Comparison of Phosphate Binding Capacities of PA21, A Novel Phosphate Binder, with those of other Phosphate Binders in vitro and in vivo

Abstract

Purpose: The phosphate binding capacity of PA21, a novel phosphate binder, was compared with those of other phosphate binders in vitro and in vivo.

Methods: 1) For in vitro studies, PA21, sevelamer hydrochloride, lanthanum carbonate hydrate, calcium carbonate, and ferric citrate hydrate were incubated with a phosphate solution at 37°C for 2 h. Phosphate binding capacity was assessed at simulated gastrointestinal tract pH levels of 2, 5, and 8 for estimation of clinical effects, and the quantity of phosphate adsorbed by each phosphate binder was determined. 2) For in vivo studies, rats were orally administered various phosphate binders after the oral administration of phosphate solution (100 mg/kg) adjusted to pH 2, 5, or 8, and the effects of PA21 and other phosphate binders on the serum phosphorus level of the rats were investigated.

Results: 1) The in vitro studies revealed that PA21 and sevelamer hydrochloride adsorbed phosphate better at all tested pH levels than lanthanum carbonate hydrate, calcium carbonate, and ferric citrate hydrate, and PA21 showed the most potent phosphate binding capacity among the tested compounds. 2) The in vivo studies showed that PA21 dose-dependently inhibited the increase in the serum phosphorus level after the administration of phosphate solution and no difference in the extent of inhibition by PA21 was observed at the different pH levels (in contrast to other phosphate binders).

Conclusion: These results indicated that PA21 has a phosphate binding capacity over the entire pH range of the GI tract.

Key words

sucroferric oxyhydroxide - lanthanum carbonate hydrate - sevelamer hydrochloride - calcium carbonate - ferric citrate hydrate

• References

• 1 Gutzwiller JP, Schneditz D, Huber AR et al. Estimating phosphate removal in haemodialysis: an additional tool to quantify dialysis dose. Nephrol Dial Transplant 2002; 17: 1037-1044
• 2 Hutchison AJ, Laville M. SPD405-313 Lanthanum Study Group. Switching to lanthanum carbonate monotherapy provides effective phosphate control with a low tablet burden. Nephrol Dial Transplant 2008; 23: 3677-3684
• 3 Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009; 76: S1-S130
• 4 Block GA, Klassen PS, Lazarus JM et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004; 15: 2208-2218
• 5 Tonelli M, Sacks F, Pfeffer M et al. Cholesterol And Recurrent Events Trial Investigators. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 2005; 112: 2627-2633
• 6 Guideline Working Group, Japanese Society for Dialysis Therapy. Clinical practice guideline for the management of secondary hyperparathyroidism in chronic dialysis patients. Ther Apher Dial 2008; 12: 514-525
• 7 Fukagawa M, Yokoyama K, Koiwa F et al. CKD-MBD Guideline Working Group; Japanese Society for Dialysis Therapy. Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder. Ther Apher Dial 2013; 17: 247-288
• 8 Friedman EA. Consequences and management of hyperphosphatemia in patients with renal insufficiency. Kidney Int Suppl 2005; 67: S1-S7
• 9 Nakano C, Hamano T, Fujii N et al. Combined use of vitamin D status and FGF23 for risk stratification of renal outcome. Clin J Am Soc Nephrol 2012; 7: 810-819
• 10 Isakova T, Wahl P, Vargas GS et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011; 79: 1370-1378
• 11 Amiri FS. Contemporary management of phosphorus retention in chronic kidney disease: a review. Clin Exp Nephrol 2015; in press
• 12 Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure. N Engl J Med 2010; 362: 1312-1324
• 13 Yokoyama K, Akiba T, Fukagawa M et al. Long-term safety and efficacy of a novel iron-containing phosphate binder, JTT-751, in patients receiving hemodialysis. J Ren Nutr 2014; 24: 261-267
• 14 Yokoyama K, Akiba T, Fukagawa M et al. A randomized trial of JTT-751 versus sevelamer hydrochloride in patients on hemodialysis. Nephrol Dial Transplant 2014; 29: 1053-1060
• 15 Shiga A, Sasaki T, Horii N. Correlations among pH and Mg, Ca, P, Na, K, Cl^- and HCO₃ ^- contents of digesta in the gastro-intestinal tract of rats. Nihon Juigaku Zasshi 1987; 49: 973-979
• 16 Phan O, Maillard M, Peregaux C et al. PA21, a new iron-based noncalcium phosphate binder, prevents vascular calcification in chronic renal failure rats. J Pharmacol Exp Ther 2013; 346: 281-289
• 17 Katsumata K, Kusano K, Hirata M et al. Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats. Kidney Int 2003; 64: 441-450
• 18 Neven E, Dams G, Postnov A et al. Adequate phosphate binding with lanthanum carbonate attenuates arterial calcification in chronic renal failure rats. Nephrol Dial Transplant 2009; 24: 1790-1799
• 19 Iida A, Kemmochi Y, Kakimoto K et al. Ferric citrate hydrate, a new phosphate binder, prevents the complications of secondary hyperparathyroidism and vascular calcification. Am J Nephrol 2013; 37: 346-358
• 20 Sheikh MS, Maguire JA, Emmett M et al. Reduction of dietary phosphorus absorption by phosphorus binders. A theoretical, in vitro, and in vivo study. J Clin Invest 1989; 83: 66-73
• 21 Kalantar-Zadeh K. Patient education for phosphorus management in chronic kidney disease. Patient Prefer Adherence 2013; 7: 379-390
• 22 Braunlin W, Zhorov E, Guo A et al. Bile acid binding to sevelamer HCl. Kidney Int 2002; 62: 611-619
• 23 Autissier V, Damment SJ, Henderson RA. Relative in vitro efficacy of the phosphate binders lanthanum carbonate and sevelamer hydrochloride. J Pharm Sci 2007; 96: 2818-2827
• 24 Matsunaga C, Izumi S, Furukubo T et al. Effect of famotidine and lansoprazole on serum phosphorus levels in hemodialysis patients on calcium carbonate therapy. Clin Nephrol 2007; 68: 93-98
• 25 Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478-1483
• 26 Guérin AP, London GM, Marchais SJ et al. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000; 15: 1014-1021
• 27 Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure?. Am J Kidney Dis 1997; 29: 641-649
• 28 Division of Dockets Management, Food and Drug Administration Re: Comments of Genzyme Corporation Docket No.: 2006P-0186. Available at http://www.fda.gov/ohrms/dockets/dockets/06p0186/06p-0186-c000001-01-vol1.pdf
• 29 Spasovski GB, Sikole A, Gelev S et al. Evolution of bone and plasma concentration of lanthanum in dialysis patients before, during 1 year of treatment with lanthanum carbonate and after 2 years of follow-up. Nephrol Dial Transplant 2006; 21: 2217-2224
• 30 Floege J, Covic AC, Ketteler M et al. PA21 Study Group. A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients. Kidney Int 2014; 86: 638-647