A Phase 1 dose-ranging study examining the effects of a superabsorbent polymer (CLP) on fluid, sodium and potassium excretion in healthy subjects

BMC Clinical Pharmacology

Detlef Albrecht⁴  Thomas Oliphant¹  Richard Newman²  Thomas M Blok⁵  Alan Strickland³  Howard C Dittrich⁴  Lee W Henderson⁴ 

[1] Innovative Analytics, 161 East Michigan Ave, Kalamazoo, MI 49007, USA;RnD Services, LLC, 635 Bent Creek Ridge, Deerfield, IL 60015, USA;Alan Strickland Consulting, 101 Waterlily, Lake Jackson, TX 77566, USA;Sorbent Therapeutics Inc, 710 Lakeway Drive, Suite 290, Sunnyvale, CA 94085, USA;Jasper Clinic’s Clinical Research Unit, 526 Jasper Street, Kalamazoo, MI 49007, USA

关键词: Gastrointestinal sodium removal;    Gastrointestinal fluid removal;    Pharmacodynamics;    Dose ranging;    Superabsorbent polymer;   

Others  :  860458
DOI  :  10.1186/2050-6511-15-2

 received in 2013-09-04, accepted in 2014-01-22,  发布年份 2014

【 摘 要 】

Background

CLP is an orally administered, non-absorbed, superabsorbent polymer being developed to increase fecal excretion of sodium, potassium and water in patients with heart failure and end-stage renal disease. This study was conducted to evaluate the safety of CLP, and to explore dose-related effects on fecal weight, fecal and urine sodium and potassium excretion, and serum electrolyte concentrations.

Methods

This Phase 1, open-label, dose-escalation study included 25 healthy volunteers, who were administered CLP orally immediately prior to four daily meals for 9 days at doses of 7.5, 15.0, and 25.0 g/day (n = 5/group). An additional dose group received 15.0 g/day CLP under fasting conditions, and an untreated cohort (n = 5) served as control. Twenty-four-hour fecal and urinary output was collected daily. Samples were weighed, and sodium, potassium, and other ion content in stool and urine were measured for each treatment group. Effects on serum cation concentrations, other standard laboratory values, and adverse events were also determined.

Results

At doses below 25.0 g/day, CLP was well tolerated, with a low frequency of self-limiting gastrointestinal adverse events. CLP increased fecal weight and fecal sodium and potassium content in a dose-related manner. Concomitant dose-related decreases in urinary sodium and potassium were observed. All serum ion concentrations remained within normal limits.

Conclusions

In this study, oral CLP removed water, sodium and potassium from the body via the gastrointestinal tract in a dose related fashion. CLP could become useful for patients with fluid overload and compromised kidney function in conditions such as congestive heart failure, salt sensitive hypertension, chronic kidney disease and end stage renal disease.

Trial registration

NCT01944007

【 授权许可】

   
2014 Henderson et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP, ADHERE Scientific Advisory Committee and Investigators: Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005, 149(2):209-216.
• [2]Brandimarte F, Mureddu GF, Boccanelli A, Cacciatore G, Brandimarte C, Fedele F, Gheorghiade M: Diuretic therapy in heart failure: current controversies and new approaches for fluid removal. J Cardiovasc Med 2010, 11(8):563-570.
• [3]Drazner MH, Rame JE, Stevenson LW, Dries DL: Prognostic importance of elevated jugular vein pressure and third heart sound in patients with heart failure. N Engl J Med 2001, 345(8):574-581.
• [4]Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA, Teerlink JR, Jaski BE, Fang JC, Feller ED, Haas GJ, Anderson AS, Schollmeyer MP, Sobotka PA, UNLOAD Trial Investigators: Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007, 49:675-683. Erratum, J Am Coll Cardiol 2007, 49:1136
• [5]Cowie MR, Komajda M, Murray-Thomas T, Underwood J, Ticho B: Prevalence and impact of worsening renal function in patients hospitalized with decompensated heart failure: results of the prospective outcomes study in heart failure (POSH). Eur Heart J 2006, 27:1216-1222.
• [6]Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran JR, Wynne J: High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail 2007, 13(6):422-430.
• [7]Ahmed A, Husain A, Love TE, Gambassi G, Dell’Italia LJ, Francis GS, Gheorghiade M, Allman RM, Meleth S, Bourge RC: Heart failure, chronic diuretic use, and increase in mortality and hospitalization: an observational study using propensity score methods. Eur Heart J 2006, 27(12):1431-1439.
• [8]Domanski M, Tian X, Haigney M, Pitt B: Diuretic use, progressive heart failure, and death in patients in the DIG study. J Card Fail 2006, 12(5):327-332.
• [9]Eshaghian S, Horwich TB, Fonarow GC: Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol 2006, 97(12):1759-1764.
• [10]Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O’Connor CM, Metra M, Massie BM, Protect Steering Committee, Investigators, and Coordinators: The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail 2008, 14(8):631-640. Epub 2008 Sep 14
• [11]Stanton BA, Kaissling B: Adaptation of distal tubule and collecting duct to increased Na delivery. II. Na + and K + transport. Am J Physiol 1988, 255:F1269-F1275.
• [12]Dock W, Frank NR: Cation exchangers: their use and hazards as aids in managing edema. Am Heart J 1950, 40:638-645.
• [13]Costanzo MR, Heywood JT, Massie BM, Iwashita J, Henderson L, Mamatsashvilli M, Sisakian H, Hayrapetyan H, Sager P, van Veldhuisen DJ, Albrecht D: A double-blind, randomized, parallel, placebo-controlled study examining the effect of cross-linked polyelectrolyte in heart failure patients with chronic kidney disease. Eur J Heart Fail 2012, 14(8):922-930.
• [14]Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang I-Z on behalf of the PEARL-HF investigators: Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J 2011, 32(7):820-828.
• [15]Linz D, Wirth K, Linz W, Heuer HOO, Frick W, Hofmeister A, Heinelt U, Arndt P, Schwahn U, Boehm M, Ruetten H: Antihypertensive and laxative effects by pharmacological inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut. Hypertension 2012, 60:1560-1567.
• [16]Appel LJ, Frohlich ED, Hall JE, Pearson TA, Sacco RL, Seals DR, Sacks FM, Smith SC, Vafiadis DK, Van Horn LV: The importance of population-wide sodium reduction as a means to prevent cardiovascular disease and stroke. Circulation 2011, 123:1138-1143.
• [17]Whelton PK, Appel LJ, Sacco RL, Anderson CAM, Antman EM, Campbell N, Dunbar SB, Frohlich ED, Hall JE, Jessup M, Labarthe DR, MacGregor DA, Sacks FM, Stamler J, Vafiadis DK, Van Horn LV: Sodium, blood pressure, and cardiovascular disease: further evidence supporting the American Heart Association Sodium Reduction Recommendations. Circulation 2012. 10.1161/CIR.0b013e318279acbf
• [18]Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW: 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009, 119(14):e391-e479.
• [19]Sacks FM, Svetkey JP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER, Simons-Morton DG, Karanja N, Lin PH: Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001, 334(1):3-10.
• [20]Cook NR, Cutler JA, Obarzanek E, Buring JE, Rexrode KM, Kumanyika SK, Appel LJ, Whelton PK: Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the Trials of Hypertension Prevention (TOHP). BMJ 2007, 334:885-888.
• [21]Pimenta E, Gaddam KK, Oparil S, Aban I, Husain S, Dell’Italia LJ, Calhoun DA: Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension 2009, 54:475-481.
• [22]Slagman MCJ, Waanders F, Hemmelder MH, Woittiez AJ, Janssen WMT, Lambers Heerspink HJ, Navis G, Laverman GD: Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomized controlled trial. BMJ 2011, 343:d4366. 10.1136/bmj.d4366
• [23]Centers for Disease Control and Prevention: Usual sodium intakes compared with current dietary guidelines — United States, 2005–2008. MMWR 2011, 60:1413-1417.
• [24]Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R, EPHESUS Investigators: Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation 2008, 118(16):1643-1650.
• [25]Sterns RH, Rojas M, Bernstein P, Chennupati S: Ion-exchange resins for treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol 2010, 21:733-735.
• [26]Watson M, Abbott KC, Yuan CM: Damned if you do, damned if you don’t: potassium binding resins in hyperkalemia. Clin J Am Soc Nephrol 2010, 5:1723-1726.