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*Department of Medicine, UCLA School of Medicine, Los Angeles, California; Division of Nephrology, University of North Carolina, Chapel Hill, North Carolina; Amgen Inc., Thousand Oaks, California; VA Medical Center, Little Rock, Arkansas; ||Presbyterian Medical Center, Philadelphia, Pennsylvania;and ¶VA Medical Center, West Los Angeles, California.
Correspondence to: Dr. William G. Goodman, Division of Nephrology, 7-155 Factor Building, UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095. Phone: 310-206-2650; Fax: 310-825-6309; E-mail: wgoodman{at}ucla.edu
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Abstract |
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25 mg but did not change in those who received placebo. In patients treated with daily doses of 25 or 50 mg of AMG 073 for 8 d, plasma PTH levels declined for the first 3 to 4 d and remained below baseline values after 8 d of treatment. Serum calcium concentrations also decreased by 5 to 10% from pretreatment levels in patients given 50 mg of AMG 073 for 8 d, but values were unchanged in those who received lower doses. Serum phosphorus levels and values for the calcium-phosphorus ion product both decreased after treatment with AMG 073. Thus, 8 d of treatment with AMG 073 effectively lowers plasma PTH levels and improves several disturbances in mineral metabolism that have been associated with soft tissue and vascular calcification and with adverse cardiovascular outcomes in patients with end-stage renal disease. |
Introduction |
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Calcimimetic agents are small organic compounds that act as allosteric activators of the calcium-sensing receptor in the parathyroid glands and other tissues (11,12). They lower the threshold for calcium-sensing receptor activation by extracellular calcium ions, thereby diminishing parathyroid hormone (PTH) secretion. By targeting directly the molecular mechanism that modulates calcium-regulated PTH release from the parathyroid cell, calcimimetic compounds provide a novel approach to managing excess PTH secretion in several clinical disorders, including secondary hyperparathyroidism due to chronic renal failure (13).
Previous short-term studies have shown that orally administered doses of the calcimimetic agent R-568 lower plasma PTH levels in hemodialysis patients with secondary hyperparathyroidism (14,15). The bioavailability of R-568 is limited, however, and the pharmacokinetics of the drug vary considerably among patients (15). As such, the effect of treatment with R-568 on plasma PTH levels, and in particular on serum calcium concentrations, is heterogeneous (15). To address these issues, another phenylalkylamine, known as AMG 073, with calcimimetic properties similar to those of R-568 has been developed. The bioavailability of AMG 073 after oral administration is greater and it exhibits a more consistent pharmacokinetic profile than R-568 (Amgen Inc., unpublished data).
The current preliminary study was undertaken to characterize the effect of various single orally administered doses of AMG 073 on plasma PTH levels and on serum calcium concentrations in adult hemodialysis patients with secondary hyperparathyroidism. The biochemical response to different doses of AMG 073 given once daily for 8 consecutive days was also evaluated.
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Materials and Methods |
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All study candidates had biochemical evidence of secondary hyperparathyroidism, as judged by the results of two plasma PTH determinations obtained at least 1 wk apart and within 21 d of the initial dose of AMG 073 that were between 250 and 1500 pg/ml. Additional inclusion criteria were serum total calcium values of 9.0 mg/dl after correcting for serum albumin concentrations, serum phosphorus levels of 2.5 mg/dl, and serum aluminum levels <40 µg/L. Study participants were also required to have a hemoglobin level 10 g/dl or a blood hematocrit 30%, a chest radiograph within the past 6 mo showing no evidence of active parenchymal disease, and a body mass index between 15 and 40 kg/m2.
Women of childbearing age were excluded from study unless they had previously been rendered sterile surgically for other medical reasons. Patients were ineligible for study if the serum levels of hepatic transaminases or bilirubin were more that twice the upper limit of normal. Additional exclusion criteria included a history of seizures within the past 12 mo, malignancy within the past 5 yr, hyperthyroidism, myocardial infarction within the previous 6 mo, a cardiac ventricular rhythm disturbance requiring active treatment, a gastrointestinal disorder that could affect the absorption of drugs given orally, or granulomatous diseases that could cause hypercalcemia.
Study Design
The study was conducted in two phases, a single-dose phase and a multiple-dose phase, each of which was completed as a randomized, double-blinded, placebo-controlled, multicenter clinical trial. All study procedures were reviewed and approved by the institutional review boards at each study site, and written informed consent was obtained from each participant.
Single-Dose Phase
The first phase of the study was undertaken to assess the biochemical response to single orally administered doses of AMG 073 or placebo. Participants were initially randomized to treatment with either placebo or 5 mg of AMG 073. Subsequent assessments that used incrementally larger doses of AMG 073 were performed only after the clinical and biochemical results for the preceding dosage cohort had been reviewed by a safety advisory committee. For the single-dose phase of the study, patients were randomly assigned to treatment with 5 mg (n = 8), 10 mg (n = 8), 25 mg (n = 6), 50 mg (n = 6), 75 mg (n = 6), or 100 mg (n = 6) of AMG 073 or placebo (n = 12). Ninety-eight patients were screened as potential study participants, and 52 of these were entered onto the trial. The mean age of patients who participated in the single dose phase of the study was 48 ± 14 yr (range, 19 to 75 yr).
Doses of AMG 073 were given orally within 3 h after completing regularly scheduled hemodialysis treatments. Patients were admitted to the hospital for 3 d beginning immediately after hemodialysis for the administration of the study drug and for safety monitoring procedures. At admission, study participants underwent a physical examination, and blood was drawn for a complete blood count and for various baseline, or pretreatment, biochemical determinations. These included measurements of serum total calcium and phosphorus levels and plasma PTH concentrations.
Additional blood samples were obtained 30 min and 1, 2, 4, 8, 12, 24, 48, and 72 h after the administration of AMG 073. Calcium concentrations in serum and PTH levels in plasma were determined for each sample. Subsequent hemodialysis sessions after test doses of AMG 073 were continued according to the patient’s regular schedule of treatment.
Multiple-Dose Phase
For the multidose phase of the trial, study participants were randomly assigned to receive single daily orally administered doses of 10 mg (n = 8), 25 mg (n = 6), or 50 mg (n = 9) of AMG 073 or placebo (n = 7) for 8 d. Follow-up evaluations were performed on days 11 and 15 of the study (3 and 7 d, respectively) after the last dose of AMG 073 or placebo. Patients who participated in the single-dose phase of the study were eligible to enroll in the 8-d multidose trial after an interval of 4 wk. Twenty-seven of the 30 patients who entered the multiple-dose phase of the study had previously received single orally administered doses of AMG 073; 3 had not. The mean age of participants in the multiple-dose phase of the trial was 46 ± 16 yr (range, 19 to 77 yr).
Because the effect of repeated daily doses of AMG 073 on serum calcium concentrations was unknown when the study was started, participants were randomized initially to treatment with placebo or the lowest dose of AMG 073: 10 mg. A safety monitoring committee reviewed the clinical and biochemical results for the 10-mg dosage cohort before patients were assigned to treatment with the next larger dose of AMG 073 (25 mg). Similarly, results from the 25-mg dosage cohort were reviewed before patients were randomized to treatment with 50 mg of AMG 073 or placebo.
Initial doses of AMG 073 on the first day of study were given within 3 h after completing regularly scheduled hemodialysis procedures and after patients had been admitted to the hospital. Subsequent doses for the remaining 8 d of treatment were given at the same time of day. Study participants were monitored in hospital for the duration of treatment. All doses of AMG 073 on days corresponding to regularly scheduled dialysis sessions were given after hemodialysis.
On the first and eighth day of treatment, blood samples were obtained immediately before and 0.5, 1, 2, 4, 8, 12, and 24 h after doses of AMG 073 for subsequent determinations of serum total calcium and plasma PTH levels. Blood specimens for plasma PTH and serum calcium measurements were collected just before dosing on each day of treatment, and serum phosphorus levels were measured on the first, fourth, and eighth day of treatment. Additional blood samples were obtained 4 and 12 h after each dose of AMG 073 to monitor serum calcium concentrations for safety purposes. For all days on which AMG 073 was given, baseline, or predose, blood samples for biochemical measurements were obtained just before drug administration. Blood samples for posttreatment biochemical determinations on study day 11 and 15 were obtained at the same time of day. Hemodialysis was continued throughout the study by means of previously established individualized treatment regimens. All dialysis parameters, including the concentration of calcium in dialysate, were kept constant throughout the study.
Three patients who were originally assigned to treatment with daily doses of 50 mg of AMG 073 had their dose reduced to 25 mg on the second or third day of study. In 2 patients, doses were reduced because serum total calcium concentrations transiently fell below 8.0 mg/dl; the dose was reduced in a third patient because of nausea that occurred together with a serum calcium concentration of 8.2 mg/dl. None of these patients experienced symptoms of hypocalcemia, and all successfully completed 8 d of treatment with AMG 073 at the lower dose of 25 mg/d.
Laboratory Determinations
Serum electrolyte concentrations and the serum levels of total calcium, phosphorus, aspartate aminotransferase, and alanine aminotransferase were measured with a Hitachi 747-200 autoanalyzer (15). Hemoglobin levels were measured by automated methods as described previously, and hematocrit values were determined by centrifugation (15). Plasma PTH levels were measured with a double-antibody immunoradiometric assay (Allegro PTH; Nichols Institute Diagnostics, San Juan Capistrano, CA) (16). Serum calcium concentrations were corrected for variations in plasma albumin levels, and corrected values are reported.
Statistical Analyses
All results are expressed as mean ± 1 SD. For the single-dose phase of the study, the maximum percentage decrease in plasma PTH levels from predose values among groups was compared by ANOVA (17). For the multiple-dose phase of the study, ANOVA was again used to compare the percentage change from baseline values in plasma PTH levels on the eighth day of treatment among treatment groups (17). For all statistical tests, P < 0.05 was considered significant.
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Results |
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Similar percentage reductions in plasma PTH levels were seen on the eighth day of treatment. Values fell from 401 ± 238 to 233 ± 84 pg/ml, or by 42%, 4 h after 25-mg doses and from 663 ± 624 to 455 ± 481 pg/ml, or by 32%, 4 h after 50-mg doses of AMG 073. In contrast to these findings, plasma PTH levels did not change on the eighth day of treatment in patients given placebo or 10-mg doses of AMG 073.
Plasma PTH levels, measured in plasma samples obtained immediately before each dose and 24 h after the dose, decreased during the first 3 to 4 d of treatment in patients who received daily doses of 25 or 50 mg of AMG 073 for 8 d (Figure 4). Values also decreased in the 50/25-mg group despite early downward adjustments to the dose. In contrast, plasma PTH values remained unchanged in patients given placebo or 10-mg doses of AMG 073 for 8 d. The decrease in plasma PTH levels from baseline values on the eighth day of treatment averaged 28 ± 17% in the 25-mg group, 27 ± 34% in the 50-mg group, and 34 ± 39% in the 50/25-mg group. Collectively, the percentage change in plasma PTH levels for these three treatment groups differed from that seen in patients given placebo (P = 0.05 by ANOVA).
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Serum phosphorus concentrations after 8 d of treatment were lower than baseline values in all 4 groups of patients given AMG 073 but did not change in those given placebo (Figure 6). Values for the calcium-phosphorus ion product in serum were also lower than baseline levels after 8 d of treatment with AMG 073 but did not differ from baseline values in patients given placebo (Figure 6).
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Discussion |
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For patients given daily doses of 25 or 50 mg of AMG 073 for 8 d, plasma PTH levels decreased by 30 to 40% within the first few days of treatment and remained below baseline values when assessed by use of results obtained immediately before each daily dose—that is, 24 h after the preceding dose. Substantially greater reductions in plasma PTH levels were evident, however, on the first and eighth day of treatment when measurements were performed in plasma samples obtained more frequently during the 24 h immediately after daily doses of AMG 073. Plasma PTH concentrations were 50 to 70% below predose values 2 to 4 h after 25- or 50-mg doses, levels substantially lower than those determined 12 to 24 h later. Thus, predose plasma PTH measurements understate the effectiveness of daily doses of AMG 073 in reducing plasma PTH levels throughout the day in patients with secondary hyperparathyroidism due to ESRD.
Serum calcium concentrations declined modestly during 8 d of treatment with daily orally administered doses of 25 or 50 mg of AMG 073, but none of the patients developed signs or symptoms of hypocalcemia. It is of particular interest that serum phosphorus levels fell by 20 to 30%. Values for the calcium-phosphorus ion product in serum also decreased, primarily as a result of reductions in serum phosphorus levels. Such findings indicate that repeated daily doses of AMG 073 not only reduce the biochemical severity of secondary hyperparathyroidism in patients undergoing regular hemodialysis, but also favorably affect several abnormalities in mineral metabolism that have been implicated as contributors to vascular and soft tissue calcification and to cardiovascular mortality in patients with ESRD (8,18). Longer-term studies will be required, however, to determine whether similar changes in serum phosphorus levels and in values for the calcium-phosphorus ion product in serum can be achieved during sustained treatment with AMG 073.
The mechanism responsible for the decreases in serum calcium and phosphorus concentrations during treatment with AMG 073 and other calcimimetic compounds remains uncertain. Reductions in serum calcium levels have been a consistent finding after the administration of sufficiently large doses of calcimimetic agents to subtotally nephrectomized rats (19–21), and serum calcium concentrations declined in some adult hemodialysis patients with secondary hyperparathyroidism who were given fixed daily doses of the calcimimetic compound R-568 for 15 d (15). Because plasma PTH levels fall abruptly after the administration of calcimimetic agents, calcium and phosphorus efflux from bone into plasma may decrease substantially, leading to reductions in the serum levels of both calcium and phosphorus within a few hours. This mechanism probably accounts for the reductions in serum calcium and phosphorus concentrations that occur after surgical parathyroidectomy, a clinical condition known as the "hungry bone syndrome." Alternatively, the activation of calcium-sensing receptor in bone or other tissues could theoretically account for rapid changes in serum calcium and phosphorus levels after the administration of calcimimetic agents (22,23). To date, little information is available that addresses this issue directly.
Additional studies are needed to clarify the role of concurrent therapy with either vitamin D sterols or orally administered calcium supplements as a means of offsetting the effect of calcimimetic agents to lower serum calcium concentrations. The proportion of patients who might require such interventions remains uncertain, and the role of alternative dosing regimens that could attenuate the calcium-lowering effect of calcimimetic compounds has yet to be fully evaluated. Calcimimetic compounds might be particularly valuable, however, in treating patients with secondary hyperparathyroidism whose serum calcium levels are already marginally or overtly elevated and in whom vitamin D therapy frequently raises serum calcium and phosphorus concentrations further.
The current management of secondary hyperparathyroidism due to chronic renal failure relies predominantly on the use of orally administered calcium supplements and the oral or intravenous administration of vitamin D sterols to control excess PTH secretion (24). Both interventions act directly on parathyroid cells to diminish pre–pro-PTH gene transcription and hormone synthesis, but they also raise serum calcium concentrations, leading indirectly to decreases in PTH secretion (24). Treatment with vitamin D often increases serum phosphorus levels and values for the calcium-phosphorus ion product in serum. These changes, together with increases in serum calcium concentrations, frequently limit the doses that can be given safely to patients with ESRD. Hypercalcemia is common during vitamin D therapy, particularly in those who are already ingesting large orally administered doses of calcium as phosphate-binding agents. Because of concerns about disturbances in calcium and phosphorus metabolism, and the therapeutic interventions used to manage them, as potential contributors to vascular and soft tissue calcification in patients with chronic renal failure, alternative strategies for controlling excess PTH secretion in such patients are of considerable interest (25).
Several new vitamin D sterols have become available for the treatment of secondary hyperparathyroidism in patients with ESRD (24). These include 19-nor-1,25-dihydroxyvitamin D2, or paricalcitol, and 1
-hydroxyvitamin D2, or doxercalciferol (3–5). Both have been shown to effectively lower plasma PTH levels in hemodialysis patients with secondary hyperparathyroidism, and serum calcium and phosphorus levels change little or rise modestly during the 12 to 16 wk of treatment. Serum calcium and phosphorus concentrations do not decline, however, even when plasma PTH levels fall in those who respond favorably to treatment with vitamin D sterols, whereas serum calcium and phosphorus levels decreased during treatment with AMG 073. Differences in the mechanism of action between calcimimetic agents and vitamin D sterols probably account for the disparate biochemical responses to these two distinct classes of therapeutic agents (24).
In summary, repeated daily orally administered doses of the calcimimetic agent AMG 073 effectively reduce plasma PTH levels, decrease serum phosphorus concentrations, and lower the calcium-phosphorus ion product in hemodialysis patients with secondary hyperparathyroidism. Calcimimetic compounds represents a novel approach for controlling excess PTH secretion in patients with chronic renal failure, and their use may favorably affect several potentially deleterious abnormalities in mineral metabolism in patients with ESRD. Additional studies will be required to establish the safety and long-term benefits of calcimimetic therapy in patients with secondary hyperparathyroidism. Nevertheless, calcimimetic compounds provide an effective therapeutic intervention to control excess PTH secretion with potentially beneficial effects on mineral metabolism in patients with ESRD.
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Acknowledgments |
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References |
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-25-dihydroxyvitamin D2 (paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol 9: 1427–1432, 1998[Abstract]
-hydroxyvitamin D2) therapy for secondary hyperparathyroidism. Am J Kidney Dis 36: 562–565, 2000[Medline]
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