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proportion of AMG 073 patients (53%) had a decrease in PTH ≥ 30% compared with

placebo patients (23%; P = 0.009). calcium-
phosphate product levels decreased by

7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P =

0.013). Adverse event rates were low and mostly mild to moderate in severity;

however, the incidence of vomiting was


higher in AMG 073 patients. In this study,
the calcimimetic AMG 073 at doses up to
100 mg for 18 wk provided a safe and

effective means to attain significant


reductions in PTH and calcium-phosphate product in ESRD patients. AMG 073
represents a novel and promising therapy to improve the management of SHPT.
Lindberg JS, Moe SM, Goodman WG, et al.
The calcimimetic AMG 073 reduces

PTH and calcium x phosphorus in secondary hyperparathyroidism. Kidney International. Vol. 63(1)(pp 248-254), 2003.

Seventy-eight hemodialysis patients with SHPT were enrolled into this 18-week, double-blind, randomized, placebo-

controlled, dose titration study. Daily oral AMG 073 doses were administered to

determine the effect on PTH, serum calcium, phosphorus, and calcium-phosphate

product. Results. The mean baseline PTH was similar in patients administered AMG 073 or placebo (632 +/- 280.1 pg/mL vs. 637 +/- 455.9 pg/mL, respectively). PTH

decreased by 26.0% in the AMG 073-treated
group, compared with an increase of 22.0%
in the placebo group (P < 0.001). A greater
proportion in the AMG 073 group (38%) had
a decrease in PTH ≥30%, compared with

the placebo group (8%) (P = 0.001).


Decreases in PTH were independent of
baseline vitamin D usage. Patients receiving
AMG 073 had an 11.9% decrease in
calcium-phosphate product compared with a

10.9% increase in the placebo group (P <

0.001). Use of vitamin D sterols, as well as
both calcium and noncalcium-containing
phosphate binders. were similar between
treatment groups. Administration of AMG
073 was safe and well tolerated in this 18-
week study. Conclusions. The calcimimetic

AMG 073 decreases both PTH and calcium-


phosphate product in hemodialysis patients with SHPT.
Goodman WG, Hladik GA, Turner SA, et al.
The calcimimetic agent AMG 073

lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism.

Journal of the American Society of Nephrology. Vol. 13(4)(pp 1017-
1024), 2002.

Fifty-two hemodialysis patients with SHPT


were given single orally administered doses
of the calcimimetic agent AMG 073 ranging
from 5 to 100 mg, or placebo. Plasma PTH
levels decreased 2 h after 25-, 50-, 75-, or
100mg doses, falling by a maximum of 43
+/- 29%, 40 +/- 36%, 54 +/- 28%, or 55 +/-
39%, respectively. Plasma PTH levels

decreased in all patients given doses of ≥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 aldecreased 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-phosphate 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 ESRD.

Goodman WG, Frazao JM, Goodkin DA, et


al.

A calcimimetic agent lowers plasma parathyroid hormone levels in

patients with secondary hyperparathyroidism.

Kidney International. Vol. 58(1)(pp 436-445),


2000.

Twenty-one patients undergoing


hemodialysis three times per week with
plasma PTH levels between 300 and 1200
pg/mL were randomly assigned to 15 days
of treatment with either 100 mg of R-568 (N
= 16) or placebo (N = 5). Plasma PTH and
blood ionized calcium levels were measured
at intervals of up to 24 hours after oral doses
on days 1, 2, 3, 5, 8, 11, 12, and 15.
Results: Pretreatment PTH levels were 599






+/- 105 (mean +/- SE) and 600 +/- 90 pg/mL in subjects given R-568 or placebo,

respectively, and values on the first day of
treatment did not change in those given
placebo. In contrast, PTH levels fell by 66
+/- 5%, 78 +/- 3%, and 70 +/- 3% at one,

two, and four hours, respectively, after initial doses of R-568, remaining below

pretreatment values for 24 hours. Blood
ionized calcium levels decreased after the
first dose of R-568 but did not change in
patients given placebo. Despite lower

ionized calcium concentrations on both the


second and third days of treatment, predose
PTH levels were 422 +/- 70 and 443 +/- 105
pg/mL, respectively, in patients given R-568,
and values fell each day by more than 50%
two hours after drug administration. Predose
PTH levels declined progressively over the
first nine days of treatment with R-568 and
remained below pretreatment levels for the
duration of study. Serum total and blood

ionized calcium concentrations decreased from pretreatment levels in patients given R-


568, whereas values were unchanged in

those given placebo. Blood ionized calcium levels fell below 1.0 mmol/L in 7 of 16

patients receiving R-568; five patients
withdrew from study after developing

symptoms of hypocalcemia, whereas three


completed treatment after the dose of R-568
was reduced. Conclusions. The calcimimetic
R-568 rapidly and markedly lowers plasma
PTH levels in patients with SHPT caused by
ESRD.
Other studies

Spiegel DM, Casey L, Bell S, Parker M, Chonchol M.

Achieving targets for bone and
mineral metabolism: The impact of
cinacalcet HCl in clinical practice.
Hemodialysis International. Vol.
10(SUPPL. 2)(pp S24-S27), 2006.
The purpose of this study was to evaluate

the effect of the introduction of combination


algorithm for managing SHPT (SHPT) on
phosphorus, calcium, and biointact PTH.
The 61 patients who dialyzed in the facility
from January 2004 (baseline) and who

remained in the facility as of April 2005


(follow-up) were included in the study. In the
baseline period, 37 (61%) of the patients
received paricalcitol at some time during the
3-month observation period. In the follow-up period, 19% or 31% of the patients received cinacalcet HCl. Of those not receiving

cinacalcet HCl, 67% had PTH at or below


target, 17% were felt to be noncompliant
with oral meds, 7% had low calcium, and
10% either could not get the medication or
were not switched to the combination

pathway. Compared with the baseline


period, the percent of patients who met the
PTH target increased from 19.7% to 37.7%,
p<0.05. The percent of patients meeting all

4 targets increased from 14.8% to 24.6%, although this did not reach statistical

significance. The introduction of cinacalcet HCl into a treatment algorithm for

management of SHPT resulted in a


significant increase in the percentage of
patients achieving the PTH target while
maintaining the other mineral metabolism
targets.

Velasco N, MacGregor MS, Innes A, et al.


Successful treatment of

calciphylaxis with cinacalcet - An alternative to parathyroidectomy? Nephrology Dialysis

Transplantation. Vol. 21(7)(pp 1999-
2004), 2006.

No abstract available.


Moe SM, Cunningham J, Bommer J, et al.
Long-term treatment of secondary

hyperparathyroidism with the calcimimetic cinacalcet HCl. Nephrology Dialysis

Transplantation. Vol. 20(10)(pp 2186-2193), 2005.

Dialysis patients with SHPT [PTH level ≥300 pg/ml] who were enrolled in one of four

phase 2 placebo-controlled studies were eligible to enrol in an open-label extension study in which all patients received

cinacalcet. For this extension study,


cinacalcet was initiated at 30 mg in all

patients and the dose was escalated to a maximum of 180 mg once daily if PTH concentrations were >250 pg/ml. Use of concomitant vitamin D sterols and

phosphate binders was not restricted.
Results. The analysis of all patients (n = 59) completing 100 weeks of cinacalcet
treatment showed long-term control of PTH and calcium-phosphate product.

Approximately 55% achieved a PTH


concentration ≤300 pg/ml at the week-100


31


study visit, and ~60% had at least a 30%


reduction in PTH from baseline. Serum
calcium, phosphorus and the calcium-

phosphate product did not increase during the study. Concomitant vitamin D sterol and phosphate binder therapy remained stable. Cinacalcet was safe and generally well

tolerated at doses up to 180 mg/day.
Conclusions. In this long-term study,

cinacalcet effectively sustained reductions in PTH for up to 3 years without increasing

concentrations of serum calcium,
phosphorus or calcium-phosphate product.
Moe SM, Chertow GM, Coburn JW, et al.
Achieving NKF-K/DOQI bone

metabolism and disease treatment goals with cinacalcet HCl. Kidney International. Vol. 67(2)(pp 760-


771), 2005.

The ability of cinacalcet HCl (Sensipar)


treatment to improve achievement of target
levels of PTH, calcium, phosphorus, and
calcium-phosphate product was investigated
in subjects on dialysis with secondary HPT.
Methods. Data were combined from three
placebo-controlled, double-blind, 26-week
studies with similar design that randomized
1136 subjects on dialysis to receive
traditional therapy plus cinacalcet or
placebo. Oral cinacalcet was titrated from 30
to 180 mg/day. Achievement of K/DOQI
goals was determined for each treatment
group overall and for subgroups defined by
baseline intact PTH (iPTH) and Ca x P
levels. Results. Cinacalcet-treated subjects
were more likely to achieve a mean iPTH
≤300 pg/mL (31.8 pmol/L) than were control
subjects on traditional therapy (56% vs.
10%, P <0.001). Cinacalcet-treated subjects
were more likely to achieve concentrations
of serum calcium within 8.4 to 9.5 mg/dL
(2.10-2.37 mmol/L) and serum phosphorus
within 3.5 to 5.5 mg/dL (1.13-1.78mmol/L)
than were control subjects (49% vs. 24%
and 46% vs. 33%, P < 0.001 for each).
Cinacalcet alimproved achievement of Ca x
P < 55 mg2/dL2 (4.44 mmol2/L2) and
concurrent achievement of Ca x P <55
mg2/dL2 (4.44 mmol2 /L2) and iPTH ≤300
pg/mL (31.8 pmol/L) (65% vs. 36% and 41%
vs. 6%, P < 0.001 for each). Conclusion. In
subjects on dialysis with secondary HPT,
cinacalcet facilitates achievement of the
K/DOQI-recommended targets for PTH,
calcium, phosphorus, and calcium-
phosphate product.
Use in Children
No papers found.
Predictors of response
No papers found.
Safety
No papers found.
Health economics, resources, risk/benefit

Cunningham J, Danese M, Olson K, et al.


Effects of the calcimimetic

cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary

hyperparathyroidism. Kidney
International. Vol. 68(4)(pp 1793-
1800), 2005.

We undertook a combined analysis of safety data (parathyroidectomy, fracture,

hospitalizations, and mortality) from 4
similarly designed randomized, double -
blind, placebo-controlled clinical trials

enrolling 1184 subjects (697 cinacalcet, 487 control) with ESRD and uncontrolled

secondary HPT (intact PTH ≥300 pg/mL). Cinacalcet or placebo was administered to subjects receiving standard care for

hyperphosphatemia and secondary HPT


(phosphate binders and vitamin D). Relative
risks (RR) and 95% CI were calculated
using proportional hazards regression with
follow-up times from 6 to 12 months.
HRQOL data were obtained from the
Medical Outcomes Study Short Form-36
(SF-36), and the Cognitive Functioning scale
from the Kidney Disease Quality of Life
instrument (KDQOL-CF). Results.
Randomization to cinacalcet resulted in
significant reductions in the risk of
parathyroidectomy (RR 0.07, 95% CI 0.01-

0.55), fracture (RR 0.46, 95% CI 0.22-0.95),


and cardiovascular hospitalization (RR0.61,






95% CI 0.43-0.86) compared with placebo.


Changes in HRQOL favored cinacalcet, with
significant changes observed for the SF-36
Physical Component Summary score and
the specific domains of Bodily Pain and

General Health Perception. Conclusion.


Combining results from 4 clinical trials,

randomization to cinacalcet led to significant


reductions in the risk of parathyroidectomy,
fracture, and cardiovascular hospitalization,
along with improvements in self-reported

physical function and diminished pain. These data suggest that, in addition to its effects on PTH and mineral metabolism, cinacalcet had favorable effects on

important clinical outcomes.
Phosphate Binders

Efficacy


RCTs - sevelamer

Liu Y-L, Lin H-H, Yu C-C, et al.


A comparison of sevelamer

hydrochloride with calcium acetate on biomarkers of bone turnover in hemodialysis patients. Renal

Failure. Vol. 28(8)(pp 701-707),
2006.

In this prospective, open-label, randomized, active-controlled study, 70 patients (38 men and 32 women) with hyperphosphatemia (serum phosphorus level >6.0 mg/dL)

underwent a two-week washout period and were randomly selected to receive

sevelamer hydrochloride (n = 37) or calcium acetate (n = 33) for eight weeks. Changes in serum levels of intact PTH, alkaline

phosphatase (Alk-P), phosphorus, and
calcium were measured and compared.
Results. After eight weeks of treatment,
calcium acetate lowered iPTH levels

significantly more than sevelamer


hydrochloride did (-178.0 vs. -69.0 pg/mL, p
= 0.0019). Levels of Alk-P were significantly
elevated in patients given sevelamer
hydrochloride compared with levels in those
given calcium acetate treatment (24.09 vs.

7.45 U/L, p = 0.0014). Changes in serum


phosphorus levels did not differ between
sevelamer hydrochloride (-1.93 mg/dL) and
calcium acetate (-2.5 mg/dL) at the end of
the study (p = 0.0514). Changes in the

calcium and phosphorous product did not


significantly differ between the sevelamer-
hydrochloride group (-18.06 mg 2 /dL2 ) and the calcium-acetate group (-19.05 mg 2 /dL2 , p = 0.6764). Fifteen patients (45.5%)

treated with calcium acetate had


hypercalcemia (serum-adjusted calcium
level >10.5 mg/dL); the rate was significantly
higher than that of patients treated with
sevelamer (five [13.5%] of 37, p = 0.0039).
Conclusion. Treatment with sevelamer
hydrochloride had the advantage of
maintaining stable iPTH levels and elevating
Alk-P levels while lowering serum
phosphorus levels and calcium-phosphate
product.

Fischer D, Cline K, Plone MA, et al.


Results of a Randomized Crossover

Study Comparing Once-Daily and Thrice-Daily Sevelamer Dosing. American Journal of Kidney

Diseases. Vol. 48(3)(pp 437-444),
2006.

Twenty-four patients were enrolled in this study, 21 of whom were randomly assigned to sevelamer administration at their

previously prescribed dose, either once daily with the largest meal or thrice daily with

meals, with crossover to the other regimen after 4 weeks. Eighteen patients completed both treatment periods. The primary efficacy measure for which the study was powered is comparison of the effect of once-daily

versus standard thrice-daily sevelamer
dosing on serum phosphorus level control,
determined by using equivalence testing.
Secondary efficacy measures are the effects
of the 2 regimens on serum calcium level
corrected for albumin level; calcium-
phosphate product; albumin; intact PTH;
total, low-density lipoprotein, high-density
lipoprotein, and non-high-density lipoprotein
cholesterol; and triglyceride levels. Results:
Once-daily sevelamer was as effective as
thrice-daily dosing of sevelamer in
controlling serum phosphorus, calcium,
calcium-phosphate product, serum albumin,
and serum lipid levels. Bioequivalence was
not shown for intact PTH, likely because of
high variability. Mean serum phosphorus
levels were 4.6 +/- 0.3 mg/dL (1.49 +/- 0.10
mmol/L) during thrice-daily dosing and 5.0
+/- 0.3 mg/dL (1.61 +/- 0.10 mmol/L) during
once-daily dosing. The average prescribed
dose of sevelamer during both treatment
regimens was 6.7 +/- 2.4 g. Routine






laboratory measures were similar in the 2 groups. Both regimens were well-tolerated. Conclusion: Despite concerted patient-

directed educational efforts, phosphorus
level control in patients with renal failure is
suboptimal and contributes to increased
mortality risk. Once-daily sevelamer could
simplify these regimens and encourage

medication compliance, perhaps improving hyperphosphatemia management.


Block GAD,Spiegel M, et al. Effects of
sevelamer and calcium on coronary

artery calcification in patients new to hemodialysis. Kidney Int 68(4):

1815-24, 2005.

One hundred and twenty-nine patients new


to hemodialysis were randomized to receive
calcium containing phosphate binders or the
noncalcium phosphate binder sevelamer

hydrochloride. Subjects underwent electron beam computed tomography scanning

(EBCT) at entry into the study and again at 6, 12, and 18 months. RESULTS: One

hundred and nine patients underwent


baseline and at least one additional

assessment of coronary calcification. At


baseline, 37% of sevelamer treated and
31% of calcium treated patients had no
evidence of coronary calcification. No

subject with a zero coronary artery calcium score (CACS) at baseline progressed to a CACS >30 over 18 months. Subjects with a CACS > 30 at baseline showed progressive increases in CACS in both treatment arms (P < 0.05 for each time point in both

groups). Subjects treated with calcium
containing phosphate binders showed more rapid and more severe increases in CACS when compared with those receiving
sevelamer hydrochloride (P= 0.056 at 12 months, P= 0.01 at 18 months).

CONCLUSION: New hemodialysis patients with no evidence of coronary calcification showed little evidence of disease

development over 18 months independent of phosphate binder therapy. However,

subjects with evidence of at least mild


coronary calcification had significant

progression at 6, 12, and 18 months. Use of calcium containing phosphate binders

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