinding. This provides a mechanism whereby the CaR

regulates the secretion of PTH in response to small [21]. Alternatively, Ca��-sensing proteins of other typesmay play a role in regulating bone metabolism [22, 23].changes in extracellular Ca�� concentration [11, 15].

It seems apparent that the very tight regulation ofblood Ca��, which is affected in a major way by PTH,

ROLE OF CaR IN THE KIDNEY calcitriol, and, to a lesser extent, by calcitonin, occursWithin the kidney, transcripts of the CaR have been due to the tight “fine tuning” that arises from activation

found in the juxtaglomerular apparatus, along the lumi- of the CaR to modulate PTH secretion and to regulatenal proximal convoluted tubule, the basolateral surface the renal excretion of calcium.of the cortical thick ascending limb (CTAL), and theapical as well as luminal membrane of the inner medul-

CALCIUM RECEPTOR IN SECONDARYlary collecting duct (IMCD) [10, 16]. The CaR localiza-HYPERPARATHYROIDISMtion in the CTAL may account for the effects of increased

extracellular concentrations of Ca�� and Mg�� to inhibit There may be acquired disorders involving the CaR.Various data indicate that parathyroid glands obtainedthe reabsorption of calcium, magnesium, sodium, and

chloride at this tubular site. Normally, Ca and Mg reab- surgically from uremic patients with secondary hyper-parathyroidism may exhibit reduced expression of thesorption occurs through the intercellular space and is

driven by the high transtubular voltage gradient that is CaR on the surface of parathyroid cells [24, 25]. In pa-tients with parathyroid adenomas or parathyroid carci-generated by the luminal Na�K�2Cl� transporter. Acti-

vation of the apical CaR stimulates phospholipase C noma the data are somewhat inconsistent, although re-duced staining is observed in some glands. It is possiblewhich releases arachidonic acid that is, in turn, metabo-

lized by cytochrome P450; the active metabolites inhibit that changes in the density of CaR in parathyroid cellsmay account, in part, for the shift in “set point” of para-the apical K� channel and may also directly inhibit the

Na�K�2Cl� cotransporter. These effects result in a marked thyroid cells (i.e., the calcium concentration required to

Frazao, Martins, and Coburn: Calcimimetic agents S-151

suppress maximal PTH secretion by 50%) observed in pg/mL; this PTH increase was believed to occur due toprogression of the parathyroid carcinoma. The patientpatients with secondary hyperparathyroidism. In experi-

mental animals, data suggesting that there is regulation remained very active, travelling extensively, and had noside effects over a follow up longer than 600 days. Inof the CaR are either negative or controversial. Two stud-

ies done in vitamin D-deficient rats have demonstrated addition, all measures of cardiac, renal, hepatic, hemato-logical, and pancreatic function remained stable through-no regulation of the mRNA for CaR by Ca�� [26, 27].

One study reported no effect of calcitriol on the mRNA out the period of treatment. Although such observationswere made only in one patient, the data showed thatfor the CaR, while another study found a 40% reduction

of mRNA for CaR in vitamin D-deficient rats that was R-568 could be given safely over a prolonged period.Several reports have documented the effectiveness ofrestored by calcitriol replacement [27]. Thus, some un-

certainty exists about the role of altered regulation of single doses or two daily doses of R-568 to reduce PTHlevels in patients with primary and secondary hyperpara-the CaR being a major factor predisposing to the devel-

opment of secondary hyperparathyroidism in patients thyroidism (abstract; Silverberg et al, J Am Soc Nephrol9:516A, 1998) [33, 34]. In primary and secondary hyper-with progressive renal failure.

Experimental data indicate a reduction in the density parathyroidism, a single initial oral dose of R-568 pro-duced a maximum suppression of PTH levels, that wasof the CaR on the parathyroid cells of rats of in-

creasing age; in the kidney, no alterations in the CaR dose-dependent, at 1 to 2 hours after administration.The decrease in blood Ca�� was significant only withwere observed [28]. If a similar process exists in man, it

could account for the changes in PTH levels with age the largest dose and occurred only after PTH levels fell.The percentage reductions of PTH from pretreatmentand the propensity for the development of hyperpara-

thyroidism with advancing years. There is evidence values were remarkably similar following 100 to 200 mgdoses of R-568, with the average PTH reductions be-that the CaR expression in renal tissue is modestly re-

duced in experimentally induced renal failure in rats; tween 63% and 73% in three reported studies (abstract;Silverberg et al, J Am Soc Nephrol 9:516A, 1998) [33, 34]this might contribute to hypocalciuria noted with renaland one preliminary report (abstract; Akizawa et al,insufficiency [29].J Am Soc Nephrol 9:516A, 1998); this suppression wasindependent from pretreatment PTH, which averaged

CLINICAL USE OF CALCIMIMETIC AGENTS 77 pg/mL in patients with primary hyperparathyroidismFor the clinician, the development of calcimimetic com- and varied from 218 to 1,287 pg/mL in the groups with

pounds that modulate the CaR, making it more sensitive secondary hyperparathyroidism.to Ca�� suppressive effect on PTH secretion, may pro- In women with mild primary hyperparathyroidism, thevide a means for the medical treatment for both primary maximal decrease in PTH occurred by 1 h after lowerand secondary hyperparathyroidism. The first generation doses of R-568, while it occurred at 2 h after larger dosescalcimimetic agent, R-568, was developed by scientists [35]. The duration of effect increased with the dose; theat NPS Pharmaceuticals [30, 31], and has undergone ex- PTH levels returned to baseline by 4 h after doses oftensive testing. Because of a poor pharmacokinetic pro- 80 mg or less but returned to baseline only at 8 h after thefile its development has been discontinued and a second 160 mg dose. A small but significant reduction of bloodgeneration calcimimetic agent, the AMG 073, has been Ca�� occurred only with the largest dose, 160 mg. Afterdeveloped and undergone clinical evaluation. this dose, urinary calcium, expressed as the calcium/cre-

The calcimimetic agent R-568 was given to a patient atinine ratio, rose by 4 h but returned close to baselinewith inoperable parathyroid carcinoma, who presented by 8 h.with hypercalcemia (blood Ca�� 1.96 mmol/L), high Two trials in dialysis patients with secondary hyper-PTH levels (1,128 pg/mL) and altered mental status; the parathyroidism employed two separate doses of R-568,hypercalcemia failed to respond to intravenous saline each given on two successive days [33] (abstract; Aki-and furosemide, several doses of intravenous pamidro- zawa et al, J Am Soc Nephrol 9:516A, 1998). In sevennate, and salmon calcitonin over 18 days [32]. The calci- patients with mild hyperparathyroidism [33], doses of 40mimetic was initiated at 200 mg/day and subsequently or 80 mg caused PTH levels to fall by more than 30%increased to 400 mg/day. The patient’s symptoms im- after the first dose in five of seven patients and moreproved after three days of R-568 treatment, and he was than 60% after the second dose in six of seven patients.discharged home after 28 days of treatment with a blood With doses of 120 and 200 mg, PTH was reduced byCa�� of 1.53 mmol/L and PTH level of 357 pg/mL. Treat- more than 60% after the first dose in six of seven patients.ment with the calcimimetic was continued and the dose After 24 h, the pretreatment PTH level was still 50%was titrated up to 600 mg/day; this treatment maintained lower than the initial basal value; nonetheless, the PTHthe total serum calcium between 2.75–3.0 mmol/L despite fell 50% or more after the second dose in six of seven

patients. Blood Ca�� was not significantly changed afterthe progressive increase in PTH levels to 2000–3500

Frazao, Martins, and Coburn: Calcimimetic agentsS-152

the low dose, but fell significantly after the high dose. secondary hyperparathyroidism and six sequential singledoses were administered (5, 10, 25, 50, 75, and 100 mgPreliminary data from hemodialysis patients with severe

secondary hyperparathyroidism (abstract; Akizawa et al, of AMG 073 or placebo) (abstract; Coburn et al, J AmSoc Nephrol 11:573A, 2000). Doses of 25, 50, 75, andJ Am Soc Nephrol 9:516A, 1998) revealed significant

reductions after 100 mg and even greater reductions after 100 mg caused a dose dependent decrease in plasmaiPTH with a maximum suppression observed between 2200 mg of R-568. The PTH levels had not returned to

baseline after 24 h, when the second dose caused a similar and 4 h after administration followed by a slow recoveryof the iPTH during the subsequent hours but remainingpercent reduction of PTH. Serum total Ca levels fell, with

more marked reductions after the larger dose. Calcitonin below the baseline values after 24 h. Single doses of 75and 100 mg of AMG 073 reduced serum calcium by 8.3%levels did not change after either dose.

The administration of R-568 in doses of 100 mg per and 9.4%, respectively.Following this result, another study evaluated the useday led to the sustained suppression of PTH levels that

persisted for the 15 days duration of treatment [34]. This of daily, fixed doses of 10, 25, and 50 mg of AMG 073 for8 consecutive days in hemodialysis patients with plasmastudy evaluated the effect of the administration of R568

(N � 16) or placebo (N � 5) in hemodialysis patients iPTH � 250 pg/mL and � 1500 pg/mL (abstract; Good-man et al, J Am Soc Nephrol 11:576A, 2000). Doses ofwith secondary hyperparathyroidism. The pretreatment

iPTH levels were 599 � 105 (mean � SE) and 600 � 90 25 and 50 mg were associated with decreases in iPTHconcentrations. The dose of 50 mg was associated withpg/mL in subjects given R-568 or placebo, respectively.

Values on the first day of treatment did not change in a decrease in the mean serum calcium levels. On day 8serum phosphorus levels and the calcium X phosphorusthose given placebo. In contrast, PTH levels fell by 66 �

5%, 78 � 3%, and 70 � 3% at 1, 2 and 4 h, respectively, product were reduced from baseline levels in all treat-ment groups receiving AMG 073.after the initial dose of R568 and then PTH levels re-

mained below the pre-treatment values for 24 h. Despite The efficacy and safety of AMG 073 was shown in adouble-blind, placebo-controlled, dose titration trial withlower ionized calcium concentrations, predose iPTH lev-

els declined progressively over the first 9 days of treat- daily doses of 10, 20, 30, 40, and 50 mg per day (abstract;Lindberg et al, J Am Soc Nephrol 11:578A, 2000). Se-ment with R-568 and remained below pretreatment lev-

els for the duration of the study, in contrast with the quential dose increases every 3 weeks for 12 weeks basedon plasma iPTH response and safety profile. The finalplacebo treated group. Serum total and blood ionized

calcium levels decreased from pretreatment levels in pa- dose of AMG 073 was then maintained for 6 weeks. The72 patients that enrolled in this study were continued ontients given R-568, whereas values were unchanged in

those given placebo. Blood ionized calcium levels fell their concurrent therapy with phosphate binders andvitamin D for secondary hyperparathyroidism. Duringbelow 1 mmol/L in 7 of 16 patients receiving R-568; five

patients withdrew from the study after developing symp- the maintenance period there was a mean decrease in theiPTH levels by 26% from the baseline value compared totoms of hypocalcemia, whereas three completed treat-

ment after the R-568 dose was reduced. Serum phospho- an increase of 22% in the placebo treated group. Thecalcium X phosphorus product at the end of the mainte-rus levels varied considerably from day to day in both

groups of subjects, but values did not change from pre- nance period was decreased by 16.9% from the baselinevalue compared to an increase of 11.4% in the placebotreatment levels during the study in either group.

The pharmacokinetic and pharmacodynamic data treated group. The serum phosphorus levels were alsoreduce by 14.4% in the AMG 073 treated patients andshowed a hight variability [34]. Peak serum levels of

R-568 were achieved an average of 2.5 to 4.4 h after the mean serum calcium levels were reduced by 3.3%from the baseline value. Transient asymptomatic hypo-daily oral doses, but there was considerable heterogene-

ity among subjects. Maximum drug concentration were calcemia occurred in 3 of the 38 patients treated withAMG 073.observed as early as 1 h and as late as 24 h after individual

doses of R-568. Peak drug levels also varied widely Because of good safety profile the previous study wasrepeated with doses titrated up to 100 mg per day (ab-among subjects, ranging from 0.42 to 42.2 ng/mL.

Due to the pharmacokinetic profile and interactions stract; Quarles et al, J Am Soc Nephrol 12:773A, 2001).Seventy one hemodialysis patients were evaluated. Thewith other drugs, the development of R-568 has been

discontinued and a second generation calcimimetic agent, baseline iPTH value was 625 � 310 pg/mL (mean � SE)for the 36 patients treated with AMG 073 and 582 �AMG 073, has been developed.

The calcimimetic AMG 073 has shown potential to treat 421 pg/mL for the placebo treated patients. The iPTHlevels decreased by 32.5% from the baseline during thehemodialysis patients with secondary hyperparathyroid-

ism with promising results in the initial clinical trials. maintenance phase in the AMG 073 group and increasedby 3% in the placebo treated patients. In the AMG 073A randomized, double blind, placebo controlled, multi-

center study was conducted in hemodialysis patients with group the calcium X phosphorus product at the end of

Frazao, Martins, and Coburn: Calcimimetic agents S-153

the maintenance period was decreased by 7.9% from the be highly useful for the treatment of hyperparathyroid-baseline value compared to an increase of 11% in the ism, parathyroid carcinoma, and probably a few other rareplacebo treated group. The serum phosphorus was also disorders, such as parathyromatosis and calciphylaxis.reduced by 2.6% in the AMG 073 treated patients and This may be an alternative to surgery in patients withthe mean serum calcium levels were reduced by 4.6% primary hyperparathyroidism or in those with a high sur-from baseline, although the absolute serum calcium lev- gical risk. The complex management of end-stage renalels remained within normal range. disease associated hyperparathyroidism might become

The potential of the second generation calcimimetic much safer with avoidance of treatment-induced hyper-for treatment of secondary hyperparathyroidism in he- calcemia, hyperphosphatemia, and high calcium X phos-modialysis patients has been shown in the combined phorus product.results of three dose-titration trials (abstract; Drueke et

Reprint requests to Joao M. Frazao, Hospital de S. Joao Servico deal, J Am Soc Nephrol 12:764A, 2001). Sequential doseNefrologia, Al. Hernani Monteiro, 4200-451 Porto, Portugal.

increments could occur every 3 weeks for 12 weeks based E-mail: jfrazao@hotmail.comon the iPTH response and safety profile. The dose rangevaried from 10 mg to 100 mg per day. Two hundred and REFERENCESfifteen hemodialysis patients (141 AMG 073 treated and

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