Combination treatment with tenapanor and sevelamer synergistically reduces urinary phosphorus excretion in rats

The majority of patients with chronic kidney disease (CKD) receiving dialysis do not reach target serum phosphorus concentrations, despite treatment with phosphate binders. Tenapanor is a non-binder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This pre-clinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-hour urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer (0-3% w/w). We also evaluated the effect of the addition of tenapanor or vehicle on 24-hour urinary phosphorus excretion to rats on a stable dose of sevelamer (1.5% w/w). When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose (1.5% w/w) reduced mean (±standard error of the mean) urinary phosphorus excretion by 42±3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37±6% (P < 0.05). While both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.

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Small Intestinal Phosphate Absorption: Novel Therapeutic Implications

American Journal of Nephrology ◽

10.1159/000518110 ◽

2021 ◽

pp. 1-9

Author(s):

Jerry Yee ◽

David Rosenbaum ◽

Jeffrey W. Jacobs ◽

Stuart M. Sprague

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Paracellular Pathway ◽

Phosphate Binders ◽

Phosphate Absorption ◽

Therapeutic Implications ◽

Sodium Hydrogen ◽

Sodium Hydrogen Exchanger ◽

Dietary Phosphate ◽

Intestinal Phosphate Absorption

Background: Chronic kidney disease (CKD) affects approximately 15% of adults in the USA. As CKD progresses, urinary phosphate excretion decreases and results in phosphate retention and, eventually, hyperphosphatemia. As hyperphosphatemia is associated with numerous adverse outcomes, including increased cardiovascular mortality, reduction in phosphorus concentrations is a guideline-recommended, established clinical practice. Dietary phosphate restriction, dialysis, and phosphate binders are currently the only options for phosphate management. However, many patients with hyperphosphatemia have phosphorus concentrations >5.5 mg/dL, despite treatment. Summary: This review presents recent advances in the understanding of intestinal phosphate absorption and therapeutic implications. Dietary phosphate is absorbed in the intestine through two distinct pathways, paracellular absorption and transcellular transport. Recent evidence indicates that the paracellular route accounts for 65–80% of total phosphate absorbed. Thus, the paracellular pathway is the dominant mechanism of phosphate absorption. Tenapanor is a first-in-class, non-phosphate binder that inhibits the sodium-hydrogen exchanger 3 or solute carrier family 9 member 3 (SLC9A3) encoded by the SLC9A3 gene, and blocks paracellular phosphate absorption. Key Messages: Targeted inhibition of sodium-hydrogen exchanger 3 effectively reduces paracellular permeability of phosphate. Novel therapies that target the paracellular pathway may improve phosphate control in chronic kidney disease.

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Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality

Cardiorenal Medicine ◽

10.1159/000516286 ◽

2021 ◽

pp. 1-10

Author(s):

Peter A. McCullough

Keyword(s):

Calcium Acetate ◽

Paracellular Pathway ◽

Ferric Citrate ◽

Morbidity And Mortality ◽

Phosphate Binders ◽

Phosphate Absorption ◽

Phosphate Retention ◽

Sevelamer Carbonate ◽

Prescribing Information ◽

Phosphate Control

Background: Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD) on dialysis. Mortality rates are still unacceptably high even though they have fallen in the past 2 decades. Hyperphosphatemia (elevated serum phosphate levels) is seen in almost all patients with advanced CKD and is by far the largest remaining modifiable contributor to CKD mortality. Summary: Phosphate retention drives multiple physiological mechanisms linked to increased risk of CVD. Fibroblast growth factor 23 and parathyroid hormone (PTH) levels, both of which have been suggested to have direct pathogenic CV effects, increase in response to phosphate retention. Phosphate, calcium, and PTH levels are linked in a progressively worsening cycle. Maladaptive upregulation of phosphate absorption is also likely to occur further exacerbating hyperphosphatemia. Even higher phosphate levels within the normal range may be a risk factor for vascular calcification and, thus, CV morbidity and mortality. A greater degree of phosphate control is important to reduce the risk of CV morbidity and mortality. Improved phosphate control and regular monitoring of phosphate levels are guideline-recommended, established clinical practices. There are several challenges with the current phosphate management approaches in patients with CKD on dialysis. Dietary restriction of phosphate and thrice-weekly dialysis alone are insufficient/unreliable to reduce phosphate to <5.5 mg/dL. Even with the addition of phosphate binders, the only pharmacological treatment currently indicated for hyperphosphatemia, the majority of patients are unable to achieve and maintain phosphate levels <5.5 mg/dL (or more normal levels) [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information), 2011, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information), 2020, RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Phosphate binders do not target the primary pathway of phosphate absorption (paracellular), have limited binding capacity, and bind nonspecifically [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information). 2013, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information) 2020]. Key Messages: Despite current phosphate management strategies, most patients on dialysis are unable to consistently achieve target phosphate levels, indicating a need for therapeutic innovations [RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway, new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.

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Intestinal phosphate absorption: The paracellular pathway predominates?

Experimental Biology and Medicine ◽

10.1177/1535370219831220 ◽

2019 ◽

Vol 244 (8) ◽

pp. 646-654 ◽

Cited By ~ 2

Author(s):

Matthew Saurette ◽

R Todd Alexander

Keyword(s):

Kidney Disease ◽

Animal Studies ◽

Western Diet ◽

Phosphate Absorption ◽

Sodium Hydrogen ◽

Sodium Hydrogen Exchanger ◽

Gradient Based ◽

Intestinal Phosphate Absorption ◽

Stage Renal Disease ◽

End Stage

Hyperphosphatemia is nearly universal in patients with advanced chronic kidney disease and end stage renal disease. Given the considerable negative sequelae associated with hyperphosphatemia, i.e. increased cardiovascular disease, hastening of renal failure and death, reducing serum phosphate is a goal of therapy. In the absence of sufficient renal function, intestinal phosphate absorption is the remaining target to reduce plasma phosphate levels. Much work has been done with respect to understanding transcellular phosphate absorption. Both animal studies using inducible or intestinal NaPi-2b knockout mice and specific NaPi-2b inhibitors revealed this transporter as the primary mechanism mediating transcellular phosphate absorption in the intestine. However, this has not translated into effective phosphate lowering therapies in patients with kidney disease. More recently, it was observed that inhibition of the epithelial sodium hydrogen exchanger, sodium–hydrogen exchanger isoform 3 (NHE3), or its genetic deletion, decreases intestinal phosphate absorption. The mechanism mediating this effect is through increased transepithelial resistance and reduced paracellular phosphate permeability. Thus, NHE3 inhibition reduces paracellular phosphate permeability in the intestine. The transepithelial potential difference across intestinal epithelium is lumen negative and phosphate commonly exists as a divalent anion. Further, consumption of the typical Western diet provides a large lumen to blood phosphate concentration gradient. Based on these observations we argue herein that the paracellular phosphate absorption route is the predominant pathway mediating intestinal phosphate absorption in humans. Impact statement This review summarizes the work on transcellular intestinal phosphate absorption, arguing why this pathway is not the predominant pathway in humans consuming a “Western” diet. We then highlight the recent evidence which is strongly consistent with paracellular intestinal phosphate absorption mediating the bulk of intestinal phosphate absorption in humans.

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THE ANTAGONISM BETWEEN CORTISONE AND VITAMIN D: EXPERIMENTS ON HYPERVITAMINOSIS D IN RATS

Journal of Endocrinology ◽

10.1677/joe.0.0170035 ◽

1958 ◽

Vol 17 (1) ◽

pp. 35-NP ◽

Cited By ~ 2

Author(s):

E. M. CRUICKSHANK ◽

E. KODICEK

Keyword(s):

Vitamin D ◽

Antagonistic Effect ◽

Metastatic Calcification ◽

Clinical Appearance ◽

Skeletal Tissue ◽

Phosphorus Excretion ◽

Hypervitaminosis D ◽

Bone Ash ◽

Urinary Phosphorus Excretion ◽

Dose Levels

SUMMARY Hypervitaminosis was produced in young growing rats and the effect of daily injections of cortisone acetate (CA) was studied on growth, metastatic calcification, urinary phosphorus excretion and bone ash. Cortisone treatment did not ameliorate the weight loss, clinical appearance, histological lesions or the increased urinary phosphorus. excretion of the hypervitaminotic rats. Control rats, treated with CA alone, showed no untoward effects at the dose levels employed. It is concluded that cortisone does not act as a direct antimetabolite towards vitamin D. The antagonistic effect of the hormone observed in man may be due to reversal of the toxic action of vitamin D by an indirect mechanism, affecting the metabolic sites, such as intestinal tissue, kidney tubules and/or skeletal tissue, on which both vitamin D and cortisone appear to act.

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EFFECT OF OESTRONE-PELLET IMPLANTATION ON PLASMA LEVELS OF PROLACTIN

Acta Endocrinologica ◽

10.1530/acta.0.0640265 ◽

1970 ◽

Vol 64 (2) ◽

pp. 265-272 ◽

Cited By ~ 7

Author(s):

A. A. van der Gugten ◽

M. Sala ◽

H. G. Kwa

Keyword(s):

Plasma Levels ◽

Male Rats ◽

Mean Values ◽

The Mean ◽

Dose Levels ◽

Higher Doses ◽

Primary Break

ABSTRACT Eight female and eight male rats were castrated at the age of 8 to 10 weeks. Four spayed and four orchidectomized rats received one oestrone/cholesterol pellet (200 μg oestrone) on the day of operation (day 0), a second pellet on day 11 and a third on day 23. The remaining animals received four oestrone/cholesterol pellets at these times. The fluctuations in the prolactin levels in the circulation induced by the oestrogen challenges in these animals were followed during 31 days by radioimmunoassays performed on days 3, 7, 9, 14, 15, 17, 23, 24, 25, 28 and 31. The results suggested that the homoeostatic mechanism regulating plasma levels of prolactin was capable of withstanding the three time-spaced oestrogen challenges only in the spayed animals receiving the lower doses of oestrogen, since it allowed the mean values of the prolactin levels to remain fairly constant during the first 4 weeks. The levels in this group rose to much higher levels only on day 31. The higher doses of oestrone in the spayed rats and both dose levels of oestrone in the orchidectomized animals apparently resulted in a primary break-down of the homoeostatic mechanism, since the prolactin levels in the animals of these groups rose to much higher levels either on day 7 or on day 9. This was followed by a period during which the prolactin levels appeared to be more or less under control, until a second and probably definitive failure of the homoeostatic mechanism allowed the mean levels to rise sharply again.

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Faculty Opinions recommendation of Comparison of dietary phosphate absorption after single doses of lanthanum carbonate and sevelamer carbonate in healthy volunteers: a balance study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.10067967.11135055 ◽

2011 ◽

Author(s):

Bradley Dixon ◽

Mony Fraer

Keyword(s):

Healthy Volunteers ◽

Lanthanum Carbonate ◽

Balance Study ◽

Phosphate Absorption ◽

Sevelamer Carbonate ◽

Dietary Phosphate

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P1404A PHASE 2 OPEN-LABEL, SINGLE-ARM, FIRST JAPANESE STUDY OF TENAPANOR, A NOVEL PHOSPHATE ABSORPTION INHIBITOR, FOCUSING ON PILL BURDEN DECREASE IN PATIENTS WITH HYPERPHOSPHATEMIA UNDERGOING HEMODIALYSIS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1404 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Tadao Akizawa ◽

Hironori Kanda ◽

Masayuki Takanuma ◽

Jun Kinoshita ◽

Masafumi Fukagawa

Keyword(s):

Primary Endpoint ◽

Serum Phosphorus ◽

Phosphate Binders ◽

Pill Burden ◽

Phosphorus Level ◽

Serum Phosphorus Level ◽

Open Label ◽

Serious Adverse Events ◽

Phosphate Absorption ◽

Phosphorus Control

Abstract Background and Aims Phosphate binders (PB) are usually prescribed to dialysis patients with hyperphosphatemia. Several studies have reported that higher PB pill burden may reduce adherence and lead to insufficient phosphorus control. Tenapanor is an investigational, minimally absorbed, orally administered, non-binder, small-molecule that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in development for the control of serum phosphorus. A previous Ph3 study sponsored by Ardelyx, Inc. (NCT02675998) showed a significant phosphorus decrease compared to the placebo in patients with hyperphosphatemia undergoing hemodialysis (HD) in the US. Tenapanor was expected to reduce PB pill burden since it is administered as one small pill, taken twice a day. This was the first study in Japanese HD patients, which aimed to confirm whether tenapanor reduces the pill burden of PB. Method This was a multicenter, open-label, single-arm Ph2 study. The study consists of a screening period, a 3-week observation period, and a 26-week treatment period. Patients whose serum phosphorus level was ≥ 3.5 and ≤ 7.0 mg/dL, taking at least two PB pills three times a day were enrolled. The patients started to receive 30 mg of tenapanor twice daily. The tenapanor dose could be reduced in a step-wise manner (60, 40, 20 and 10 mg/day) at the investigator’s discretion, based on GI tolerability. PB treatment was continued according to individual regimens, however, the dose could be adjusted appropriately to maintain serum phosphorus level within ±0.5 mg/dL from the baseline. The primary endpoint was an achievement of at least a 30% decrease in the mean of the total number of PB and tenapanor pills compared to the number of PB pills at baseline. The proportion of patients who achieved at least a 30 % decrease were tested using binomial test with a threshold level of 20% and a one-sided significance level of 0.025. The analysis was conducted using the data as of Dec25, 2019. Results The primary endpoint was met. Of 67 enrolled patients at the timing of analysis, 48 patients (71.6%, [95% CI: 59.3% - 82.0%], p<0.001) achieved a 30% decrease in the total number of PB and tenapanor pills, and of those, 35 patients (52.2%, [95% CI: 39.7% - 64.6%]) achieved a 50% decrease and 18 patients (26.9%) no longer required the use of any PB at week 26. Mean phosphorus levels were maintained during the study from 5.2 mg/dL at the baseline to 4.7 mg/dL at week 26. The most frequent adverse event was diarrhea (76.1%), which was mostly mild to moderate. Only four patients discontinued the study due to diarrhea. Serious adverse events were reported in five patients, only two of which were related to tenapanor (diarrhea and acute myocardial infarction). Conclusion Tenapanor was able to provide phosphorus control with significantly fewer pills compared to PB. AE profile was similar to previous US studies. This result suggests that tenapanor, a non-binder, phosphate absorption inhibitor that provides a novel approach to the management of hyperphosphatemia, could potentially improve drug adherence by reducing PB pill burden while maintaining effective phosphorus control.

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