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Assessment of phosphate binding by sevelamer carbonate powder for oral suspension mixed in foods.

The prevalence and consequences of hyperphosphatemia in the dialysis population are well known. Chronic hyperphosphatemia is associated with vascular calcification, progression of secondary hyperparathyroidism, and increased mortality risk (Block et al., 2004; Danese, Belozeroff, Smirnakis, & Rothman, 2008; Kalantar-Zadeh et al., 2006; Raggi et al., 2002; Saliba & El-Haddad, 2009).

Sevelamer carbonate is a phosphate binder that effectively controls serum phosphorus in patients with chronic kidney disease (CKD) (Delmez et al., 2007; Fan et al., 2009; Ketteler et al., 2008). Studies in the dialysis population also report that sevelamer use results in less hypercalcemia, attenuation of arterial calcification, lower incidence of coronary artery calcification, decreased mortality, and reduced hospitalization compared to calcium-based phosphate binders (Block et al., 2005; Block, Raggi, Bellasi, Kooienga, & Spiegel, 2007; Chertow, Burke, & Raggi, 2002; Suki et al., 2007). As a non-calcium, metal-free phosphate binder, the clinical benefits of sevelamer make it a viable first-line therapy for patients receiving maintenance dialysis.

Arenas et al. (2010) found that non-adherence to medications was evident in 40% of the patients on hemodialysis who participated in their study. Several factors that impact patient adherence to phosphate binders include pill burden resulting from multiple co-morbidities, swallowing difficulty, and intolerance. Sevelamer carbonate for oral suspension (powder) was developed as an alternative dosage form to allow for greater options and flexibility for physicians and patients. In clinical trials, sevelamer carbonate powder demonstrated the same efficacy controlling phosphorus as sevelamer in a tablet form (Fan et al., 2009).

To prepare the suspension, sevelamer carbonate powder sachet (2.4 grams) is mixed with two ounces of water. Each 2.4 grams of sevelamer carbonate sachet is the equivalent of three sevelamer carbonate tablets. This study investigated the possibility of mixing sevelamer carbonate powder with foods and beverages other than water to enhance ease of use and adherence to prescribed regime, and limit total fluid intake if mixed with food.

Using assay conditions that simulate the pH effects that occur after food ingestion in people, these experiments were designed to examine if there was a difference in the amount of phosphate bound by sevelamer carbonate powder when pre-exposed to food versus concurrent exposure.

The strategy of pre-exposing food to sevelamer was intended to mimic a situation in which patients may either sprinkle on or mix sevelamer powder with food or beverages--as opposed to water--prior to ingestion. The strategy of concurrent exposure of sevelamer with food was intended to mimic the clinical situation of ingesting sevelamer mixed in water with a meal.

Methods

Study Design

Sevelamer carbonate powder 2.4 grams was either mixed with a single serving of each food and allowed to sit for 30 minutes prior to exposure to the stomach phase of the assay conditions (we-exposed) or added to the food during the stomach phase of the assay conditions (co-exposed). A description of the foods and serving sizes of each are listed in Table 1.

The assay experiments were conducted in a dissolution bath held at 37[degrees] C (98.6[degrees] F). Two wells were used as the control samples (no sevelamer carbonate), three wells were used for sevelamer samples pre-exposed to food, and three wells for sevelamer samples co-exposed to food. Water was added to each well and allowed to equilibrate to 37[degrees] C. Phosphate (derived from 14.8 M phosphoric acid stock) was added to the food sample, and then a volume of hydrochloric acid (HC1, 1N) was added to the well with the goal of achieving a target phosphate concentration in each of about 14.5 mM and pH of 1.5. Food samples and 2.4 grams of sevelamer carbonate powder were then added to the appropriate wells (corresponding to either pre-exposed or coexposed samples). For the first incubation period, the pH in each well was adjusted to a pH of 1.5. The pH 1.5 incubation simulates the stomach and allows the active binding moieties on the polymer to become fully available as they would in a patient. The volume in each vessel was brought to 900 mL with water, and samples were stirred for one hour. For the second incubation period, the pH in each well was increased to approximately 5.8 using sodium hydroxide. The pH 5.8 incubation simulates conditions in the small intestine where phosphate in solution is expected to bind to sevelamer prior to absorption. The samples were then stirred for an additional hour. No attempt was made to control the pH during either of the incubation periods.

After the second incubation, a portion of each sample was withdrawn from each of the eight wells. Each was centrifuged briefly. The supernatant was filtered, diluted with water, and analyzed by ion chromatography for the concentration of unbound phosphate in solution. Dilutions of the 14.8 M phosphoric acid used as the phosphate source in the experiment were prepared and used as an external calibration. An ion chromatography system was used in anion mode with an eluent generator, producing 40 mM potassium hydroxide as the mobile phase. A graphical depiction of the experimental design can be seen in Figure 1.

Statistical Analyses

The amount of phosphate bound (retool/g) by sevelamer pre-exposed to food versus concurrent exposure of sevelamer to food following the assay conditions was determined indirectly by quantifying the unbound phosphate in each sample. The difference in the amount of phosphate bound per gram of sevelamer carbonate in pre-exposed samples compared to co-exposed samples was calculated.

Results

Phosphate Binding

There was no difference in the average phosphate binding to serelamer when pre-exposed to food (4.18 mmol phosphate/gram sevelamer) compared to those co-exposed to food (4.18 mmol phosphate/gram serelamer) as assayed. In all cases, the difference in the amount of bound phosphate between pre-exposed and co-exposed samples was less than 3% (see Table 2), which is substantially smaller than the allowable potency deviation in manufactured dosage forms.

[FIGURE 1 OMITTED]

Appearance/Smell

The majority of foods tested did not change appearance when combined with sevelamer (see Figure 2). There were slight discolorations in the applesauce and oatmeal pre-exposed to sevelamer carbonate powder. There was no significant change in the olfactory profile of any of the samples beyond the added "citrus note" imparted by the flavoring added to the powder formulation.

Discussion

Hyperphosphatemia has emerged as one of the more important risk factors for mortality in patients with CKD who are on dialysis. Associations of serum phosphorous level with mortality are robust across diverse dialysis populations and have been shown to intensify at higher phosphorous levels (Block et al., 2004; Block, Hulbert-Shearon, Levin, & Port, 1998; Ganesh, Stack, Levin, Hulbert-Shearon, & Port, 2001; Kestenbaum & Belozeroff, 2007; Lowrie & Lew, 1990; Slinin, Foley, & Collins, 2005). In particular, Isakova and colleagues (2009) demonstrated that patients in whom phosphate binders were prescribed within the first 90 days of starting dialysis compared to patients who did not receive phosphate binders within 90 days of initiating dialysis had a survival advantage. In that study, patients who were prescribed phosphate binders prior to initiating dialysis had the greatest survival advantage among all three groups.

[FIGURE 2 OMITTED]

In a cohort study that evaluated consistent control of serum phosphorus over the first 12 months of hemodialysis, Danese et al. (2008) found that patients with phosphorus in target for one-quarter or less had a 62% higher risk of death. Target goals for serum phosphorus for patients on dialysis are recommended to be 3.5 to 5.5 mg/dL (1.13 to 1.78 mmol/L) by the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) (NKF, 2003) and towards normal 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol/L) by the Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Workgroup (2009). The ability of patients to be able to adhere to these guidelines can be challenging; thus, finding ways to increase patient adherence to phosphate binders for better management of serum phosphorus may be an important aspect in improving patient outcomes.

Sevelamer carbonate is a non-calcium, non-metal-containing phosphate binder. Per the product label, sevelamer carbonate powder is to be mixed in water and then ingested with meals. If patients were safely able to mix sevelamer carbonate powder with meals or alternative beverages other than water, this flexibility with regard to drug administration may give nephrology healthcare providers alternative ways of prescribing phosphate binders, allowing patients with CKD to find the most palatable option to fit their lifestyles and preferences and thereby potentially improve adherence.

The objective of this study was to examine if there was a difference in the amount of phosphate bound by sevelamer carbonate powder when pre-exposed to food versus concurrently exposed to food following exposure to pH conditions simulating the stomach and small intestine. The results indicated that pre-exposing sevelamer carbonate powder versus concurrently exposing sevelamer carbonate powder with applesauce, oatmeal, whey protein powder, ginger ale, diet ginger ale, scrambled eggs, and baked boneless-skinless chicken breast had no effect on the ability to bind phosphate.

The assay was designed to simulate the pH effects that occur after food ingestion in people. No added enzymes or other metabolic constituents were added; therefore, the aim of these experiments was not to model the digestive tract, but rather, to simulate pH changes that may be important for polymer activation. If an irreversible reaction between any particular food and sevelamer carbonate occurred in this in vitro simulation, a significant difference between the pre-exposed and co-exposed samples would have been expected and noted.

Summary/Implications for Nephrology Nurses

Today's nephrology environment is challenging nurses, dietitians, and all practitioners to find new ways to achieve outcomes. We are faced with more challenging calcium, phosphorus, and PTH goals with the hope of decreasing hospitalization and mortality rates of patients on dialysis.

Based on the results of the tests in this study, pre-mixing sevelamer carbonate powder as compared to concurrently exposing it to selected food or beverages prior to conditions that simulate the pH effects that occur after food ingestion in people had no effect on the ability of sevelamer carbonate to bind phosphate. While this study suggests an alternative way to administer sevelamer carbonate powder and perhaps improve patient adherence to phosphate binder therapy, clinical testing is needed to further evaluate the safety and efficacy of this finding.

References

Arenas, M.D., Malek, T., Gil, M.T., Moledous, A., Alvarez-Ude, F., & Reig-Ferrer, A. (2010). Challenge of phosphorus control in hemodialysis patients: A problem of adherence? Journal of Nephrology, 23, 525-534.

Block, G.A., Hulbert-Shearon, T.E., Levin, N.W., & Port, F.K. (1998). Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study. American Journal of Kidney Disease, 37(4), 607-617.

Block, G.A., Klassen, P.S., Lazarus, J.M., Ofsthun, N., Lowrie, E.G., & Chertow, G.M. (2004). Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. Journal of the American Society of Nephrology, 15(8), 2208-2218.

Block, G.A., Spiegel, D.M., Ehrlich, J., Mehta, R., Lindbergh, J., Dreisbach, A., & Raggi, P. (2005). Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney International, 68, 1815-1824.

Block, G.A., Raggi, P., Bellasi, A., Kooienga, L., & Spiegel, D.M. (2007). Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney International, 71, 438-441.

Chertow, G.M., Burke, S.K., & Raggi, P. (2002). Sevelamer attenuates the pro gression of coronary and aortic calcification in hemodialysis patients. Kidney International, 62, 245-252.

Danese, M.D., Belozeroff, V., Smirnakis, K., & Rothman, K.J. (2008). Consistent control of mineral and bone disorder in incident hemodialysis patients. Clinical Journal of the American Society of Nephrology, 3, 1423-1429.

Delmez, J., Block, G., Robertson, J., Chasan-Taber, S., Blair, A., Dillon, M., & Bleyer, A.J. (2007). A randomized, double-blind, crossover design study of sevelamer hydrochloride and sevelamer carbonate in patients on hemodialysis. Clinical Nephrology, 68, 386-391.

Fan, S., Ross, C., Mitra, S., Kalra, P., Heaton, J., Hunter, J., ... Pritchard, N. (2009). A randomized crossover design study of sevelamer carbonate powder and sevelamer hydrochloride tablets in chronic kidney disease patients on haemodialysis. Nephrology Dialysis and Transplantation, 24, 3794-3799.

Ganesh, S.K., Stack, A.G., Levin, N.W., Hulbert-Shearon, T.E., & Port, F.K. (2001). Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. Journal of the American Society of Nephrology, 12, 2131-2138.

Isakova, T., Gutierrez, O.M., Chang, Y., Shah, A., Tamez, H., Smith, K., ... Wolf, M. (2009). Phosphate binders and survival on hemodialysis. Journal of the American Society of Nephrology, 20, 388-396.

Kalantar-Zadeh, K., Kuwae, N., Regidor, D.L., Kovesdy, C.P., Kilpatrick, R.D., Shinaberger, C.S., ... Kopple, J.D. (2006). Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients Kidney International, 70(4), 771-780.

Kestenbaum, B., & Belozeroff, V. (2007). Mineral metabolism disturbances in patients with chronic kidney disease. European Journal of Clinical Investigation, 37, 607-622.

Ketteler, M., Rix, M., Fan, S., Pritchard, N., Oestergaard, O., Chasan-Taber, S., ... Kalra, E (2008). Efficacy and tolerability of sevelamer carbonate in hyperphosphatemic patients who have chronic kidney disease and are not on dialysis. Clinical Journal of the American Society of Nephrology, 3, 1125-1130.

Kidney Disease: Improving Global Outcomes CKD-MBD Workgroup. (2009). KDIGO clinical practice guidelines for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease--Mineral bone disorder. Kidney International, 76, S1-S130.

Lowrie, E.G., & Lew, N.L. (1990). Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. American Journal of Kidney Disease, 15(5), 458-482.

National Kidney Foundation (NKF). (2003). KDOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. American Journal of Kidney Disease, 42, S1-S201.

Raggi, P., Boulay, A., Chasan-Taber, S., Amin, N., Dillon, M., Burke, S.K., & Chertow, G.M. (2002). Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? Journal of the American Collage of Cardiology, 39(4), 695-701.

Saliba, W., & El-Haddad, B. (2009). Secondary hyperparathyroidism: Pathophysiology and treatment. Journal of the American Board of Family Medicine, 22, 574-581.

Slinin, Y., Foley, R.N., & Collins, A.J. (2005). Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study. Journal of the American Society of Nephrology, 16(6), 1788-1793.

Suki, W.N., Zabaneh, R., Cangiano, J.L., Reed, J., Fischer, D., Garrett, L., ... Burke, S.K. (2007). Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney International, 72, 1130-1137.

Martin Hanus, BS, is a Staff Scientist, Analytical Research and Development, Genzyme Corporation, Waltham, MA. He may be contacted directly via email at martin.hanus@genzyme.com

Eugene Zhorov, Phi), is a Senior Scientific Director, Analytical Research and Development, Genzyme Corporation, Waltham, MA.

Deborah Brommage, MS, RD, CSR, CDN, is an Adjunct Professor, Long Island University, New York, NY. At the time of this research, she was Senior Renal Clinical Consultant, Genzyme Corporation, Cambridge, MA.

Melissa Plone, MA, is an Associate Director, Medical Writing, Genzyme Corporation, Waltham, MA.

Stephen Randall Holmes-Farley, PhD, is a Distinguished Scientific Fellow and Vice President, Polymer Chemistry, Genzyme Corporation, Waltham, MA.

Acknowledgments: This study was conducted by Genzyme Corporation. The authors are grateful to Betty Parry Fisher, MS, RD, and Michelle Shields, MSN, RN, CRNP, for their input on the article.
Table 1
Serving Sizes of Food

       Food               Serving Size               Notes

Applesauce (Molt's    4 oz single serving
Original[TM])         cup

Oatmeal (Quaker       28 g individual         Oatmeal was about
Instant[TM],          serving packet,         50[degree]C at the
Original)             reconstituted with      time sevelamer
                      water                   carbonate was added.

Whey protein powder   6.6 g reconstituted
(ProCel[TM])          with 60 mL of water

Ginger ale (Canada    4 oz (120 mL)
Dry[TM])

Diet ginger ale       4 oz (120 mL)
(Canada Dry[TM])

Scrambled eggs        43 g (1/8 of a          Scrambled eggs were
                      scramble of 8 eggs in   at ambient room
                      1 tablespoon of         temperature at the
                      vegetable oil)          time sevelamer
                                              carbonate was added.

Baked boneless-       2 oz (56.7g), cubed     Chicken was at
skinless chicken                              ambient room
breast                                        temperature at the
                                              time sevelamer
                                              carbonate was added.

Table 2
Comparison of Phosphate Binding in Various Foods

                 Bound Phosphate (mmol/g)

Foods Tested                                % Difference
                 Pre-Exposed   Co-Exposed

Applesauce          3.79          3.68           2.9
Oatmeal             4.39          4.45          -1.4
Chicken             4.30          4.41          -2.5
Protein Powder      3.99          3.99           0.0
Scrambled Eggs      4.20          4.17           0.7
Ginger Ale          4.33          4.30           0.7
Diet Ginger Ale     4.27          4.24           0.7
Average             4.18          4.18      No Difference
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Article Details
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Title Annotation:Continuing Nursing Education
Author:Hanus, Martin; Zhorov, Eugene; Brommage, Deborah; Plone, Melissa; Holmes-Farley, Stephen Randall
Publication:Nephrology Nursing Journal
Article Type:Report
Date:May 1, 2012
Words:2768
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