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Department of Medicine (D.M.S.), Veterans Affairs Medical Center, University of California-San Francisco, San Francisco, California 94121; Department of Medicine (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Amgen Inc. (S.A.T., L.C.M., M.D.G.), Thousand Oaks, California 91320; and Department of Medicine (M.P.), Indiana University School of Medicine, Indianapolis, Indiana 46202
Address all correspondence and requests for reprints to: Dolores Shoback, M.D., University of California-San Francisco, San Francisco Veterans Affairs Medical Center, Endocrine Unit–111N, 4150 Clement Street, San Francisco, California 94121. E-mail: address: Dolores{at}itsa.ucsf.edu
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The only definitive treatment for primary hyperparathyroidism is parathyroidectomy. Surgery is usually recommended for patients who meet one or more guidelines as set forth by the recommendations of the National Institutes of Health’s (NIH) Consensus Development Panel on Asymptomatic Primary Hyperparathyroidism (3). There is considerable debate, however, regarding the most appropriate management for asymptomatic patients. Many patients remain untreated because they are asymptomatic and do not meet any of the currently accepted guidelines for surgery. For those who do not undergo parathyroidectomy, regular monitoring with serum calcium and urinary calcium and yearly bone mass measurements are recommended (3). Because untreated asymptomatic primary hyperparathyroidism may be silently progressive in some patients, the recommendation not to treat is fraught with uncertainty over the possibility that the disease might progress (4, 5, 6, 7, 8).
No medical therapies have been approved for the treatment of primary hyperparathyroidism. The pathogenesis of the condition involves an increase in the mass of the parathyroid tissue, usually from the development of an adenoma. Cells from parathyroid adenomas demonstrate a reduced suppression of PTH secretion by high extracellular calcium concentrations. Calcium-sensing receptors (CaRs) on parathyroid cells are responsible for the control of PTH secretion, and they accomplish this by sensing small changes in serum calcium concentration and altering secretory rates (9). Identification of the CaR has facilitated the development of calcimimetics, compounds that allosterically modulate the CaR, thereby enhancing its sensitivity to circulating serum calcium concentrations and decreasing PTH secretion (10, 11, 12). The summary statement from a recent workshop on the Management of Asymptomatic Primary Hyperparathyroidism held at the NIH (13) notes the potential for calcimimetics in the medical therapy of primary hyperparathyroidism.
A first-generation calcimimetic, R-568, has been shown to reduce PTH and serum calcium in patients with primary hyperparathyroidism (14). Clinical development of R-568 was discontinued due to its low bioavailability and its high intra- and interindividual variability (Amgen data on file). Therefore, cinacalcet was developed as a second-generation calcimimetic for the treatment of primary and secondary hyperparathyroidism. Cinacalcet has improved bioavailability and decreased pharmacokinetic variability compared with R-568. This study was a two-phase, dose-finding study. Initially, once-daily dosing was investigated using an initial dose of 50 mg cinacalcet, then the dose was increased by 25 mg sequentially in a cohort of patients (up to 100 mg). Using once-daily dosing, maximal PTH suppression was observed at 2 and 4 h after dosing (54.9% and 38.5% reduction, respectively) but was not sustained over the dosing interval; PTH concentrations were not reduced immediately preceding the next dose of study medication (5% reduction). In addition, a high incidence of nausea and dizziness, compared with placebo, was observed with once-daily dosing. Therefore, the second phase of the study evaluated twice-daily dosing of cinacalcet or placebo using doses that were approximately one half of the 50-, 75-, and 100-mg once-daily doses. A 7-d follow-up period occurred after 15 d of twice-daily dosing to assess the safety of cinacalcet. The results from the twice-daily dosing phase and 7-d follow-up period of the study are reported here. This study evaluated the ability of cinacalcet to reduce serum calcium and PTH concentrations safely and effectively in patients with primary hyperparathyroidism.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The study protocol was approved by the institutional review boards at each of the 15 investigative sites, and written informed consent was obtained from each study participant before the protocol was initiated.
Patients were eligible if they were 18 yr of age or older and were medically stable. Potential participants were evaluated during a 21-d screening period immediately preceding their initial dose of cinacalcet or placebo. All candidates for the study had primary hyperparathyroidism as defined by a PTH concentration 
45 pg/ml on at least two occasions during the 12 months before the first dose of study medication and two serum calcium concentrations between 10.3 and 12.5 mg/dl. Acceptable hepatic (serum aspartate aminotransferase, alanine aminotransferase, and total bilirubin 
2 times the upper limit of normal) and renal (estimated glomerular filtration rate 50 ml/min, based on 24-h urine for creatinine clearance) function were required for entry onto the study. Exclusion criteria were a history of seizures, malignancy, myocardial infarction, or diseases other than primary hyperparathyroidism known to cause hypercalcemia. No limitations were placed on dietary calcium intake during the course of the study.
Study drugs and compliance
Cinacalcet is a small organic molecule that is synthesized and administered as a hydrochloride salt of the dextrorotary isomer. The dosage strengths of cinacalcet were 30, 40, and 50 mg. Matching placebo capsules were provided. Study drug was administered twice daily, 12 h apart.
Twelve of the 22 patients received all doses of study drug. Eight patients missed one or two doses (six cinacalcet patients and two placebo patients), and two missed five or six doses (two cinacalcet patients).
Study design
This was a randomized, double-blind, placebo-controlled, multicentered study in which cinacalcet or placebo was administered orally twice daily. The key endpoints were serum calcium, PTH, 24-h urine calcium, and fasting and 24-h urine calcium to creatinine ratios. Patients were randomized to receive twice-daily doses of 30 (n = 5), 40 (n = 6), or 50 mg (n = 5) cinacalcet or placebo (n = 6) for 15 consecutive days. Patients were hospitalized on the first and last day of the study to obtain kinetic measurements of PTH and serum calcium at predose and 1, 2, 4, 8, and 12 h after the first and second doses of cinacalcet or placebo. Fasting and 24-h urine specimens were collected for total calcium excretion the day before the first dose of study drug and on d 6–7 and 14–15. Patients were followed for 7 d (d 16–22) after the final dose of study drug. Safety was assessed by monitoring adverse events in all groups.
Laboratory determinations
Total serum calcium (normal range, 8.4–10.3 mg/dl), urinary calcium, and plasma PTH were determined by Covance Central Laboratory (Indianapolis, IN). Plasma intact PTH concentrations were measured using a double-antibody immunoradiometric assay (Allegro PTH; Nichols Institute Diagnostics, San Juan Capistrano, CA) (normal range, 10–65 pg/ml).
Statistical analysis
Statistical testing was conducted on the intent-to-treat data set with a nonparametric Wilcoxon rank sum test using data from the combined and individual cinacalcet dose groups compared with placebo. Safety was assessed by summarizing all adverse events by treatment group (cinacalcet or placebo) according to the body system affected and by preferred term within body system according to a modified World Health Organization Adverse Reaction Terminology dictionary.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Twenty-two patients with primary hyperparathyroidism were enrolled. Four patients had undergone an unsuccessful parathyroidectomy. One patient was withdrawn before completing the study because of inadequate vascular access for phlebotomy. Patients in the cinacalcet and placebo groups had similar demographics and baseline biochemistries (Table 1
). Patients had mild to moderate hypercalcemia, with a mean baseline serum calcium of 10.6 mg/dl (range, 9.4–12.7 mg/dl) and a mean PTH of 102 pg/ml (range, 55–186 pg/ml).
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Cinacalcet caused significant decreases in serum calcium concentrations through the 15 d of dosing in all dose groups (Fig. 1). Mean serum calcium concentrations were decreased into the normal range 2 h after the second dose on d 1 in the cinacalcet-treated patients and remained within the normal range through the last dose on d 15.
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On d 15, the final day of dosing, serum calcium concentrations before the first dose in the cinacalcet-treated patients were decreased from baseline by 11.0%, 18.7%, and 18.5% in the 30-, 40-, and 50-mg dose groups, respectively, compared with a 0.3% increase from baseline in the placebo group (P = 0.09 for 30 mg, P = 0.03 for 40 mg, and P = 0.06 for 50 mg). Combining data from all cinacalcet dose groups led to a mean reduction in serum calcium of 16.0% (P = 0.004). Serum calcium concentrations before the first dose on d 15 were well within the normal range (9.4 mg/dl for 30 mg, 8.6 mg/dl for 40 mg, and 8.8 mg/dl for 50 mg) but remained at baseline in the placebo group (10.4 mg/dl). Combining data from all cinacalcet dose groups, the mean ± SD serum calcium was 8.9 ± 0.7 mg/dl. Serum calcium concentrations were relatively constant throughout the 12-h dosing interval on d 15 in all dose groups (Fig. 2). Serum calcium returned to baseline concentrations 7 d after the last dose of study drug in the 30- and 50-mg dose groups but remained slightly below baseline levels in the 40-mg dose group (10.0 mg/dl), indicating that the calcium-lowering effect of cinacalcet is likely reversible (Fig. 1
).
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Baseline serum phosphorus is presented for each dose group in Table 1. Cinacalcet increased serum phosphorus concentrations through the 15 d of dosing in all dose groups. Serum phosphorus concentrations before the first dose on d 15 were within the normal range (3.1 mg/dl for 30 mg, 3.2 mg/dl for 40 mg, and 3.2 mg/dl for 50 mg) and remained at baseline in the placebo group (2.8 mg/dl). Combining data from all cinacalcet dose groups, the mean ± SD serum calcium was 3.2 ± 0.3 mg/d.
Changes in plasma PTH
Cinacalcet caused significant, time-dependent reductions in PTH that reached a nadir at 4 h after dosing in all cinacalcet dose groups. These nadirs were evident throughout the study as assessed on d 1 and 15. The mean PTH value in the combined cinacalcet dose groups 4 h after the first dose was 46.9% below baseline, compared with a 2.6% reduction in the placebo group (P = 0.001). Although PTH increased from its nadir concentrations in the cinacalcet-treated patients, it remained below baseline throughout the 12-h dosing interval in all cinacalcet groups (Fig. 3). The PTH concentration immediately before the second dose on d 1 was not significantly different from placebo (14.4% reduction from baseline in the combined cinacalcet dose groups, compared with a 1.1% increase in the placebo group; P = 0.392). The PTH profile after the second dose on d 1 was similar to the profile after the first dose (Fig. 3). The reduction in PTH of the combined cinacalcet groups 4 h after the second dose was 35.3% below baseline, compared with a 5.5% increase in the placebo group (P = 0.004). The PTH concentrations in the cinacalcet dose groups remained 14.4% below baseline 12 h after the second dose, compared with a 1.4% increase in the placebo group (P = 0.043).
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). On d 15, the mean reductions in PTH in the cinacalcet groups 4 h after dose were -50.4% in the 30-mg dose group, -48.8% in the 40-mg dose group, and -50.6% in the 50-mg dose group, compared with an increase of 0.3% in the placebo group (P = 0.033 for 30 mg, P = 0.023 for 40 mg, and P = 0.052 for 50 mg). Four hours after the second dose on d 15, the mean reductions in PTH were -15.2% in the 30-mg dose group, -37.2% in the 40-mg dose group, and -47.3% in the 50-mg dose group, compared with an increase of 7.6% in the placebo group (P = 0.393 for 30 mg, P = 0.030 for 40 mg, and P = 0.037 for 50 mg). In the combined cinacalcet dose groups, mean PTH was 49.8% and 35.2% below baseline in the cinacalcet-treated patients 4 h after the first and second doses, respectively (P = 0.001 and P = 0.005, respectively). Mean predose PTH values on d 15 were reduced by 20.3% in the combined cinacalcet dose groups and by 1.8% in the placebo group (P = 0.070). Although PTH concentrations increased from nadir values, PTH remained below baseline throughout the 12-h dosing intervals in all dose groups. Seven days after the last dose of cinacalcet, the PTH was reduced by 2.0% in the 30-mg dose group, increased by 9.0% in the 40-mg dose group, and reduced by 8.0% in the 50-mg dose group, compared with an increase of 14.1% in the placebo group. These changes were not significantly different from placebo (P = 0.339 for 30 mg, P = 0.430 for 40 mg, and P = 0.199 for 50 mg).
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No significant differences between the cinacalcet and placebo groups were observed in the 24-h urine calcium excretion, the 24-h urine calcium to creatinine ratio, or the fasting urine calcium to creatinine ratio. At d 15, 24-h urine calcium excretion increased by 51% in the 30-mg dose group, by 15% in the 40-mg dose group, and by 13% in the 50-mg dose group, compared with an increase of 11% in the placebo group (P = 0.756 for 30 mg, P = 1.000 for 40 mg, and P = 0.756 for 50 mg). In the combined cinacalcet dose groups, 24-h urine calcium increased by 25% (P = 0.492). At d 15, the 24-h urine calcium to creatinine ratio decreased by 17% in the 30-mg dose group, by 32% in the 40-mg dose group, and by 11% in the 50-mg dose group, compared with an increase in the placebo group of 16% (P = 0.362 for 30 mg, P = 0.093 for 40 mg, and P = 0.475 for 50 mg). In the combined cinacalcet dose groups, the 24-h urine calcium to creatinine ratio decreased by 22% (P = 0.061). At d 15, the fasting urine calcium to creatinine ratio increased by 8% in the 30-mg dose group, decreased by 30% in the 40-mg dose group, and decreased by 19% in the 50-mg dose group, compared with an increase of 22% in the placebo group (P = 0.475 for 30 mg, P = 0.070 for 40 mg, and P = 0.271 for 50 mg). In the combined cinacalcet dose groups, the fasting urine calcium to creatinine ratio decreased by 16% (P = 0.183). Patients treated with cinacalcet tended to have decreases in their 24-h urine calcium to creatinine ratios compared with baseline values, although the differences were not statistically significant (Fig. 5).
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Adverse events were similar between treatment groups and were mild to moderate in severity as deemed by the investigators. The most common adverse event was paresthesia, and it occurred in three patients receiving cinacalcet and in two patients receiving placebo. All other adverse events occurred in two or fewer patients (Table 2). Mean changes in laboratory parameters from baseline to the end of study were comparable between the two groups, except for the expected pharmacodynamic changes in the endpoint indices of the study.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Currently, no approved medical treatment for primary hyperparathyroidism is available. Nonsurgical alternatives would be desirable for patients with primary hyperparathyroidism who have failed surgery, have metastatic parathyroid carcinoma, or in whom comorbidities place them at higher surgical risk (3). Furthermore, a nonsurgical alternative for asymptomatic primary hyperparathyroidism may be desirable because patients may be at risk for developing progressive bone disease and renal complications (16). Estrogen therapy has been used with some success in patients with primary hyperparathyroidism, with reports suggesting modest reduction in serum calcium and increases in bone mass (17, 18). Alendronate has also recently been shown to increase bone mass in patients with primary hyperparathyroidism (19, 20, 21). However, neither estrogens nor bisphosphonates treat the elevated PTH. Therefore, a need exists for a nonsurgical therapy that can simultaneously suppress PTH and normalize serum calcium, especially in patients with moderate to severe hypercalcemia and in patients who are not surgical candidates.
The results of this study demonstrate that the calcimimetic cinacalcet normalizes serum calcium and lowers PTH concentrations in the study subjects. At all doses tested, serum calcium was reduced to the normal range after 1 d of cinacalcet therapy and remained within the normal range over the course of treatment. Cinacalcet doses of 40 and 50 mg resulted in larger reductions in serum calcium, compared with the 30-mg dose. Serum calcium remained constant throughout the 12-h dosing interval, indicating that calcium homeostasis may have reestablished a new steady state. Significant reductions in PTH were observed at all cinacalcet doses tested 4 h after dosing on both d 1 and d 15. After 15 d of therapy, the predose PTH level was reduced by an average of 20% in the combined cinacalcet groups, compared with no significant change in the placebo group. Maximum decreases in PTH occurred between 2–4 h after dose. PTH drifted upwards from its nadir concentration throughout the 12-h dosing interval; however, it remained below baseline concentrations. Also, mean PTH was reduced to the normal range (10–65 pg/ml) 2–4 h after dosing on both d 1 and d 15 in patients receiving the 50-mg dose. Reductions in PTH were observed after the second daily dose of cinacalcet, although the maximal PTH response (nadir) to the second dose of 30 mg on the 2 d studied in detail was attenuated compared with the first daily dose. A dose-dependent reduction in predose PTH levels was not observed, although a dose response may exist for nadir PTH levels. Among the cinacalcet doses tested, no consistent dose-response trend was observed for serum calcium or PTH, potentially due to the small sample sizes (and large variation) in each group. Furthermore, as expected, cinacalcet also increased serum phosphorus concentrations, likely as a result of reductions in PTH and serum calcium.
No consistent trends in urinary calcium excretion were observed in patients treated with cinacalcet. An increase in urine calcium excretion may be expected after treatment with cinacalcet if it sensitizes the CaRs in the kidney to the ambient calcium level. In addition, a reduction in PTH due to cinacalcet would be expected to decrease the tubular reabsorption of calcium and result in increased urine calcium excretion. These effects to increase urine calcium are offset by a decreased filtered load of calcium that occurs when serum calcium is decreased. More detailed studies are necessary to quantify these effects.
Cinacalcet was well tolerated in the study subjects. The incidence and types of adverse events were similar between the cinacalcet and placebo groups.
In summary, this short-term study demonstrates that the oral calcimimetic cinacalcet, given twice daily, effectively and safely normalized serum calcium and decreased PTH in the study subjects. It has the potential to provide a specific, medical approach to managing primary hyperparathyroidism. Longer-term studies to assess the ability of cinacalcet to control serum calcium and PTH in primary hyperparathyroidism are currently in progress with a goal of evaluating skeletal endpoints.
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Acknowledgments |
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Footnotes |
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Abbreviation: CaR, Calcium-sensing receptor.
Received October 14, 2002.
Accepted August 25, 2003.
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), 40 mg cinacalcet (
), or 50 mg cinacalcet (
) twice daily for the first 15 d and no study drug for the last 7 d (d 16–22). Serum calcium concentration measurements were taken before dosing on d 1 (baseline), 2, 8, 15, and 16. The measurement on d 22 was taken 7 d after the last dose of study drug. The normal range of serum calcium concentrations (8.4–10.3 mg/dl) is demarcated by two horizontal lines.
