Effect of Tenapanor on Serum Phosphate in Patients Receiving Hemodialysis

Abstract

Hyperphosphatemia is common among patients with CKD stage 5D and is associated with morbidity and mortality. Current guidelines recommend lowering serum phosphate concentrations toward normal. Tenapanor is a minimally absorbed small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 that functions in the gut to reduce sodium and phosphate absorption. This randomized, double-blind, placebocontrolled trial assessed the effects of tenapanor on serum phosphate concentration in patients with hyperphosphatemia receiving hemodialysis. After a 1-to 3-week washout of phosphate binders, we randomly assigned 162 eligible patients (serum phosphate =6.0 to ,10.0 mg/dl and a 1.5-mg/dl increase from before washout) to one of six tenapanor regimens (3 or 30 mg once daily or 1, 3, 10, or 30 mg twice daily) or placebo for 4 weeks. The primary efficacy end point was change in serum phosphate concentration from baseline (randomization) to end of treatment. In total, 115 patients (71%) completed the study. Mean serum phosphate concentrations at baseline (after washout) were 7.32-7.92 mg/dl for tenapanor groups and 7.87 mg/dl for the placebo group. Tenapanor provided dose-dependent reductions in serum phosphate level from baseline (least squares mean change: tenapanor =0.47-1.98 mg/dl; placebo =0.54 mg/dl; P=0.01). Diarrhea was the most common adverse event (tenapanor =18%-68%; placebo =12%) and frequent at the highest tenapanor doses. In conclusion, tenapanor treatment resulted in statistically significant, dose-dependent reductions in serum phosphate concentrations in patients with hyperphosphatemia receiving hemodialysis. Additional studies are required to clarify the optimal dosing of tenapanor in patients with CKD-related hyperphosphatemia. 28: 193328: -194228: , 201728: . doi: https://doi.org/10.1681 Disorders of mineral metabolism are common among persons with CKD. 1 Impaired kidney function reduces urinary phosphate excretion, the principal mechanism by which normal phosphate balance is maintained. 2 Modulation of tubular reabsorption of phosphate, mediated in large part by parathyroid hormone (PTH) and the phosphatonin fibroblast growth factor 23 (FGF23), allows for maintenance of serum phosphate concentrations within a physiologic range, despite wide variation in phosphate intake on a day to day basis. However, in advanced CKD, dietary phosphate intake generally exceeds excretory capacity; for patients on dialysis, even with dietary phosphate restriction, hyperphosphatemia is almost inevitable without specific treatment. 3 Among patients receiving dialysis, evidence from observational studies, 1,4 retrospective database analyses, 5,6 and to a lesser extent, prospective controlled trials 7,8 has shown that hyperphosphatemia is associated with mortality, 1,4-6 fractures, 5 and cardiovascular disease, including vascular calcification 8 and left ventricular hypertrophy. 7 J Am Soc Nephrol

Effect of Food Intake on the Pharmacodynamics of Tenapanor: A Phase 1 Study

“…In a rat model of CKD and vascular calcification, tenapanor significantly decreased ectopic calcification, serum creatinine, phosphorus and fibroblast growth factor‐23 levels, and heart mass . Collectively, these findings have led to clinical trials of tenapanor for the treatment of hyperphosphatemia in patients with CKD on dialysis, in which the pharmacodynamic effects of the drug have been found to translate into clinically meaningful reductions in serum phosphate versus placebo …”

“…Studies in animals and humans have shown that tenapanor acts locally in the gut to selectively reduce absorption of sodium and phosphate . These effects may be beneficial in the management of constipation‐related disorders and CKD; tenapanor is currently being evaluated for the treatment of patients with IBS‐C and hyperphosphatemia in patients with CKD on dialysis . This phase 1 study evaluated the influence of the timing of food intake in relation to tenapanor administration on the pharmacodynamic effects of the drug in healthy volunteers.…”

“…In healthy volunteers treated with tenapanor for 7 days, mean stool phosphorus content was increased by up to 20 mmol/day versus placebo . As a result of these findings, tenapanor is currently being evaluated in clinical trials for the treatment of hyperphosphatemia in patients with CKD on dialysis . The mechanism by which tenapanor reduces gastrointestinal phosphate uptake is currently being investigated; ongoing work suggests that it does not involve direct inhibition of intestinal phosphate transporters type 1 (PiT1) or NaPi2b (also known as NpT2b) …”

Visceral Congestion in Heart Failure: Right Ventricular Dysfunction, Splanchnic Hemodynamics, and the Intestinal Microenvironment

“…Furthermore, there may be interactions between NHE3 and phosphate absorption based on the observation that tenapanor, a gut NHE3 inhibitor also inhibits phosphate absorption [64]. Thus, the gut-kidney-pulmonary-RV interaction could possibly also involve deranged mineral metabolism.…”

High Phosphate-Induced Calcification of Vascular Smooth Muscle Cells is Associated with the TLR4/NF-κb Signaling Pathway

“…In order to attenuate the severity of hyperphosphatemia, dietary phosphate restriction and oral phosphate binders are first-line treatments for CKD stage 5D patients [17][18][19]. More recently, tenapanor, a small-molecule inhibitor of sodium/hydrogen exchanger isoform 3, was found to reduce serum phosphate concentrations significantly in patients receiving hemodialysis [20]. All of these data suggest that hyperphosphatemia in CKD patients is a critical cardiovascular risk factor.…”