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Results of the CARE study. Kidney International - Supplement. Vol.

66(90)(pp S33-S38), 2004.


Most patients with ESRD develop

hyperphosphatemia because their dietary intake exceeds phosphorus elimination by intermittent thrice-weekly dialysis.

Inadequately treated hyperphosphatemia plays a central role in the pathogenesis of SHPT and extraosseous calcification.

Moreover, in the last 15 years, this


biochemical abnormality has become
increasingly important following the

publication of two epidemiologic studies that demonstrated an association between

elevated serum phosphorus and increased mortality risk in patients with ESRD. As a result, the National Kidney Foundation

Kidney Disease Outcome and Quality


Initiative (K/DOQI) Bone Metabolism and
Chronic Kidney Disease Guidelines
recommend that serum phosphorus levels
be maintained between 3.5 and 5.5 mg/dL.






Unfortunately, cross-sectional studies have shown a mean serum phosphorus of 6.2 mg/dL in the maintenance hemodialysis

population in the United States. An alarming 60% of patients have serum phosphorus in excess of the 5.5 mg/dL level recommended by K/DOQI guidelines. In order to achieve this new target for serum phosphorus, the most efficacious and cost-effective

phosphate binders currently available should be utilized. In this review, we discuss the

results of the Calcium Acetate Renagel
Evaluation (CARE study), which clearly
demonstrated the superiority of calcium
acetate over sevelamer hydrochloride for

controlling serum phosphorus and calcium-


phosphate product to the levels

recommended by the K/DOQI guidelines.


Pai AB, Smeeding JE, Brook RA.
The role of sevelamer in achieving

the kidney disease outcomes quality initiative (K/DOQI) guidelines for

hyperphosphatemia. Current
Medical Research & Opinion. Vol. 20(7) (pp 991-999), 2004.

Disregulation of mineral metabolism


(principally hyperphosphatemia and

hypercalcemia) contributes to substantial morbidity and mortality. Accordingly, new and more-aggressive Kidney Disease

Outcomes Quality Initiative (K/DOQI) Guidelines from the National Kidney Foundation promote lower serum

phosphorus (3.5-5.5 mg/dL), lower calcium (8.4-9.5 mg/dL), and lower calcium-

phosphate product (< 55 mg2/dL2) targets.
Review findings: Traditional calcium-based
and metal-based phosphate binders are

effective but are associated with side effects and toxicity that limit their use. Achieving

rigorous K/DOQI goals demands higher
therapeutic doses of phosphate binders and
may require more-aggressive use of
calcium-free and metal-free phosphate
binders. Sevelamer hydrochloride is a
calcium- and metal-free polymer that binds
phosphate effectively without contributing to
calcium load or metal accumulation. In the
Treat-to-Goal trial, sevelamer-treated
dialysis patients had less progression of
coronary and aortic calcification than
patients treated with calcium-based binders.
This offers the potential promise of reducing
cardiovascular morbidity and mortality. The
800mg tablet (Renagel*) increases the daily
sevelamer dose while reducing the number of tablets required per meal. Nine of the

800mg tablets per day (3 x 800mg tablets tid with meals) of sevelamer monotherapy have been shown to achieve K/DOQI serum

phosphorus and calcium-phosphate product
targets. Conclusion: In summary, this review
of the current evidence-base concludes that
the new, more-aggressive, K/DOQI goals
limit the use of metal-based and calcium-

based phosphate binders. Sevelamer offers the advantages of lowering serum

phosphorus without the risks of calcium or metal accumulation - and offers the promise of slowing the progression of vascular

calcification and potentially reducing the morbidity and mortality of hemodialysis patients.

Swainston Harrison T, Scott LJ.
Lanthanum carbonate. Drugs. Vol.

64(9)(pp 985-996), 2004.

Lanthanum carbonate (elemental lanthanum 375-3000 mg/day) reduced serum

phosphorus levels compared with placebo in


two randomised, double-blind, multicentre 4-
week trials in patients with CRF receiving

regular haemodialysis. In two large,


randomised trials in patients with CRF
requiring haemodialysis, lanthanum

carbonate (elemental lanthanum 375-3000 mg/day) was as effective as calcium

carbonate and/ or other conventional
phosphate binders in reducing and

maintaining serum phosphorus levels (≤5.6


mg/ dL over 6 months and ≤5.9 mg/dL over

2 years). Lanthanum carbonate was


generally well tolerated. Most adverse

events were mild-to-moderate in severity, with gastrointestinal events being the most common. The tolerability profile of

lanthanum carbonate was similar to those of conventional phosphate binders; however, hypercalcaemic episodes occurred

significantly less frequently over 6 months with lanthanum carbonate than with calcium carbonate. In a randomised 1-year trial,

numerically fewer lanthanum carbonate
(elemental lanthanum ≤3750 mg/day)

recipients had renal bone disease at study end than at baseline; however, in the

calcium carbonate 59000 mg/day group, numerically more patients had renal bone disease at study end compared with

baseline.






Charytan C, Coburn JW, Chonchol M, et al.



Clinical Studies

Cinacalcet

Efficacy

RCTs


Lindberg JS, Culleton B, Wong G, et al.
Cinacalcet HCl, an oral calcimimetic

agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: A

randomized, double-blind,
multicenter study. Journal of the
American Society of Nephrology.
Vol. 16(3)(pp 800-807), 2005.
This phase 3, multicenter, randomized,

placebo-controlled, double-blind study


evaluated the efficacy and safety of
cinacalcet in hemodialysis (HD) and

peritoneal dialysis (PD) patients with PTH


≥300 pg/ml despite traditional therapy. A

total of 395 patients received once-daily oral cinacalcet (260 HD, 34 PD) or placebo (89 HD, 12 PD) titrated from 30 to 180 mg to

achieve a target intact PTH (iPTH) level of ≤250 pg/ml. During a 10-wk efficacy

assessment phase, cinacalcet was more


effective than control for PTH reduction
outcomes, including proportion of patients
with mean iPTH levels ≤300 pg/ml (46

versus 9%), proportion of patients with


≥30% reduction in iPTH from baseline (65
versus 13%), and proportion of patients with
≥20, ≥40, or ≥50% reduction from baseline.
Cinacalcet had comparable efficacy in HD
and PD patients; 50% of PD patients
achieved a mean iPTH ≤300 pg/ml.
Cinacalcet alsignificantly reduced serum
calcium, phosphorus, and calcium-
phosphate product levels compared with
control treatment. The most common side
effects, nausea and vomiting, were usually
mild to moderate in severity and transient.
Once-daily oral cinacalcet was effective in
rapidly and safely reducing PTH, Ca P,
calcium, and phosphorus levels in patients
who received HD or PD. Cinacalcet offers a
new therapeutic option for controlling SHPT
in patients with CKD on dialysis.

Cinacalcet hydrochloride is an


effective treatment for secondary

hyperparathyroidism in patients with CKD not receiving dialysis.

American Journal of Kidney
Diseases. Vol. 46(1)(pp 58-67),
2005.

This phase 2 study evaluated the effects of the oral calcimimetic cinacalcet

hydrochloride in patients with CKD not on dialysis therapy. Methods: A randomized, double-blind, placebo-controlled, 18-week study enrolled adults with an estimated glomerular filtration rate of 15 to 50

mL/min/1.73 m2 (0.25 to 0.83 mL/s/1.73 m2)


and an intact PTH (iPTH) level greater than
130 pg/mL (ng/L). Cinacalcet (or placebo)
was titrated from 30 to 180 mg once daily to
obtain a 30% or greater reduction in iPTH
levels from baseline. Results: Baseline

mean iPTH levels were 243 pg/mL (ng/L) in the cinacalcet group (n = 27) and 236 pg/mL (ng/L) in the control group (n = 27). At

baseline, 28% of subjects were being
administered vitamin D sterols and 43%

were being administered phosphate binders or calcium supplements. The addition of

cinacalcet significantly decreased iPTH
concentrations compared with controls

during the efficacy-assessment phase: 56%


versus 19% of subjects achieved a 30% or
greater reduction in iPTH levels (P = 0.006),
and mean iPTH levels decreased by 32% in
the cinacalcet group, but increased by 6% in
the control group (P < 0.001). Mean serum
calcium and phosphorus levels remained

within normal range throughout the study. Cinacalcet generally was well tolerated; the most frequent adverse events were

gastrointestinal. Conclusion: This
preliminary study provides evidence that
cinacalcet is efficacious for the treatment of
SHPT in subjects with CKD not receiving
dialysis.
Lien Y-HH, Silva AL, Whittman D.
Effects of cinacalcet on bone

mineral density in patients with secondary hyperparathyroidism. Nephrology Dialysis

Transplantation. Vol. 20(pp 1232-
1237), 2005.

We investigated the effects of cinacalcet


treatment on bone mineral density (BMD) in
patients with SHPT due to CKD. Methods.






Ten patients who were receiving


haemodialysis and four patients, who had
stage 4 CKD participated and completed the
multicentre, randomized, double-blind,
placebo-controlled trials evaluating the
safety and efficacy of cinacalcet for treating
SHPT. The efficacy of cinacalcet was
assessed by plasma intact PTH levels. A
dual energy X-ray absorptiometry was
performed to measure the BMD of total
proximal femurs and lumbar spine (L2-L4)
before and after 26 weeks of treatment.
Results. Cinacalcet reduced iPTH from 912
+/- 296 to 515 +/- 359 pg/ml in

haemodialysis patients and from 210 +/- 46


to 56 +/- 51 pg/ml in pre-dialysis patients
(means +/- SD; both P < 0.05). When data

from haemodialysis and pre-dialysis patients were pooled for analysis, cinacalcet

treatment increased proximal femur BMD from 0.945 +/- 0.169 to 0.961 +/- 0.174 g/cm2 (P < 0.05), but did not affect lumbar spine BMD. There was a correlation

between the change in femur BMD and the


change in iPTH during the study period (R2
= 0.39, P < 0.05). Conclusions. SHPT is
associated with progressive bone loss.

Suppression of plasma iPTH with cinacalcet appears to reverse bone loss in the proximal femur, but does not affect BMD of the

lumbar spine. A larger study is warranted to confirm that cinacalcet has a beneficial

effect on the skeletal system in patients with SHPT.


Harris RZ, Padhi D, Marbury TC, et al.
Pharmacokinetics,

pharmacodynamics, and safety of cinacalcet hydrochloride in

hemodialysis patients at doses up to 200 mg once daily. American

Journal of Kidney Diseases. Vol. 44(6) (pp 1070-1076), 2004.

This study investigated the

pharmacokinetics, pharmacodynamics,


safety, and tolerability of cinacalcet HCl over
a dose range of 25 to 300 mg/d in patients
receiving dialysis. Methods: Hemodialysis
patients were randomly assigned 4:1 to
receive cinacalcet HCl or placebo in this
double-blind study. Cinacalcet HCl doses
were escalated weekly in 25mg increments
from 25 to 300 mg/d. Noncompartmental
methods were used to analyze the
pharmacokinetic parameters of cinacalcet
(the free-base). The effects of cinacalcet
concentration on plasma PTH and serum
calcium levels were evaluated. Results: Of

23 patients enrolled (17 patients, cinacalcet HCl; 6 patients, placebo), 10 patients (8

patients, cinacalcet HCl; 2 patients, placebo) completed the study. Plasma concentration, median area under the plasma

concentration-time curve from time 0 to 24 hours after dosing, and maximal plasma concentration (Cmax) of cinacalcet

increased with doses up to 200 mg once
daily. Median oral clearance ranged from
222 to 599 L/h, and median time after

dosing when Cmax occurred ranged from 2 to 3 hours across all doses. The

pharmacokinetics were linear over the 25- to 200mg once-daily dose range, with no

substantial increase in exposure at greater than 200 mg. Changes in plasma PTH

concentrations correlated inversely with
cinacalcet concentration. The concentration-
effect relationship was well described by an
inhibitory maximal effect model. Cinacalcet
HCl was reasonably tolerated, and the
incidence of adverse events was similar
between groups (76%, cinacalcet; 80%,
placebo). Gastrointestinal events were noted
at greater doses and may be dose related.
Conclusion: Cinacalcet HCl shows a dose-
proportional increase in exposure over the
range of 25 to 200 mg once daily in patients
on hemodialysis therapy, and kinetics were
linear up to 200 mg once daily. The
incidence of adverse events was similar
between groups.
Block GA, Martin KJ, De Francisco ALM, et
al.

Cinacalcet for Secondary


Hyperparathyroidism in Patients
Receiving Hemodialysis. New
England Journal of Medicine. Vol.
350(15) (pp 1516-1525), 2004.
We report the results of two identical

randomized, double-blind, placebo-


controlled trials evaluating the safety and
effectiveness of the calcimimetic agent
cinacalcet hydrochloride. METHODS:
Patients who were receiving hemodialysis
and who had inadequately controlled SHPT
despite standard treatment were randomly
assigned to receive cinacalcet (371 patients)
or placebo (370 patients) for 26 weeks.
Once-daily doses were increased from 30
mg to 180 mg to achieve intact PTH levels
of 250 pg per milliliter or less. The primary






end point was the percentage of patients


with values in this range during a 14-week
efficacy-assessment phase. RESULTS:
Forty-three percent of the cinacalcet group

reached the primary end point, as compared with 5 percent of the placebo group

(P<0.001). Overall, mean PTH values
decreased 43 percent in those receiving
cinacalcet but increased 9 percent in the
placebo group (P<0.001). The serum

calcium-phosphate product declined by 15 percent in the cinacalcet group and

remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced PTH levels independently of disease

severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers PTH

levels and improves calcium-phosphorus homeostasis in patients receiving

hemodialysis who have uncontrolled SHPT.

Malluche HH, Monier-Faugere MC, Wang G,
et al.

Cinacalcet reduces bone turnover and bone marrow fibrosis in

hemodialysis patients with

secondary hyperparathyroidism. 41st ERA-EDTA Congress, May 15-18, 2004,Lisbon, Portugal, 2004;

abstract MO16, available at
www.era-edta.org/congresses.htm
The effects of the calcimimetic cinacalcet on
bone turnover, bone marrow fibrosis, serum
intact PTH (iPTH), bone-specific alkaline
phosphatase (BALP), and N-telopeptide
were investigated in a randomized, double-
blind, placebo-controlled study in patients on
chronic maintenance dialysis. Patients with
iPTH levels ≥300 pg/mL on standard therapy
were randomly assigned 2:1 to cinacalcet or
placebo treatment. Doses were adjusted
from 30 to 180 mg/day to achieve a target
iPTH ≤250 pg/mL during a 24-week titration
phase and a 28-week maintenance phase.
Forty-eight patients (32 cinacalcet, 16
placebo) received treatment and 32 patients
(19 cinacalcet, 13 placebo) had bone
biopsies at baseline and after 1 year of
treatment. At baseline, secondary HPT
(elevated bone turnover, increased
osteoblasts and osteoclasts, marrow
fibrosis, and woven bone) was found in
16/19 patients randomized to cinacalcet and
11/13 patients randomized to placebo.
Adynamic bone disease (ABD) was found in

1 patient in each group. Treatment with


cinacalcet reduced iPTH (-51%), BALP (-
18%), and N-telopeptide (-24%). After

treatment, improvements in bone turnover parameters were observed in the cinacalcet group as reflected by reductions in activation frequency (-0.51/yr), bone formation

rate/bone surface (-1.88 mm3/cm2/yr),
marrow fibrosis (-1.99%), and numbers of
osteoblasts (-202/100 mm) and osteoclasts
(-64/100 mm). The placebo group showed
reduction in activation frequency (-0.12/yr)
and osteoclast number (-61/100 mm). At
baseline and at end of study, mean values
for mineralization parameters (mineralization
lag time, osteoid thickness, and osteoid
surface) were normal in both treatment
groups. At end of study, mixed uremic
osteodystrophy occurred in 4/13 patients in
the placebo group, compared with 2/19
patients in the cinacalcet group. ABD
developed in 3 patients treated with
cinacalcet, 2 of whom had sustained
oversuppression of PTH (<100 pg/mL). In
conclusion, in patients with secondary HPT
receiving dialysis, cinacalcet improved
control of PTH, which was associated with
reductions in bone turnover and bone
marrow fibrosis.
Quarles LD, Sherrard DJ, Adler S, et al.
The calcimimetic AMG 073 as a

potential treatment for secondary hyperparathyroidism of end-stage renal disease. Journal of the

American Society of Nephrology. Vol. 14(3)(pp 575-583), 2003.

The current study evaluates the efficacy and safety of AMG 073 when added to

conventional treatment of SHPT in ESRD. Seventy-one hemodialysis patients with uncontrolled SHPT, despite standard

therapy with calcium, phosphate binders,


and active vitamin D sterols, were treated in
this 18-wk, dose-titration study with single
daily oral doses of AMG 073/ placebo up to
100 mg. Changes in plasma PTH, serum
calcium, serum phosphorus, and calcium-
phosphate product levels were compared
between AMG 073 and placebo groups.

Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P = 0.001). A

significantly greater proportion of AMG 073
patients (44%) had a mean PTH ≤ 250 pg/ml
compared with placebo patients (20%; P =

0.029). Also, a significantly greater





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