The Treatment Concepts of Hyperphosphatemia in CKD And

Home , Lanthanum carbonate

New Drugs and Novel Concepts 13 – 17 June 2016 Talk Outlines: Hyperphosphatemia as a CKD complication: The Treatment Concepts of Hyperphosphatemia in CKD and  Phosphate homeostasis New Phosphate Binders  Hyperphosphatemia and its consequences  Treatment options: Current and new drugs DARAPORN RUNGPRAI, RPh - B Pharm, BCP, FACP - Certified Pharmacy Practice Residency - Specialized Residency in Nephrology Pharmacotherapy - Fellowship in Nephrology Pharmacotherapy Department of Pharmacy, Faculty of Pharmacy 2 Silpakorn University, Nakhon Pathom, THAILAND

Phosphate Balance:

. Calcium . Bone turnover . Phosphorus . Bone mineralization . iPTH . Bone volume, . Vitamin D linear growth, or strength

. Vascular or other soft tissue calcification

Kidney Int. 2006 Jun;69(11):1945-53.3 4 From: KDIGO CKD-MBD guideline 2009 Adv Chronic Kidney Dis 2007;14(1):3-12. Semin Dial 2007; 20(4): 295-301.

1 Phosphate Homeostasis: Hyperphosphatemia Consequences:

Hormone synthesis by osteocytes

5 6 J Am Board Fam Med 2009; 22(5): 574-81. J Am Board Fam Med 2009; 22(5): 574-81.

Endothelial cells Media

Intima Adventitia

Conduit Calcified coronary atherosclerotic plaque of a patient with CKD

Heavy calcification of a peripheral vein of a patient with CKD

7 8 Circulation 2007;116;85-97 Kidney and Blood Pressure Research 2005;28:280–289

2 Arterial calcification increases mortality risk

Hypertension 2001;38:938–42.10

Patient all-cause and cardiovascular mortality risk associated with 10%more facility patients within each serum phosphorus category versus reference category CKD-MBD Management

2003 2009

11 12 American Journal of Kidney Diseases 2008;52(3):519-30.

3 Parameter Stage 3 Stage 4 Stage 5 < 15 GFR (mL/min/1.73m2) 30 –59 15 –29 Management of Hyperphosphatemia Or dialysis Corrected Calcium 8.4 – 9.5 8.4 – 9.5 8.4 – 9.5 (mg/dL) Not > 10.2 Not > 10.2 Not > 10.2  High phosphate diet restriction = measure Ca + 8.5 – 10.0 8.5 – 10.0 8.5 – 10.0 [0.8x(4 – alb)] Not > 10.5 Not > 10.5 Not > 10.5  Medication: phosphate binders Phosphorus 2.7 –4.6 2.7 –4.6 3.5 –5.5 (mg/dL) 2.5 – 4.5 2.5 – 4.5 Toward normal  Dialysis intervention: HD or PD Ca x P Product (mg2/dL2) < 55

Individualized evaluate Ca and P together (2D) iPTH (pg/mL) 35 – 70 70 – 110 150– 300

Optimal: NOT KNOWN 2-9 x UNL 13 14 AJKD 2003;42(4):S12-S28. Kidney Int 2009;76(Suppl 113):S1–S130.

Management of Hyperphosphatemia Management of Hyperphosphatemia

 Limiting dietary phosphate intake: KDIGO: In patients with CKD stages 3–5D, we suggest limiting dietary phosphate intake in  KDOQI: Dietary phosphorus should be the treatment of hyperphosphatemia alone or restricted to 800 to 1,000 mg/day when; in combination with other treatments (2D). . The serum phosphorus levels are elevated Primary intervention for the management of CKD–MBD, strongly recommend? (> 4.6 in CKD S3,4 or > 5.5 in CKD S5) . Insufficient data, esp. in stage 5D . The plasma levels of intact PTH are elevated . Helpful in early CKD . Adjunct to phosphate binders and dialytic above target range of the CKD stage removal of phosphate in 5D patients. 15 16 American Journal of Kidney Diseases 2003;42(4):S12-S28. Kidney Int 2009;76(Suppl 113):S1–S130.

4  อาหารประเภทถัว ทุกชนิด ทงั ชนิดแปรรูป และ ไม่ Management of Hyperphosphatemia แปรรูป เช่น ถวั ลิสง ถวั เขียว ถัวแดง ถัว เหลือง เมลด็ อลั มอนด์ เมลด็ มะม่วงหิมพานต์ เมลด็ ฟักทอง เมลด็ แตงโม เมลด็ ทานตะวนั เป็นต้น If phosphorus or intact PTH levels cannot  สตั ว์ทีร บั ประทานทงเปลือกั หรือกระดูก เช่น ปลา be controlled within the target range, ซารด์ ีนกระป๋ อง ก้งุ แห้ง ปลากรอบ กะปิ เป็นต้น despite dietary phosphorus restriction,  อาหารทีม ีส่วนผสมของนม และผลิตภณั ฑ์จากนม Phosphate binders should be prescribed. เช่น นมผง ขนมเค้ก ขนมปังบิสกิท ขนมปังกรอบ  ขนมและเครืองดื ม ต่างๆ เช่น ขนมทีผสมไข่แดง

ธญั พืชทีไมไ่ ด้ขดั สี ชอ็ กโกแลต โกโก้ กาแฟ เป็นต้น 17 18 American Journal of Kidney Diseases 2003;42(4):S12-S28.

Phosphate Binder Mechanism The Ideal Phosphate Binders

Few side effects Minimal Low pill systemic burden absorption

Avidly bind IDEAL dietary Inexpensive phosphate BINDERS

20 19 Drugs 2014;74: 863–877. N Engl J Med 2010;362:1312-24 .

5 Management of Hyperphosphatemia Management of Hyperphosphatemia Current phosphate binders: Current phosphate binders: . Calcium based phosphate binders: usually . Non-calcium, non-aluminum, non-magnesium Calcium -carbonate, Calcium acetate containing phosphate binders: . Non-calcium-based phosphate binders: Sevelamer (polymer-based): Magnesium hydroxide, Magnesium carbonate, Sevelamer HCl (approved in 1998) Magnesium carbonate/Calcium carbonate, Sevelamer carbonate (approved in 2009) Magnesium carbonate/Calcium acetate Aluminium hydroxide (1980s)** Lanthanum: Lanthanum carbonate (Usually not use in US) (approved in 2004)

N Engl J Med 2010;362:1312-2421 N Engl J Med 2010;362:1312-2422 American Journal of Kidney Diseases 2003;42(4):S12-S28.. American Journal of Kidney Diseases 2003;42(4):S12-S28..

Management of Hyperphosphatemia Phosphate Binding Capacity Current phosphate binders: . Metal – based phosphate binders:

Aluminum Lanthanum

Drugs 2014;74: 863–877. 23 24 Semin Dial 2011;24(1):41-9.

6 Management of Hyperphosphatemia Management of Hyperphosphatemia

Use of Phosphate Binders:  Ca-based phosphate binders limitation: . Calcium-based phosphate binders are .  Serum Ca level: 25 – 45% of Ca absorbs

effective in lowering serum phosphorus from GI tract   episodes of levels and may be used as the initial hypercalcemia binder therapy. .  serum PTH level  adynamic bone . Total dose of elemental calcium should disease not exceed 1,500 mg/day and total calcium intake should not exceed 2,000 . Vascular calcification: progression of arterial calcification mg/day Kidney Int 2009;76(Suppl 113):S1–S130. 25 26 American Journal of Kidney Diseases 2003;42(4):S12-S28. American Journal of Kidney Diseases 2003;42(4):S12-S28.

Management of Hyperphosphatemia Management of Hyperphosphatemia Calcium-based phosphate binders should  Use of Phosphate Binders: restrict the dose or not be used in patients with CKD stages 3 – 5D who are: . In patients with serum phosphorus levels > 7.0 mg/dL, aluminum-based phosphate . Hypercalcemic binders may be used as a short-term . Arterial calciﬁcation therapy (4 weeks), and for one course only, to be replaced thereafter by other . Adynamic bone disease phosphate binders. . Serum PTH levels are persistently low . In such patients, more frequent dialysis (or prefers non-calcium based phosphate binders high flux HD) should also be considered. Kidney Int 2009;76(Suppl 113):S1–S130. 27 28 American Journal of Kidney Diseases 2003;42(4):S12-S28. American Journal of Kidney Diseases 2003;42(4):S12-S28.

7 Aluminum deposition: Leads to systemic Aluminum Management of Hyperphosphatemia toxicity manifested as;  Lanthanum carbonate  Encephalopathy: neurotoxin Lanthanum:  Alzheimer’s and other . Non-calcium, non-aluminium phosphate neurodegenerative processes binders  FDA approve indication in adult  Osteomalacia: ESRD patients (on HD or CAPD)  Impairs mineralization of the AVAILABLE IN matrix; interfering with calcium THAILAND deposition . Chewable tablet:  Inhibits the bone-building osteoblasts 250 mg, 500 mg, 750 mg and 1,000 mg  Anemia and partial resistance to . Administration: taking with meal /or EPO: Influencing intestinal iron absorption, transport in the serum and immediately after meals by chewing /or crushing uptake by cells. 29 the tablet completely before swallowing. 30 Seminars in Dialysis 2006;19(3):195–99. Nephrol Dial Transplant 2002;17(Suppl 2) 9–12. :

Management of Hyperphosphatemia

Initial : 1,500 mg ORALLY per day in divided doses with meals

LANTHANUM CARBONATE Titrate in increments of 750 (FOSRENOL®) mg/day at intervals of 2 to 3 weeks

US FDA approve since 2004 Maintenance : 1,500 to 3,000 mg ORALLY per day in divided doses with meals 31 32 PILL CRUSHER

8 Important Safety Information

Lanthanum carbonate is contraindicated in patients with bowel obstruction, ileus, and fecal impaction. U.S. available since May 2015 Dosage available: 750 mg, 1,000 mg . Serious cases of GI obstruction, ileus, and fecal impaction have been associated with lanthanum use, some requiring surgery or hospitalization. Risk factors: altered GI anatomy, hypomotility disorders, and concomitant medications.

. Instruct patients to chew or crush the tablet The first FDA-approved phosphate binder that is specifically completely to reduce the risk of serious adverse formulated to be mixed with applesauce or other similar food, gastrointestinal events. and not liquid 33 https://www.fosrenol.com/oral-powder/dosing-and-administration https://www.fosrenol.com/oral-powder/dosing-and-administration 34

Calcium : 25-45% absorbs from GI tract Lanthanum Carbonate Oral Powder (Curr Med Res Opin. 2008 Mar;24(3):708)

35 36 https://www.fosrenol.com/oral-powder/dosing-and-administration J Am Soc Nephrol 15:2219–2228, 2004

9 Long Term ADRs/La Toxicity: Long Term ADRs/La Toxicity: Lanthanum carbonate did not show toxicity on BONE osteoblast in animal models (renal failure rats) BRAIN/CNS

No evidence of CNS toxicity was demonstrated after 2 years.

37 Kidney Int 2007;71:252–9.38 Int J Nephrol Renovasc Dis 2012;5:81-9. Ther Apher Dial. 2011;15(2):176–184. Int J Nephrol Renovasc Dis 2012;5:81-9.

Long Term ADRs/La Toxicity: Common ADRs:

LIVER Mostly, GI side effects: Lanthanum carbonate is excreted via bile, accumulation in the liver and hepatotoxicity, which are not observed . Nausea [11 –26 %] with aluminum products, were investigated. . Vomiting [9 – 18%] No hepatotoxicity was observed. . Abdominal pain [5%] No liver toxicity in HD patients treated with Others (not serious): lanthanum carbonate . Peripheral edema [23%] for 6 years’ long-term

follow-up. . Myalgia [21%] ® 39 Fosrenol Product Information40 J Am Soc Nephrol 15:2219–2228, 2004 Int J Nephrol Renovasc Dis 2012;5:81-9. Curr Med Res Opin 2005;21:657-64.

10 Management of Hyperphosphatemia Management of Hyperphosphatemia

 Sevelamer: Sevelamer HCl, Sevelamer CO3  Sevelamer carbonate (Renvela®)  Non-calcium, non-aluminium (polymer based) phosphate binders: quaternary amine anion  Buffered form of Sevelamer, same exchange resin  exchanges chloride ions for polymeric structureAVAILABLE as IN Sevelamer HCl phosphate ions THAILAND  Dosage form:  Pros: Lower LDL and total cholesterol 800 mg tablet and 2.4 g powder  Cons: expensive, low binding capacity -  Less acidosis, rise HCO 3 level  Sevelamer HCl can cause acidosis  need to - monitor HCO 3 Drugs 2014;74: 863–877. 41 Drugs 2014;74: 863–877. 42

Management of Hyperphosphatemia

 Sevelamer: Sevelamer HCl, Sevelamer CO3  Administration: Swallow whole tablet w/ meal, do not crush or chew the tablet.  Drug interaction: bind with other drugs Should administrate another medication 1 hour before or 3 hours after Sevelamer SEVELAMER CARBONATE (RENVELA®)  Adverse reaction: mostly GI side effects (N/V, abdominal pain, bloating, constipation)

43 Metabolic acidosis, peritonitis 44 Drugs 2014;74: 863–877.

11 Sevelamer carbonate (Renvela®) Other Polymer-Based Phosphate Binders . Colestilan (colestimide, MCI-196) is an anion- Serum phosphorus level Total daily dose of exchange resin that binds bile salts and in patients sevelamer carbonate to be phosphate. Colestilan is marketed in Japan taken over 3 meals per day and Europe. . Bixalomer (AMG 223, ASP1585, formerly 5.5 – 7.5 mg/dL 800 mg (1 tab) ILY101) is a metal-free, non-absorbed polymeric phosphate-binding agent launched in Japan in 2012. > 7.5 mg/dL 1,600 mg (2 tab) . Chitosan: a cationic biopolymer  Chitosan chewing gum 45 46 Renvera® Product Information Drugs 2014;74: 863–877.

Management of Hyperphosphatemia Management of Hyperphosphatemia

Use of Phosphate Binders Use of Phosphate Binders Previous studies (systematic review published It is reasonable that the choice of in KDOQI guideline) showed that: phosphate binder takes into: . All medications currently used as phosphate . Account CKD stage  binders calcium salts, aluminum salts, . The presence of other components of magnesium salts, sevelamer, and lanthanum CKD–MBD concomitant therapies carbonate are effective in lowering serum phosphorus levels. . Side-effect proﬁles (not graded) Kidney Int 2009;76(Suppl 113):S1–S130. 47 48 American Journal of Kidney Diseases 2003;42(4):S12-S28. Kidney Int 2009;76(Suppl 113):S1–S130.

12 Management of Hyperphosphatemia New Lanthanum-Based Phosphate Binder ® Currently available binders have been associated  SPI-014 (RenaZorb ): Lanthanum dioxycarbonate with impaired outcomes Second-generation lanthanum-based phosphate . Calcium-based phosphate binders: binders: Nanopartical technology - Hypercalcemia 2012: A Double Blind, Dose-Ranging, Phase 1 Study In - Vascular calcification Healthy Volunteers to Assess Safety and the Phosphate Binding Capacity of Lanthanum Dioxycarbonate (SPI-014, - Adynamic bone disease ® RenaZorb ) . Aluminum-based phosphate binders: - Aluminum toxicity: Blood/Brain/Bone . Lanthanum, Sevelamer: Safety Phase 1 - Expensive, large pill size, pill burden (Sevelamer) Binding capacity Healthy volunteers Drugs 2014;74: 863–877. 49 50 https://clinicaltrials.gov/ct2/show/study/NCT01560884

New Lanthanum-Based Phosphate Binder New Lanthanum-Based Phosphate Binder  SPI-014: Lanthanum dioxycarbonate  SPI-014: Lanthanum dioxycarbonate . The Phase 1 clinical findings showed that . Effective phosphate lowering (1) SPI-014 is well-tolerated up to the maximum . Convenient, easy-to-swallow pill formulation administered dose of 6,000 mg/day, showing no serious adverse events, low systemic exposure, and  Higher phosphate-binding capacity of RenaZorb® no discontinuations of therapy. compared to current products, as shown in in vitro studies, allows the manufacturer to offer lower (2) SPI-014 resulted in statistically significant dosing and a smaller, patient-friendly tablet size. reductions in daily urinary phosphorous excretions at 1,500 mg/day; 3,000 mg/day; 4,500 mg/day and . Can address substantially the poor compliance 6,000 mg/day) compared to placebo. associated with current therapies.

SPECTRUM PHARMACEUTICALS: 51 SPECTRUM PHARMACEUTICALS: 52 http://investor.sppirx.com/releasedetail.cfm?releaseid=731677#top http://investor.sppirx.com/releasedetail.cfm?releaseid=731677#top

13 New Lanthanum-Based Phosphate Binder

®  RenaZorb (SPI-014): Lanthanum dioxycarbonate . Planning for Phase II Study: Testing of drug on CKD patients to assess efficacy and safety . Seeking a licensing partner outside of the U.S., Objectives: PHASE II STUDY in particular, in Japan and other countries in . Evaluating the ability of Genz-644470 to lower serum Asia. phosphorus in patients on HD. . Compared serum phosphorus lowering of Genz-644470 with sevelamer carbonate and placebo. SPECTRUM PHARMACEUTICALS: 53 54 http://investor.sppirx.com/releasedetail.cfm?releaseid=731677#top Int J Nephrol Renovasc Dis 2014;7:141-52.

IN VITRO

Genz-644470 did not provide any advantage over sevelamer carbonate in phosphate lowering in vivo

55 56 Int J Nephrol Renovasc Dis 2014;7:141-52. Int J Nephrol Renovasc Dis 2014;7:141-52.

14 Iron-magnesium hydroxycarbonate NEW PHOSPHATE BINDERS Fermagate, Alpharen: . One Phase II study, Two Phase III RCTs  terminated in 2010 Iron based phosphate binders (commercial reasons). . Iron-magnesium hydroxycarbonate . Low binding capacity (Fermagate, Alpharen) . Frequent adverse effects (95% . Polymeric complex of iron (III) (SBR-759) of patients): Mainly GI side effects  diarrhea (48%), . Sucroferric oxyhydroxide (PA21) dyspepsia (14%), vomiting (14%), feces discoloration (38%) . Ferric citrate (JTT-751, KRX-0502) Restarted Phase III study in 2014 . Ferric oxide adipate (PT20) Expected to complete by 2017

57 58 Drugs 2014;74: 863–877. Clin Kidney J 2015;8: 161–167. Clin J Am Soc Nephrol. 2009 Feb; 4(2): 401–409. Drugs 2014;74: 863–877.

Polymeric complex of iron (III) SBR-759 . SBR-759 is a polymeric complex of ferric- oxyhydroxide and starch [Fe3+O(OH)-starch- saccharose-carbonate complex] . Formulated as a non-flavored powder in an attempt to reduce the pill burden and improve compliance. . SBR-759 product development (Phase II trial) was terminated for Western populations in 2010  Less efficacy than sevelamer (serum phosphate responders 52 vs. 66 %) more GI

adverse effects (diarrhea 34 vs. 16%) 59 60 Drugs 2014;74: 863–877. Data available from: http://adisinsight.springer.com/drugs/800023014

15 NEW PHOSPHATE BINDERS Iron based phosphate binders . Iron-magnesium hydroxycarbonate (Fermagate, Alpharen) . Polymeric complex of iron (III) (SBR-759) . Sucroferric oxyhydroxide (PA21) . Ferric citrate (JTT-751, KRX-0502) . Ferric oxide adipate (PT20)

Drugs 2014;74: 863–877. Clin Kidney J 2015;8: 161–167. 61 62 Kidney International 2010;77: 845 – 847.

New Phosphate Binders Sucroferric oxyhydroxide Stabilize (PA21) the iron Iron-based phosphate binders: . Sucroferric oxyhydroxide (PA21): - US FDA approved in November 2013 Iron(III)-oxyhydroxide core - European Medicines Agency (EMA) in August 2014

- Japanese approval in September 2015 Help during drug production process CKD patients with dialysis

63 64 Clin Kidney J 2015; 8(2): 161-7. Int J Nephrol Renovasc Dis. 2016; 9: 11–19. Drugs 2015;75: 533–542. Int J Nephrol Renovasc Dis. 2016; 9: 11–19.

16 Sucroferric oxyhydroxide (PA21) Efficacy, Safety and Tolerability of PA21 Authors Mechanism of Action: Subjects Duration Journal, year Comparator Main results enrolled of study . The adsorption of phosphate to the iron [Study phase] Geisser P, Philipp E. - 8 CKD pts. Intervention: 7 days . A significant complex [the iron(III)-oxyhydroxide core] 1 Clin Nephrol, 2010 (S3 – 4) PA21 10 g/day decrease in  - 8 HD pts.2 serum phosphate happens in intestinal lumen. [Phase I] - 8 healthy No comparator . S/E: Diarrhea . subjects3 . Iron uptake was The formation of iron phosphate through a low: 0.06%1, 2 3 chemical reaction that is favored by low pH Clin Nephrol 2010;74(1):4-11. 0.02% , 0.43% values, such as those present within the Wüthrich RP, et al. 154 HD pts. . PA21 at 1.25, 6 weeks Similar decrease Pi CJASN, 2013 5.0, 7.5,10.0, . SEV 4.8 g/day  or 12.5 g/day -1.06 ±1.35 mg/dL stomach. [Phase II – dose . PA21 5.0 g/day  finding] . Sevelamer HCl -1.08±2.12 mg/dL Excretion of bound phosphate in the feces S/E: Discolored feces (11.4%), hypophos ~ Int J Nephrol Renovasc Dis. 2016; 9: 11–19. 65 66 Clin J Am Soc Nephrol. 2013;8(2):280-9. (18%)

Authors Subjects Duration Journal, year Comparator Main results enrolled of study Sucroferric oxyhydroxide (PA21) [Study phase] ® ® Floege J, et al. 1,055 HD . PA21 at 1.0 – 24 weeks Serum phosphate level . Velphoro /P-TOL : A chewable tablet Kidney Int, 2014 and PD pts. 3.0 g/day at 12 weeks ® (2 – 6 tab/d) . PA21: -0.71 mmol/L containing 250 mg, 500 mg (Velphoro ; 500 mg [Phase III] . Sevelamer (avg: 3 tablets) only) iron as polynuclear iron(III)-oxyhydroxide, carbonate . SEV: -0.79 mmol/L (avg: 8 tablets) sucrose and starches 4.8 – 14.4 . Partially water soluble g/day . Non-inferiority (6-18 tab/d) . Lower pill burden .  . S/E: diarrhea, Sucrose glucose + fructose Kidney Int 2014;86(3):638-47. discolored feces  absorbed Floege J, et al. 1,055 HD . PA21 at 1.0 – 28 weeks . Serum phosphate . Starch  glucose + maltose and PD pts. 3.0 g/day Extension lowering effect of Nephrol Dial  Transplant, 2015 (2 – 6 tab/d) study PA21 was maintained absorbed over 1 year (not . Polynuclear iron(III)-oxyhydroxide [Phase III – . Sevelamer different from SEV) extension study] carbonate  nearly insoluble  prevent 2.4 – 14.4 . Lower pill burden . No evidence of iron Woodberry flavor iron absorption at duodenum g/day 67 68 Nephrol Dial Transplant 2015;30(6):1037-46. (6-18 tab/d) accumulation http://www.drugs.com/pro/velphoro.html Int J Nephrol Renovasc Dis. 2016; 9: 11–19.

17 Sucroferric oxyhydroxide (PA21) Sucroferric oxyhydroxide (PA21) ® ® . Velphoro /P-TOL : . Starting dose: 1,500 mg/day (500 mg, t.i.d.) o A chewable tablet – chewing and disintegration Max. 3,000 mg/day into smaller particles to allow for optimal adsorption. . PA21 must be taken with meals, with the total o Chewable tablets offer the advantage of more daily dose divided across the meals of the day flexibility in not requiring access to water and to maximize dietary phosphate binding. in the fact that the medication can be more discretely taken. . PA21 tablets must be chewed and not o PA21 - Good benefit for CKD or dialysis patients who swallowed whole. require fluid restriction because it can be taken orally without water. Drugs 2015;75: 533–542. 69 70 Drug Dev Ind Pharm. 2014;40(12): 1623-31. Int J Nephrol Renovasc Dis. 2016; 9: 11–19.

Sucroferric oxyhydroxide (PA21) . Things to be concerned: o Some of saccharides contents of PA21 could be metabolized to glucose, fructose, and maltose. o Contraindicated in patients with fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency. o The use of PA21 in diabetic patients, in particular in those treated with PD, could interfere with capillary glucose tests  induce false results. 71 Drugs 2015;75: 533–542. 72 Kidney Int 2014;86(3):638-47. Drugs 2015;75: 533–542. Clin Kidney J 2015; 8(2): 161-7. Int J Nephrol Renovasc Dis. 2016; 9: 11–19.

18 Sucroferric oxyhydroxide (PA21) New Phosphate Binders Iron-based phosphate binders: . Things to be concerned: . Ferric citrate (JTT-751, KRX-0502): o The chemical structure of PA21 prevents iron - US FDA approved in September 2014 absorption in the GI tract, but PK study  minimal percentage of iron is actually absorbed. - Japanese approval in 2014 - European Medicines Agency (EMA) in o Contraindicated in pts with haemochromatosis 2015 or any other iron accumulation disorders and iron homeostasis should be monitored. Approved indication: 1. Hyperphosphatemia in patients receiving dialysis. (US) 2. Hyperphosphatemia in all CKD patients. (EU) Drugs 2015;75: 533–542. 73 74 Clin Kidney J 2015; 8(2): 161-7. Int J Nephrol Renovasc Dis. 2016; 9: 11–19. Clin Kidney J 2015; 8(2): 161-7. Semin Nephrol 2016;36(2):130-5.

Ferric Citrate (JTT-751, KRX-0502) Efficacy, Safety and Tolerability of FC

. Ferric iron binds with dietary phosphate in the GI tract. . Precipitates as ferric phosphate.

. Ferric phosphate is insoluble. . Excrete via feces

. Iron can be absorbed through the GI tract.

75 76 Picture available from: https://www.auryxia.com/mechanism-of-action/ Clin Kidney J 2015; 8(2): 161-7.

19 Results: Serum Phosphate Levels (mg/dL)

. 441 subjects on dialysis (HD, or PD) were randomized to ─ Ferric citrate (FC) ─ Active control (AC): sevelamer or calcium acetate . AC: Sevelamer or calcium acetate or combination Duration: 52-week 77 78 J Am Soc Nephrol 2015;26(2):493-503. J Am Soc Nephrol 2015;26(2):493-503.

Results: Iron parameters (serum ferritin, TSAT)

79 80 J Am Soc Nephrol 2015;26(2):493-503. Drugs R D 2015;15:271–279

20 Ferric Citrate (JTT-751, KRX-0502) ® ® . AURYXIA (ZERENEX ): U.S. ® . FEXERIC : European Union ® . RIONA : Japan 210 mg of ferric iron equivalent to 1 g of ferric citrate.

Starting dose: 2x3 w/ meal Swallow NOT chew

81 82 Drugs R D 2015;15:271–279 Picture available from: http://www.webmd.com/drugs/2/drug-167468/auryxia-oral/details#images

Ferric Citrate (JTT-751, KRX-0502) New Phosphate Binders . Adverse Drug Reaction: . Iron-based phosphate binders and FGF23: Mostly GI adverse events: o Hyperphosphatemia  FGF23.mid-chamber of the left ventricle o Diarrhea (21%) o FGF23   Progression of CKD FGF23   LVH, Cardiovascular events o Discolored feces (17%) (MI, amutation, stroke, death). o N/V o Iron status is an independent negative o IRON OVERLOAD: Contraindicated in predictor of plasma FGF23 concentration and pts with haemochromatosis or any iron supplementation is associated with a other iron accumulation disorders and significant decrease in FGF23 values. iron homeostasis should be monitored. 83 J Clin Invest. 2011 Nov;121(11):4393-408. 84 J Am Soc Nephrol 2015;26(2):493-503. Clin Kidney J 2015; 8(2): 161-7. Kidney Int 2012;82(7):737-747. Int J Nephrol Renovasc Dis. 2016; 9: 11–19.

21 New Phosphate Binders

. Iron-based phosphate binders and FGF23: o Iron administration per se and also treatment with iron-based phosphate binders   FGF23 both directly and by reducing phosphate intestinal absorption. o PA21, FC   FGF23. o PA21 (dialysis patients) o FC (non-dialysis CKD patients)

85 86 Kidney Int 2012;82(7):737-747. Int J Nephrol Renovasc Dis. 2016; 9: 11–19.

Iron-Based Phosphate Binders Ferric oxide adipate (PT20) . Both sucroferric oxyhydroxide and ferric citrate are effective phosphate binders,  FGF23 : o Sucroferric oxyhydroxide may be more suited for hyperphosphatemic CKD patients not requiring iron supplementation. o Sucroferric oxyhydroxide  low pill burden o Ferric citrate: more suited to treat hyperphosphatemia in CKD patients who require iron supplementation. o Monitoring: Serum phosphate, iron status 87 88 Clin Kidney J 2015; 8(2): 161-7. Data available from: http://adisinsight.springer.com/drugs/800036595

22 Management of Hyperphosphatemia Management of Hyperphosphatemia The important aspects that should be New Phosphate binders: considered in phosphate binders therapy . Iron-based phosphate binders: . GI absorption of the active moieties. Sucroferric oxyhydroxide: . Phosphate binders also bind harmful or Approval: US FDA 2013, EMA 2014, JP 2015 useful substances in the gut. Ferric citrate: . The compliance to phosphate binders Approval: US FDA and JP 2014, EMA 2015 . The effect of different phosphate NOW IRON-BASED PHOSPHATE BINDERS ARE binders on FGF-23 serum levels. NOT AVAILABLE IN THAILAND 89 90 Clin Kidney J 2015;8: 161–167 Clin Kidney J 2015; 8(2): 161-7.

ควรเคี้ยว หรือบดยาใหละเอียด เคี้ยว รบั ประทานพรอมอาหาร

หามเคี้ยว

Calcium based phosphate binders should not be use in patients with: Chewable tab. (เคี้ยว) . Hypercalcemia . Arterial calcification . iPTH < 100 pg/mL ดาราพร รงุ้ พราย. การจดั การภาวะฟอสเฟตในเลอื ดสูง: จากแนวทางการรกั ษาสู่การปฏบิ ตั .ิ ใน: บุษบา จนิ ดาวจิ กั ษณ์, ธนรตั น์ สรวลเสน่ห,์ ดาราพร รงุ้ พราย. การจดั การภาวะฟอสเฟตในเลอื ดสูง: จากแนวทางการรกั ษาสู่การปฏบิ ตั .ิ ใน: บุษบา จนิ ดาวจิ กั ษณ์, ธนรตั น์ สรว91ลเสน่ห,์ 92 ปรชี า มนทกานตกิ ุล, บรรณาธกิ าร. Connecting Pharmaceutical Care and Outcomes. กรงุ เทพฯ: ประชาชน; 2558, หน้า 97 – 113. ปรชี า มนทกานตกิ ุล, บรรณาธกิ าร. Connecting Pharmaceutical Care and Outcomes. กรงุ เทพฯ: ประชาชน; 2558, หน้า 97 – 113.

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