REVIEW ARTICLE

An Update on Phosphate Binders:

A Dietitian’s Perspective
Lisa Gutekunst, MSEd, RD, CSR, CDN, FNKF

Control of serum phosphorus (PO4) has been long recognized as a goal in the nutritional and medical management of the patients with
chronic kidney disease. Phosphate-binding compounds were introduced in the 1970s for the treatment of hyperphosphatemia in pa-
tients on dialysis after it was observed that oral administration of aluminum hydroxide as an antacid also reduced serum PO4 levels. Forty
years later, aluminum is very seldom used as a phosphate binder as many other safer compounds are now available. This article is a
comprehensive review, geared to the renal dietitian, of the most common binder categories. It will discuss pharmacokinetics, side ef-
fects, initial and optimal doses, phosphate affinity, and controversies of use. It will also review two novel approaches to serum PO4 man-
agement in chronic kidney disease patients receiving dialysis and provide a new calculation by which binders can be compared.
Ó 2016 by the National Kidney Foundation, Inc. All rights reserved.

This article has an online CPE activity available at www.kidney.org/professionals/CRN/ceuMain.cfm

C ONTROL OF SERUM phosphorus (PO4) has been

long recognized as a goal in the nutritional and med-
ical management of the patients with chronic kidney disease
(CKD). The negative sequelae of hyperphosphatemia in the
CKD population have been well established.1-4 Current
therapies for management include providing renal
replacement therapy, limiting dietary PO4, and prescribing
phosphate-binding compounds.
Management of serum PO4 is a primary responsibility of
the renal dietitian by providing the dialysis patient with
continual, ongoing education of dietary PO4 sources, and
the use of phosphate binders. This education has become
more challenging over the past decade as we have learned
that the bioavailability of PO4 differs between organic
and inorganic sources. The understanding of bioavailability
challenges some of the previous education about which
foods are highest in PO4. Another challenge is keeping
up with the development and approval of new
phosphate-binding compounds and identifying the most
appropriate binder for individual patients. The number of
Food and Drug Administration (FDA) approved
phosphate-binding compounds continues to grow, each
having advantages and disadvantages for use. The renal die-
titian must understand the use, dosage, and adverse events
of phosphate binders and navigate the world of medication
insurance before making a binder recommendation.
Phosphate-binding compounds were introduced in the
1970s for the treatment of hyperphosphatemia in patients
Davita, Inc., Denver, CO, Keryx Biopharmaceuticals, New York, New York.
Support: See Acknowledgments on page 216.
Address correspondence to Lisa Gutekunst, MSEd, RD, CSR, CDN,
FNKF, 1542 Maple Road, Williamsville, New York 14221. E-mail:
lgutekunstrd@gmail.com
Ó 2016 by the National Kidney Foundation, Inc. All rights reserved.
1051-2276/$36.00
http://dx.doi.org/10.1053/j.jrn.2016.01.009
on dialysis after it was observed that oral administration of
aluminum hydroxide as an antacid also reduced serum PO4
levels.5 Forty years later, aluminum is almost never used as
a phosphate binder as many other safer compounds are
now available. Calcium-based binders (calcium bicarbonate
and calcium acetate) became the binder of choice in the
1980s and 1990s. They were effective and did not lead to
the encephalopathy and bone disease seen with aluminum
compounds; however, in more recent years, their use has
been linked to the development of cardiac and metastatic
calcification.4,6-10 In 2001, the first nonmetal,
nonabsorbable anion exchange binder, sevelamer
hydrochloride (SH) was launched.11,12 SH has the
advantage of reducing a patient’s exposure to calcium.
However, in the ion exchange, hydrochloride (HCl) was
released increasing a patient’s acid load and contributing to
metabolic acidosis. In 2004, lanthanum carbonate was
launched as the first chewable non–calcium-based binder
(now also available in powder form).12,13 Between 2007
and 2015, PhoslyraÒ (calcium acetate), the first
prescription liquid-based binder, and RenvelaÒ (sevelamer
carbonate) became available.14,15 Bixalomer another
nonmetal, nonabsorbable is available in Japan.16,17
VelphoroÒ (sucroferric oxyhydroxide), a chewable, iron-
based binder with no significant change on iron parame-
ters,18 and AuryxiaÒ (ferric citrate) an iron-based binder
with clinically and statistically significant increases in iron pa-
rameters.19 Additionally, studies have looked into once daily
dosing of sevelamer, the use of niacin/nicotinamide, and the
use of a salivary phosphate-binding chewing gum to improve
serum PO4 levels.15,20,21 Table 1 shows the various FDA-
approved compounds to demonstrate comparable efficacy.
This article is a comprehensive review, geared to the
renal dietitian, of the most common binder categories. It
will discuss pharmacokinetics, side effects, initial and
optimal doses, phosphate affinity, and controversies of

Journal of Renal Nutrition, Vol 26, No 4 (July), 2016: pp 209-218 209

Table 1. Comparison of Phosphate-Binding Agents

210
Potential Side
Estimated PO4- Effects/
Agent Common Name How Supplied Starting Dose Binding Capacity Advantages Disadvantages References

Calcium carbonate Tums, Oscal, Varies
39 mg/g Inexpensive, wide Not covered by 6,8,9,27

Calcichew, variety of insurance,

Caltrate products, easily hypercalcemia,
available, no hypoparathyroid,
prescription metastatic
required calcification, GI
side effects,
constipation
Calcium acetate Phoslo Phoslyra Tablet: 667 mg; 2 tablets per meal; 2
45 mg/g Less Ca absorption Hypercalcemia, 6,8,9,14,27

Gelcap: 667 mg; gelcaps per meal; than calcium hypoparathyroid,

Liquid: 667 mg 10 mL per meal carbonate metastatic
per 5 mL calcification, GI
side effects,
constipation
Sevelamer HCl Renagel Tablet: 400 mg, 2-4 400 mg per Varies
21 mg/g Noncalcium Contraindicated 11,15,24,45

800 mg; max meal; 1-2 800 mg nonmetal binder, with pts who are
dose: 13 g per meal not absorbed, at risk for small
reduces serum bowel

GUTEKUNST
lipid levels obstruction,
[S.Cl, YS.CO2
Sevelamer Renvela Tablet: 800 mg; 1-2 per meal; 0.8- Varies
21 mg/g Same as above Contraindicated 11,15,24,45

carbonate Powder: 800 mg, 1.6 g per meal with pts who are
2,400 mg; max at risk for small
dose: 13 g bowel
obstruction,
[S.CO2. Not
available
worldwide
16,17
Bixalomer Kiklin (Japan) Tablet Not known Noncalcium, Less lipid lowering
nonmetal, effects than
reduced GI Renagel. Not
effects than available
Renagel, no effect worldwide.
on S. Cl, [S.CO2.
13,24,29
Lanthanum Fosrenol Chewable tablet: 500 mg per meal; Varies on reference Reduced pill GI side effects may
carbonate 500 mg, 750 mg, max dose: 135 mg/g, 45 mg/ burden, high interfere with
(LaCO3) 1000 mg; Powder: 4500 mg/day 500 mg binding capacity, radiocontrast
750 mg, 1000 mg noncalcium, diagnostic results
crushable
18,25
Sucroferric Velphoro Chewable tablet: 500 mg per meal. 130 mg/tab Reduced pill GI side effects
oxyhydroxide 500 mg Max dose: burden,
3000 mg/day noncalcium,
crushable
 UPDATE ON PHOSPHATE BINDERS 211

use. It will also review two novel approaches to serum PO4

management in CKD patients receiving dialysis and pro-
19,30,46,51

vide a new calculation by which binders can be compared.

Aluminum and magnesium-based binders are not included
in this discussion. Aluminum is rarely used due to its toxic
effects on the body, and little is known about the long-term
hemochromatosis
with patients who

safety and efficacy of magnesium-based binders. Addition-

contraindicated
GI side effects,

ally, patients taking magnesium-based binders are at risk for

syndromes

hypermagnesemia.22
have iron
overload

such as

All phosphate-binding compounds work by reducing

the absorption of dietary PO4 in the gastrointestinal (GI)
tract. Compounds use the anionic nature of PO4 for ionic
exchange with an active cation to form a nonabsorbable
compound that is excreted in the feces.13-16,18,19
increases iron

Calcium-, lanthanum-, and the newer iron-based salts ex-

parameters
Noncalcium,

change carbonate, acetate, oxyhydroxide, and citrate to

bind with PO4. Sevelamer is a nonselective anion that
will not only bind with PO4 but also binds with bile salts
and other medications.15,23
To obtain FDA approval for use in the United States, all
binders have shown that they are effective in reducing
serum PO4 levels in patients with CKD undergoing dial-
46 mg/gram

ysis. Some companies compared effectiveness with placebo,

and others used FDA-approved PO4-binding compounds
to compare to current standard of care.

Relative Phosphate-Binding Coefficient and

the Phosphate Binder Equivalent Dose
2 g per meal; max
dose: 12 g/day

Given the number of phosphate-binding agents, com-

parison between agents is challenging. Researchers in the
Frequent Hemodialysis Network Trial faced this challenge
when trying to interpret changes in serum PO4 levels. Their
question was how much of the change was due to the
increase in dialysis frequency and how much was due to
the use of various phosphate binders? Daugirdas et al.24
reviewed stool and urinary in vivo phosphate-binding
capacities (PBC) in subjects with non-CKD and CKD.
Tablet: 1 g

From here, they devised the ‘‘relative phosphate-

binding coefficient’’ (RPBC) and the ‘‘phosphate binder
equivalent dose’’ (PBED) to compare phosphate-binding
capabilities in terms of milligrams of PO4 bound per
gram of compound or per gram of active ingredient
(lanthanum, sucroferric oxyhydroxide, and ferric citrate),
GI, gastrointestinal; HCl, hydrochloride.
Auryxia Riona

arbitrarily choosing 1 g of calcium carbonate as the stan-

(Japan)

dard. Results from the Frequent Hemodialysis Network

Trial suggest that patients with CKD and little urine
output receiving conventional thrice weekly hemodialysis
require approximately 6 g/day of a calcium carbonate to
control serum PO4, and equivalent number of tablets
required was established.24,25 Table 2 shows the RPBC,
Ferric citrate

PBED, and the number of tablets required to reach the

6 g/day dose.
The RPBC is a useful tool for practitioners switching be-
tween agents as a starting dose. Serum PO4 levels should be
monitored, and dose titration was made per FDA package
212 GUTEKUNST

Table 2. Dosages of Selected Phosphorus Binders Required to Reach a Phosphorus Binder Equivalent Dose of 6.0 g/day
Phosphate Binder
Equivalent Dose of Dose of Binder Approximate Number
Unit Dose One Tablet to 1 g Ca Needed to Reach of Tablets to Reach g of Calcium in a
Phosphorus Binder Size (mg) Carbonate a PBED of 6 g/day PBED of 6 g/day 6 g PBED Dose

Calcium carbonate 750 0.75 6.0 8 2.4

Calcium acetate 667 0.67 6.0 9 1.5
Osvaren (Mg carbonate 1 435/235* 0.75 — 8 0.5
Ca acetate)
Lanthanum 500† 1.0 3.0 6 0
Sevelamer carbonate 800 0.60 8.0 10 0
Sucroferric oxyhydroxide 500 1.6 1.5 3.75 0
(Velphoro)
Ferric citrate 210 0.64 2.0 9 0
The equivalent dose of PA21 is based on a single randomized controlled trial versus sevelamer (Floege, 2014), and thus, the equivalent dose is
not as precise as for some of the other binders, where multiple studies were considered. Ferric citrate numbers were obtained from a single clin-
ical randomized controlled trial versus sevelamer and calcium acetate (Lewis et al. 2014); Osvaren is not available in the United States.
Reproduced with permission from Wolter Kluwer.
*Each tablet contains 435 mg Mg carbonate and 235 mg Ca acetate.
†Tablets are sold by weight of lanthanum and not of lanthanum carbonate.

insert recommendations to reach optimal serum PO4 levels.
For example, if a patient is prescribed six (6) 750-mg
calcium carbonate tablets per day (4.5 g), the sevelamer
equivalent dose would be
4 tablets per day.
6 tablets 3 750 mg54500 mgð4:5 gramsÞ of calcium
carbonate
4:5 grams of calcium 3 0:75ðsevelamer equivalent doseÞ
53:375 grams of sevelamer
3375 mg sevelamerO800 mg=tablet54:2 tablets
Daugirdas et al. caution that the PBED is an estimate as
the PBC studies showed an inverse relationship between
PBC and binder dose. For example, urinary excretion
studies using sevelamer revealed higher PBC with lower
doses of sevelamer (1.6 gm/day sevelamer 5 50 mg/g
PBC) than with higher doses of sevelamer (7.5 gm/day
sevelamer 5 33 mg/g PBC), and urinary studies using
lanthanum carbonate showed PBC of 96 mg/g with
1.93 g lanthanum versus 75 mg/g with 2.65 g lanthanum.24
The estimated RPBC and PBED described for all phos-
phate binders provide tools practitioners can use to
compare binders and determine initial phosphate binder
prescriptions. Please note that on-label indications provide
starting doses for each compound and are included in each
section.
Calcium-Based Binders
Calcium-based–binding agents are the most commonly
used medication for serum PO4 control despite multiple
studies linking them to coronary and metastatic calcifica-
tion.6,8-10 KDIGO and KDOQI guidelines recommend
limiting or avoiding the use of calcium binders in patients
who have elevated serum calcium levels, have low serum
parathyroid levels, or have known calcification.22,26 Some
studies have shown that many patients have calcification
before dialysis is initiated calling into question the use
calcium-based binders even in earlier stages of CKD.27,28
Despite the research, practitioners continue to use
calcium-based binders to control serum PO4 and for its
ability to lower parathyroid.29
Calcium carbonate is available over-the-counter without
a prescription and is inexpensive. Various strengths are
available; therefore, it is important to review with the pa-
tient the appropriate strength to use because approximately
20% to 30% of the elemental calcium will be absorbed.30
There are multiple studies comparing the effectiveness of
calcium carbonate with calcium acetate as a phosphate
binder.31-33 In these cases, calcium acetate was equally
effective or more effective in lowering serum PO4 levels
when compared to calcium acetate. In all, exposure to
calcium and the incidence of hypercalcemia were less in
the calcium acetate arm.
The PBC of calcium carbonate is
39 mg PO4 per 1 g of
calcium carbonate.26 Daugirdas et al.24 use the phosphate-
binding efficiency of 1 g calcium carbonate as the reference
standard. Therefore, the RPBC of calcium carbonate is 1.0.
For dosing prescription, the strength of the calcium car-
bonate should be considered. For example, a 750-mg tablet
of calcium carbonate would have a PBED of 0.75 (750 mg/
1,000 mg) requiring 8 tablets to get an equivalent dose of 6
(1.0 g) tables of calcium carbonate.24
The calcium found in calcium acetate is less absorbable
(21 6 1% with meals, mean 6 standard deviation [SD])
and has a slightly higher binding capacity of 45 mg per
1 g of calcium acetate.22 The RPBC is 1.0, meaning that
the binding strength of calcium acetate is similar to the
binding capacity of calcium carbonate. However, the
PBED is 0.67 meaning that one 667-mg tablet of calcium
acetate will bind less phosphate than 1 g of calcium
 UPDATE ON PHOSPHATE BINDERS
carbonate requiring 9 tablets to get equivalent dose to 6 g of
calcium carbonate.24
Adverse events associated with the use of calcium-based
binders include constipation, hypercalcemia, and hypo-
parathyroidism. Additionally, there is evidence that overex-
posure to calcium can contribute to metastatic
calcification.4,5,14,26
The recommended starting dose for the PhosLo gelcaps
(667 mg) and tablets is 2 gelcaps per meal and 10 mL
(667 mg/5 mL) per meal for Phoslyra.14,34
Noncalcium/Nonmetal Binders
Sevelamer hydrochloride (RenagelÒ, Sanofi US,
Bridgewater, NJ), and sevelamer carbonate (RenvelaÒ, Sa-
nofi US, Bridgewater, NJ) are the two products currently
available in this class. Sevelamer is a nonabsorbable cross-
linked polymer that exchanges HCl or carbonate
(HCO32) for PO4 in the GI tract.15,23 The HCl and
HCO32 are absorbed into the body while the resulting
PO4-laden polymer passes through the GI tract and is
excreted.
In two pivotal studies examining the effectiveness of SH,
serum PO4 levels improved during the course of the studies
without increasing serum calcium levels.35,36 After a
2-week washout period in the first study, serum PO4 levels
dropped from 9.1 6 2.4 mg/dL to 6.6 6 1.9 mg/dL in 144
patients with an average dose of 5.4 g of SH after 8 weeks.35
The second study was an open-label crossover study
comparing the effectiveness of SH with calcium acetate
in 84 patients. After a 2-week washout period, patients
were randomized to receive either SH or calcium acetate
for 8 weeks. After completion of this arm, patients under-
went another 2-week washout period, then received the
other phosphate binder. Effectiveness between both arms
were similar (serum PO4 decline 22.0 6 2.3 mg/dL
with SH vs. 22.1 6 1.9 mg/dL with calcium acetate);
however, 22% of the participants experienced serum cal-
cium levels greater than 11.0 mg/dL in the calcium acetate
arm resulting in the discontinuation of the medication until
serum calcium levels declined.36
In addition to PO4, the sevelamer complex also binds
bile salts resulting in a 15% to 31% decline in serum mean
total cholesterol and serum low-density lipoprotein choles-
terol level.23 Because of its ability to bind bile salts, it may
interfere with normal fat absorption and the absorption
of fat soluble vitamins (A, D, E, and K). The FDA-
approved package insert for SH and sevelamer carbonate
encourages monitoring fat soluble vitamin and folic acid
levels with the use of the product.
Sevelamer is contraindicated with patients who have a
history of or are at risk of a bowel obstruction. Postmarket-
ing experiences reveal esophageal tablet retention with
patients who have dysphagia, bowel perforation, and
fecal impaction requiring hospitalization and intervention.
Less serious adverse events associated with sevelamer
213
include vomiting (22%), nausea (20%), diarrhea (19%),
dyspepsia (16%), abdominal pain (9%), flatulence (8%),
and constipation (8%).23
In concomitant drug therapy, sevelamer did not affect the
bioavailability of digoxin, warfarin, enalapril, metoprolol,
and ferrous sulfate. Sevelamer does decrease the bioavail-
ability of ciprofloxacin by approximately 50%, and in
postmarketing experience, reduced concentration of
cyclosporine, mycophenolate mofetil, and tacrolimus
have been reported. It is recommended that thyroid-
stimulating hormone levels be monitored when the prod-
uct is used with levothyroxine.15,23
The recommended starting dose for both SH and
sevelamer carbonate ranges from 800 to 1,600 mg per
meal, depending on serum PO4 levels.
PBC studies have been completed in healthy volunteers.
One study compared the net absorption of PO4 from a stan-
dardized meal ingested with a typical clinical dose of phos-
phate binders. After undergoing gastric lavage, 31 healthy
volunteers were given a meal consisting of
380 mg of
phosphate and a single 2,400 mg dose of sevelamer carbon-
ate. Stool samples were collected and analyzed for PO4 con-
tent showed. There was a 21% reduction in PO4 absorption
which indicated an approximate 21 mg PBC for one seve-
lamer carbonate tablet or
26 mg PO4 per 1 g sevelamer
carbonate.24 Other studies have evaluated the binding ca-
pacity of SH in 24 healthy volunteers. In one study, a diet
of 1,200 mg PO4 was given to healthy individuals for
18 days. During days 5 through 9, subjects were given
either placebo or SH in divided doses of 3, 7.5, or 15 g.
The finding showed an inverse binding capacity with the
dose of SH (36 mg/g; 33 mg/g; 23 mg/g, respectively).
These findings are confirmed in two other studies that
looked at the binding capacity of 1.6 g (50 mg/g) and
6.4 g (32 mg/g).24 Practitioners should be aware that an in-
verse relationship of dose and binding capacity has been
shown in several studies.
The RPBC of sevelamer is 0.75 with a standard 800 mg
dose having a PBED of 0.60 such that 9 tablets of sevelamer
will be required to be equivalent to 6 tablets (1 g/tablet) of
calcium carbonate.30
Bixalomer (KiklinÒ, Astellas Pharma, Tokyo, Japan) is
another nonabsorbable polymer that is currently only avail-
able in Japan.37 It is similar to sevelamer; however; it
absorbs less water thus showing less swelling and higher
fluidity than sevelamer.16,17
In phase 3 studies conducted in Japan, bixalomer was
shown to be as effective as sevelamer for the management
of serum PO4 levels with 72.2% of subjects achieving target
PO4 levels, between 3.5 and 6.0 mg/dL as compared with
the sevelamer group, which only had 68% achieve those
levels. Additionally, the percentage of GI adverse events
was significantly lower in the bixalomer group with
29.1% reporting events versus 47.3% in the sevelamer
group.16,17 As sevelamer carbonate is not available in
214 GUTEKUNST
Japan, KiklinÒ is a noncalcium, nonmetal binder option
that does not contribute to acid load.
Lanthanum
Lanthanum carbonate (FosrenolÒ, Shire US Inc.,
Wayne, PA) is the first phosphate-binding compound to
use the metal lanthanum to bind phosphate. Each chewable
tablet contains lanthanum carbonate hydrate equal to 500,
750, or 1,000 mg of elemental lanthanum. In the GI track,
lanthanum binds PO4 to form the nonabsorbable com-
pound lanthanum phosphate. In vitro studies demonstrate
that lanthanum binds phosphate at pH levels from 3 to 7.
Most phosphate binding to lanthanum occurs at pH levels
between 3 and 5 at 97%, whereas 67% binding occurs at
pH 7.13
In phase 2 and 3 studies, lanthanum carbonate has been
shown to reduce and maintain PO4 levels in goal range of
4.03 to 5.58 mg/dL. Additionally, when compared with
calcium acetate and SH, lanthanum showed no superiority;
however, the number of wafers required to maintain serum
PO4 levels was much less with lanthanum.38-40
The recommended starting dose is 1,500 mg, distributed
equally at meals. Doses should be titrated every 2 to 3 weeks
until target serum PO4 levels are reached, with a maximum
dose of 4,500 mg.
In clinical trials, the most common adverse reactions
were nausea (11%), vomiting (9%), and abdominal pain
(5%). Postmarketing experience revealed additional adverse
reactions including constipation, dyspepsia, allergic skin re-
action, hypophosphatemia, and tooth injury while chew-
ing the tablet.13
Serious GI complications have been seen with the use of
lanthanum, and caution should be taken when prescribed
to patients with altered GI anatomy. The product is contra-
indicated with patients who have a history of bowel
obstruction. Some of those who have experienced severe
cases of GI obstruction have required hospitalization and/
or surgery. Additionally, as lanthanum is a heavy metal, it
has radio-opaque properties that may alter images from
abdominal X-ray procedures.13,41
The concomitant administration of lanthanum with
other medications may decrease medication bioavailability
or action of the second drug. Bioavailability of tetracy-
clines, fluoroquinolones, and quinolone is decreased
when taken with lanthanum. The bioavailability of levo-
thyroxine is decreased by approximately 40% when given
in conjunction with lanthanum, thus should be spaced at
least 2 hours before or 2 hours after lanthanum administra-
tion. Aluminum-, magnesium-, and calcium-based ant-
acids should not be administered within 2 hours of
lanthanum.13
A systematic review and meta-analysis of 16 randomized
controlled trials involving 3,789 patients looked at the
long-term efficiency and safety of lanthanum. Zhang
et al. identified 10 studies that gathered data on lanthanum
accumulation in bone and blood. Most results showed a
slight increase in serum lanthanum levels; however, these
increases did not indicate any statistical differences.37 Three
significant bone histology studies followed 85 patients for 1
to 2 years, obtaining bone biopsies at baseline and then
annually. Although lanthanum did accumulate within the
bone, the accumulation was shown to be minor (,5.5
mcg/g), and the bone released the deposits once therapy
was stopped.42-44
In vivo phosphate absorption studies using lanthanum
have been competed in healthy individuals. Thirty-one
volunteers were given one 1,000 mg dose of lanthanum
and a meal containing 375 mg phosphate. Stool recovery
showed that lanthanum reduced phosphate absorption by
45% in contrast to ingesting the meal without a phosphate
binder, thus estimating that 1,000 mg of lanthanum can
bind 135.1 6 12.3 mg of PO4 (mean 6 SD).45 Daugirdas
found that 500 mg of lanthanum has an RPBC of 2.0
with a PBED of 1.0 requiring 6 tablets to be equivalent
to 6 tablets of calcium carbonate.24,30
Iron-Based Binders
Sucroferric oxyhydroxide (VelphoroÒ, Fresenius Medi-
cal Care North America) is the first iron-based phosphate
binder introduced to North America. Each chewable tablet
contains 500 mg of iron equivalent to 2,500 mg sucroferric
oxyhydroxide. In the GI tract, phosphate binds to sucrofer-
ric oxyhydroxide to form an insoluble compound. The su-
crose and starch components of the tablet are absorbed.
In vitro studies show that the phosphate binding takes place
between pH ranges of 1.2 to 7.5 with a PBC of 130 mg per
tablet.18,46
Two phase 3 studies were conducted to show that sucro-
ferric oxyhydroxide is effective in reducing serum PO4
levels in patients receiving dialysis. The first study was a
6-week, randomized, open-label, active control study to
investigate optimal dose. Fifty clinical sites in Europe and
the United States randomized 154 patients to receive either
sucroferric oxyhydroxide or active control (SH). Those
randomized to receive sucroferric oxyhydroxide were
randomized to receive either 1.25, 5.0, 7.5, 10.0, or
12.5 g/day. All groups showed a significant decrease in
serum PO4 with the exception of 1.25 g/day dose.
Mean 6 SD decreases in serum PO4 in the 5, 7.5, 10,
and 12.5 g/day were 21.08 6 2.12 mg/dL,
21.25 6 1.21 mg/dL, 22.0 6 1.71 mg/dL, and
21.69 6 1.81 mg/dL, respectively.47
The second phase 3 study was a 55-week, multistage,
randomized, open-label, active controlled study to investi-
gate safety and efficacy.48,49 A total of 1,059 dialysis patients
were randomized after a 2-week phosphate binder washout
period to receive either sucroferric oxyhydroxide or seve-
lamer carbonate in the first stage of this study lasting
24 weeks. Starting doses for each were 1,000 mg and
4,800 mg, respectively, with titration to maintain serum
 UPDATE ON PHOSPHATE BINDERS
phosphate levels ,5.5 mg/dL. At the end of 24 weeks,
those receiving sucroferric oxyhydroxide with controlled
phosphate levels were then randomized into a
3 weeks second phase 2 of the study. Participants either
maintained their current dose of sucroferric oxyhydroxide
or received a lower dose of 250 mg/day.48 The final stage
consisted of 658 dialysis patients who were treated for
28 weeks with either study drug or active control according
to their original randomization.49
Serum PO4 levels declined 2.2 and 2.4 mg/dL for sucro-
ferric oxyhydroxide and sevelamer carbonate, respectively,
at the end of week 12 showing noninferiority of sucroferric
oxyhydroxide to sevelamer carbonate. Efficacy was main-
tained through week 24 with patients requiring an average
dose of 3 tablets per day sucroferric oxyhydroxide to main-
tain serum PO4 levels versus 8 tablets of sevelamer.48
Additionally, both studies revealed that there were no
significant or clinical changes in iron parameters with su-
croferric oxyhydroxide. After the 6-week study receiving
various doses of sucroferric oxyhydroxide, serum ferritin
and transferrin saturation levels remained stable (baseline
ferritin levels range: 242.2 to 438.7 ng/mL, change from
baseline at week 4 range: 210.5 to 21.0 ng/mL, baseline
transferrin saturation levels: 21.2% to 26.2%, change from
baseline at week 4: 20.1 to 3.1%).48 Similar results were
seen in the 52-week study.49
Most common adverse reactions include diarrhea
(24%), discolored feces (16%), and nausea (10%).18 Dis-
colored feces is an expected adverse reaction due to the
product’s iron content. Other studies did not include
patient with peritonitis, significant gastric or hepatic dis-
orders, hemochromatosis, or other iron accumulation
disorders. Patients taking doxycycline should take it at
least 1 hour before taking sucroferric oxyhydroxide. Lev-
othyroxine should not be administered to patients taking
sucroferric oxyhydroxide.18
The recommended starting dose for is 500 mg at each
meal with titration as often as weekly until serum phosphate
levels are ,5.5 mg/dL. The maximum dose studied was
3,000 mg/day.18
Daugirdas found that 500 mg of sucroferric oxyhydrox-
ide to have a PBED of 1.6 requiring 3.75 tablets to be
equivalent to 6 tablets of calcium carbonate.30
A second iron-based phosphate binder (AuryxiaÒ, Keryx
Biopharmaceuticals, New York, NY; RionaÒ, Japan To-
bacco Inc, Tokyo, Japan, NephoxilÒ, Panion BF Biotech
Inc, Taiwan) was also recently approved and also clinically
increases iron parameters. Each pill contains 210 mg of
ferric iron, which is equivalent to 1 g ferric citrate. In the
GI tract, ferric iron binds with phosphate to create ferric
phosphate, which is insoluble and excreted.19
A phase 3 study demonstrated the efficacy, tolerability,
and safety study enrolled 441 dialysis patients into a multi-
center, sequential, randomized, open-label, 52-week active
controlled, followed by a 4-week placebo controlled trial
215
looking at the effectiveness of reaching and maintaining
serum PO4 levels between 3.5 and 5.5 mg/dL.50 After
completing a 2-week phosphate binder washout, eligible
participants were randomized to receiving either ferric cit-
rate or active control (calcium acetate and/or sevelamer
carbonate). Patients receiving ferric citrate started on 6 g
per day (2 pills at 3 meals) with weekly titration until serum
PO4 levels reached the target range. At the end of 52 weeks,
patients receiving ferric citrate were rerandomized to
continue current dose therapy or receive placebo.
Mean baseline serum PO4 levels were 7.41 6 0.10 mg/
dL in the ferric arm and 7.56 6 0.14 mg/dL in the active
control arm (mean 6 SD). Reduction in levels to the
goal of 3.5 to 5.5 mg/dL was reached by week 12 in both
arms and maintained through week 52 with final mean
levels of 5.2 (4.4-6.1) mg/dL and 5.1 (4.4-6.2) mg/dL,
respectively (mean [range]). Additionally, against placebo,
ferric citrate reduced serum PO4 levels by 2.2 6 0.2 mg/
dL (P ,.001).50
The study revealed that 8 tablets (8 g) of ferric citrate suc-
cessfully treated and maintained serum PO4 levels between
3.5 and 5.5 mg/dL. This is a consistent pill dose required to
reach and maintain the same goal in the active control arm:
7.7 tablets/day (5.14 g) for calcium acetate and 9.0 tablets/
day (7.2 g) for sevelamer carbonate.51
Studies also demonstrated an increase iron parameters
with ferric citrate administered as a phosphate binder. In
the long-term study, serum ferritin levels improved from
a mean baseline of 593 6 18 ng/mL to 899 6 31 ng/mL
(mean 6 SD) with ferric citrate, whereas those receiving
active control had little change from baseline
(609 6 26 ng/mL) at week 52 (628 6 31 ng/mL). Addi-
tionally, those in the ferric citrate arm received less intrave-
nous elemental iron (median 5 12.9 mg/week ferric
citrate; 26.8 mg/week active control; P , .001) and less
erythropoietin-stimulating agent (median epoetin-
equivalent units per week: 5,303 units/week ferric citrate;
6,954 units/week active control; P 5.04) than those in the
active control arm by the end of week 52.52
The most common adverse events associated with ferric
citrate were diarrhea (21%), nausea (11%), constipation
(8%), vomiting (7%), and cough (6%). Discolored feces
are common with ferric citrate use related to the iron
content, but are not clinically relevant and do not affect lab-
oratory testing for occult bleeding. Patients with inflamma-
tory bowel disease or active, symptomatic GI bleeding were
not included in studies. Medications most commonly taken
by dialysis patients can be taken concomitantly with ferric
citrate. Patients taking doxycycline should take doses at least
1 hour before and ciprofloxacin 2 hour before or after tak-
ing ferric citrate.19 Oral citrate has been known to increase
GI absorption of aluminum. Serum aluminum levels
were followed in the long-term 52-week study. For the
185 participants in the ferric citrate arm, the median
aluminum level was 6.0 (5-24, range) mg/L at baseline
216 GUTEKUNST
and 7.0 (5-23, range) m/L at week 52. For the active control
arm, baseline levels were 6.0 (5-14) m/L and 6.0 (5-15) m/L
at week 52. Researchers concluded that there were no
meaningful changes in aluminum levels observed in the
study between either group (P 5.1).51
The recommended starting dose for ferric citrate is 2
tablets three times per day with each meal with titration
every 1 to 2 weeks based on serum PO4 levels until target
range is reached, up to a maximum dose of 12 tablets daily.
Ferric citrate is contraindicated with patients who have iron
overload syndromes such as hemochromatosis.19 Addition-
ally, patients’ iron statuses should be monitored so that ad-
justments can be made in IV iron therapy to keep levels in
therapeutic ranges.19
In vitro PBC of ferric citrate showed the amount of
bound PO4 and the reaction conditions of pH 2 to 7 was
46 6 2 mg PO4/g of ferric citrate.52 Daugirdas lists the
PBED for 1 tablet as 0.64 such that 9 tablets are required
to get equivalent dose of 6 g calcium carbonate.30
Novel Approaches to Phosphate Control
Two novel ways to approach controlling serum PO4
levels used in the past few years are the use of niacin and
the use of chitosan-containing chewing gum.
Niacin and nicotinamide reduce phosphate absorption
by inhibiting intestinal sodium–phosphate cotransporter-
2b. In an 8-week trial using nicotinamide in addition to
the patient’s PO4 binder, serum PO4 was lowered from
6.45 mg/dL to 5.28 mg/dL.20 Using these products in addi-
tion to PO4 binder therapy may be a benefit as it has been
shown that both PO4 dietary restrictions and the use of
PO4-binding agents can cause an upregulation of intestinal
sodium–phosphate cotransporter-2b which may allow for
high PO4 absorption when PO4 binder doses are either
skipped or inappropriately low for the meal phosphate
load.53
Binding salivary phosphate is a newer approach to
improving serum phosphate levels in the CKD popula-
tion.54 Chitin is a cellulose-like biopolymer found mainly
in the exoskeleton of crustaceans that has been used in wa-
ter purification plants to absorb greases, oils, metals, and
toxic substances. Studies using chitosan chewing gum to
bind salivary phosphate have shown mixed results in
improving serum phosphate.17,21,55,56 Overall, chitosan is
not an effective phosphate binder; it may improve fluid
control by controlling thirst.
Conclusion
Improving serum PO4 levels continues to be a primary
goal in the nutrition and medical management of the
CKD patient on dialysis. Multiple strategies are used to
control serum PO4 levels including phosphate-binding
agents, dietary phosphate restrictions, and adequate dialysis
therapy. The number of phosphate-binding agents has
increased over the past 40 years giving practitioners a vari-
ety of agents and forms (powder, liquid, wafer, pills) to
tailor binder regimens to the patient’s preference, tolerance,
phosphate load, comorbidities, and contraindications.
Some binders provide additional benefits such as reducing
serum cholesterol levels and increasing iron stores, whereas
others require minimal dosing to be effective. Tools, such as
the PBED and RPBC, allow the health care provider to
determine equivalent doses for the many binder
compounds. Barring lack of insurance coverage, we have
a lot more weapons to battle hyperphosphatemia in our
arsenal.
Practical Application
Over the last 2 decades, the number of FDA-approved
phosphate-binding agents has increased. This article serves
as a tool for practitioners to use when comparing potential
phosphate binders. Additionally, the phosphate-binding
equivalent dose (PBED) in conjunction with package insert
dosing instructions can be used to guide dosing when ther-
apies are changed.
Acknowledgments
The author thanks Dr. John Daugirdas for his review of the phosphate-
binding capacity section. This article was researched and written with
support from Keryx Biopharmaceuticals, Inc.
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