In Vitro Study on Combined Effect of Drugs for Hyperphosphatemia on Phosphorus Adsorption Capacity

Abstract

Phosphorus binders are often used in combination to produce synergistic effects. However, the synergistic effect may be affected by the change in pH or concomitant drugs. Nonetheless, the data on the adsorption capacities of these binders when used in combination with other binders are limited. In this study, we evaluated the adsorption capacity of phosphorus binders when used in combination. Precipitated calcium carbonate (CC), ferric citrate hydrate (FC), lanthanum carbonate hydrate (LC), and sucroferric oxyhydroxide (SO) were used as phosphorus binders. SO showed high adsorption capacity in the 1st and 2nd fluid, and the adsorption capacity of SO in combination with other binders was stable. In contrast, the adsorption capacities of CC + FC and FC + LC decreased in the 1st and 2nd fluid compared with that when used alone because of the release of citrate ions that chelate calcium or lanthanum ions. These results suggest that SO is less affected by interactions with other phosphorus binders and changes in pH and may be suitable for patients receiving concomitant drugs.

Introduction

Chronic kidney disease (CKD) is defined as the presence of kidney failure or decreased kidney function for three or more months. Patients with decreased kidney function represent a condition in which the ion balance is not regulated in their body. Owing to kidney dysfunction, biological abnormalities such as hyperphosphatemia occurs, which is reported to increase mortality.¹⁾ Hyperphosphatemia causes ectopic calcification in blood vessels and is a risk factor for cardiovascular events.²⁾ The management of serum phosphorus levels in CKD includes dietary therapy and administration of oral phosphorus binders.³⁾ Among these, phosphorus binders are often administered to patients with CKD.

Phosphorus binders suppress phosphorus absorption by binding to phosphorus in the gastrointestinal tract. Precipitated calcium carbonate (CC), ferric citrate hydrate (FC), lanthanum carbonate hydrate (LC), and sucroferric oxyhydroxide (SO) are currently used to treat hyperphosphatemia in Japan. Among these drugs, CC is the first-line therapy in clinical practice⁴⁾ and can improve hyperphosphatemia; however, it also contributes as a risk factor for cardiovascular calcification.⁵⁾ Thus, other calcium-free phosphorus binders such as FC, LC, and SO are often used concomitantly with CC to avoid the administration of high dose of CC. FC and LC combine with dietary phosphate ions to form insoluble phosphate salts in the gastrointestinal tract via their trivalent cations.^6,7) SO is composed of iron(III)-oxyhydroxide, sucrose, and starch, and its mechanism of action involves ligand exchange after sucrose and starch are digested in the gastrointestinal tract.^8,9) Regarding the current status of combination therapy, a previous study reported that 50.2% of patients were prescribed a single drug, 43.7% were prescribed two drugs, with the most common combination being CC + LC.¹⁰⁾ Another study reported that the proportions of patients with single drug use, two drug use, and three drug use were 55.1, 36.3, and 8.4%, respectively, and of those on the two drugs, the proportions of CC + LC, CC + FC, and CC + SO were 16.7, 7.3, and 3.6%, respectively.¹¹⁾ Although the status of combination prescription varies among facilities, the effectiveness of combination therapy should be examined.

Previous studies have reported the phosphorus adsorption ability of CC, LC, FC, and SO used alone under different pH conditions in vitro,^12,13) but data on the phosphorus adsorption capacity of these binders in concomitant use are limited. With the concomitant use of CC and other phosphorus binders, the phosphorus adsorption capacity has been reported to be equal to or better than the theoretical values in vitro.¹⁴⁾ However, this previous study only evaluated the phosphorus binding capacity of CC with the concomitant use of other phosphorus binders and did not evaluate other combinations. In clinical practice, phosphorus binders are often used concomitantly, and it is necessary to evaluate the phosphorus adsorption capacity of various combinations.

As described above, the main mechanism of action of phosphorus binders is binding with phosphorus in the gastrointestinal tract; therefore, the concomitant use of these drugs may affect the phosphorus adsorption capacity. In this study, we evaluated the phosphorus adsorption capacities of CC, LC, and SO when used alone or in combination.

Results and Discussion

Figure 1 shows the adsorption isotherm of the phosphorus binder used alone in the 1st or 2nd fluid of the disintegration test. In the 1st fluid, the adsorption capacity was the highest for SO and the lowest for CC. In the 2nd fluid, the adsorption capacity was the highest for CC, followed by SO, FC, and LC. Previous studies have reported the phosphorus adsorption capacity as follows: for CC, it was low at pH 2 and high at pH 5–6; for FC, it was high at pH 2 and low at other pH values; for LC, it decreased with increase in pH; and for SO, it decreased slightly with increase in pH and was high over a wide pH range.^13,14) The present study showed similar trends to those of previous studies, except for FC.

Fig. 1. Adsorption Isotherms of Phosphorus Binders Used Alone in the (A) 1st and (B) 2nd Fluid of the Disintegration Test

First, the phosphorus adsorption capacity of CC was higher in the 2nd fluid than in the 1st fluid, showing a tendency opposite to the other phosphorus binders, and this result was consistent with previous studies.^13,14) This may be attributed to two reasons as follows: at lower pH levels, high concentration of H⁺ effectively competes with calcium for phosphorus; at higher pH levels, phosphorus adsorption capacity of calcium ions increases but solubility of calcium carbonate decreases.^13,15) Second, the phosphorus adsorption capacity of FC was low in the 1st and 2nd fluid. In a previous study, the adsorption capacity of FC was higher at pH 2 than at pH 7.¹³⁾ It is unclear why the results of our study showed a different trend. Third, the phosphorus adsorption capacity of LC was higher in the 1st fluid than in the 2nd fluid, and this result was consistent with previous studies.^13,14,16) This is because LC is more soluble at pH 1.2 than at pH 6.5. Fourth, the phosphorus adsorption capacity of SO was higher in the 1st fluid than in the 2nd fluid, and this capacity was stable in the 1st and 2nd fluid, which was consistent with previous studies.^13,14,16) The mechanism of action of SO differs from that of other binders in that it involves ligand exchange mechanism, and this mechanism may be less susceptible to pH effects.

Figure 2 shows the adsorption isotherm of phosphorus binder when used in combination in the 1st or 2nd fluid of the disintegration test. In the 1st and 2nd fluid, the adsorption capacities of CC + LC, CC + SO, and FC + SO were higher than those of CC + FC and FC + LC. Figure 3 shows a comparison of the phosphorus adsorption capacity of adsorbents when used alone and concomitant use in the 1st or 2nd fluid of the disintegration test. Compared with when used alone, in the 1st fluid, the adsorption capacity was almost nonexistent in CC + FC, significantly increased in CC + LC, and was approximate average of that of the two binders in other combinations. Compared with a single use in the 2nd fluid, the adsorption capacity significantly decreased in CC + FC and FC + LC and was average of that of the two binders in other combinations.

Fig. 2. Adsorption Isotherms of Phosphorus Binders Used in Combination in the (A) 1st and (B) 2nd Fluid of the Disintegration Test

Fig. 3. Comparison of the Phosphorus Adsorption Capacities of Adsorbents When Used Alone and in Combination in the 1st or 2nd Fluid of the Disintegration Test

In the combinations CC + FC and FC + LC, the adsorption capacity decreased in the 1st and 2nd fluid compared with that when used alone. This may be attributed to the citrate ions released from FC that chelate calcium or lanthanum ions. In case of high phosphorus concentration in the 1st and 2nd fluid, the adsorption capacity was approximately 20 mg/g; however, these combinations should not be used. In the combination CC + LC, the adsorption capacity in the 1st fluid increased compared with that when used alone, whereas that in the 2nd fluid decreased compared with that in the 1st fluid, but it was equal to that of the other combinations. A previous study reported that the serum phosphorus level in hemodialysis patients decreased significantly after the introduction of CC + LC therapy.¹⁷⁾ Additionally, adding LC to existing phosphorus binders or switching to LC reduced serum phosphorus levels and improved the achievement rate at which target control values for serum calcium levels were achieved.^18,19) These results showed that this combination is highly effective in actual clinical practice. The adsorption capacity of this combination was synergistic in the 1st fluid and stable in the 2nd fluid, and is considered a recommended combination. In the other combinations CC + SO, FC + SO, and LC + SO, the adsorption capacity was not synergistic, but was stable in the 1st and 2nd fluid. In particular, the adsorption capacities of CC + SO and FC + SO were equal to that of CC + LC, which showed synergism in the 1st fluid. Thus, CC + SO and FC + SO are recommended combinations. Furthermore, our results showed that the combined pattern of phosphorus adsorbents, such as FC + SO and LC + SO, did not show any decrease in adsorption capacity compared to that when used alone. The previous study reported that the proportions of patients using LC + FC and LC + SO among patients who used two drugs were 9.4 and 3.6%, respectively,¹¹⁾ and that these combination patterns are less common than the combined patterns that include CC. However, this combination has not been previously examined. These combinations may be beneficial in reducing CC dosing.

Our study has several limitations. First, further studies are needed to confirm whether the results of our in vitro study reflect those of the in vivo study. The previous study reported that the results of the in vitro study mostly reflected those of the in vivo¹⁴⁾ and our study might have a similar trend. Second, the variation in phosphorus adsorption capacity due to the combination pattern in this study must be clarified in clinical studies. This should be performed in a retrospective or multicenter study using hospital electronic medical records. Nevertheless, this is the first study to evaluate the phosphorus adsorption capacity of the combination pattern, excluding CC, and these findings may contribute to the management of serum phosphorus levels in patients with CKD.

Conclusion

In this study, we evaluated the phosphorus adsorption capacities of CC, FC, LC, and SO when used alone and in concomitant use. SO showed a high adsorption capacity in 1st and 2nd fluid, suggesting that it is less sensitive to pH and may be suitable for patients receiving concomitant drugs. Additionally, the adsorption capacity of the combination containing SO was stable. This suggests that SO is less affected by its interactions with other phosphorus binders. In contrast, the adsorption capacity of the combinations CC + FC and FC + LC decreased in the 1st and 2nd fluid compared with that when used alone. This may be attributed to the release of citrate ions that chelate calcium or lanthanum ions. In summary, the combination of phosphorus binders may improve the adsorption capacity; however, such combinations that reduce this capacity should be avoided.

Experimental

Materials and Chemicals

Precipitated calcium carbonate (CC; Mylan Pharmaceuticals Co., Ltd., Osaka, Japan), ferric citrate hydrate (FC; Torii Pharmaceutical Co., Ltd., Tokyo, Japan), lanthanum carbonate hydrate (LC; Bayer Yakuhin Ltd., Osaka, Japan), and sucroferric oxyhydroxide (SO; Kissei Pharmaceutical Co., Ltd., Nagano, Japan) were used as adsorbents. Potassium dihydrogen phosphate (K₂HPO₄) was used as an adsorbate and dissolved in the 1st (pH 1.2) or 2nd (pH 6.8) fluid for the disintegration test. These fluids were prepared according to the Japanese Pharmacopoeia guidelines. All reagents were purchased from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan).

Phosphorus Adsorption Capacity of Different Phosphorus Binders

Each adsorbent (0.05 g) was added to the 1st or 2nd fluid adjusted to an initial phosphorus concentration of 10–1032 mg/L. The suspension was shaken at a reaction temperature of 37 °C and an agitation speed of 100 rpm for 2 h using a water bath shaker and then filtered through a 0.45-µm membrane filter. When evaluating two adsorbents in combination, 0.05 g of each adsorbent was added. The equilibrium phosphorus concentration was measured using inductively coupled plasma-optical emission spectroscopy (ICP-OES; iCAP-7600, Thermo Fisher Scientific Inc., Japan). The amount of phosphorus adsorbed was calculated using the following equation:

  

(1)

where q is the amount of phosphorus adsorbed (mg/g), C₀ is the initial concentration (mg/L), C_e is the equilibrium concentration (mg/L), V is the solvent volume (L), and W is the mass of each adsorbent (g).

Conflict of Interest

The  authors  declare  no  conflict  of interest.

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