Effect of Tenapanor on Interdialytic Weight Gain in Patients on Hemodialysis

Abstract

Background and objectives Interdialytic weight gain in patients on hemodialysis is associated with adverse cardiovascular outcomes and increased mortality. The degree of interdialytic weight gain is influenced by sodium intake. We evaluated the effects of tenapanor (AZD1722 and RDX5791), a minimally systemically available inhibitor of the sodium/hydrogen exchanger isoform 3, on interdialytic weight gain in patients with CKD stage 5D treated with hemodialysis.Design, setting, participants, & measurements This phase 2, randomized, double-blind study (NCT01764854; conducted January to September of 2013) enrolled adults on maintenance hemodialysis with interdialytic weight gain $3.0% of postdialysis weight and $2 kg. Patients were randomly assigned (1:1) to receive tenapanor or placebo. The primary end point was change in mean interdialytic weight gain (percentage of baseline postdialysis weight) from baseline (mean across a 2-week run-in period) to week 4. In a subgroup of inpatients, 24-hour stool sodium and stool weight were assessed for 1 week.Results Sixteen patients received 1 week of inpatient treatment (tenapanor, eight; placebo, eight), and 72 patients received 4 weeks of treatment in an outpatient setting (tenapanor, 37; placebo, 35; completers: tenapanor, 31; placebo, 33). In the outpatient cohort, no significant effect on interdialytic weight gain was detected; least squares mean changes in relative interdialytic weight gain from baseline to week 4 were tenapanor, 20.26% (95% confidence interval, 20.57% to 0.06%) and placebo, 20.23% (95% confidence interval, 20.54% to 0.07%; P=0.46). During week 1 (inpatient cohort only), compared with placebo, tenapanor treatment resulted in higher stool sodium content (mean [6SD]: tenapanor, 36.6 [621.8] mmol/d; placebo, 2.8 [62.7] mmol/d; P,0.001) and higher stool weight (tenapanor, 172.5 [668.1] g/d; placebo, 86.3 [630.0] g/d; P,0.01). A similar safety profile was observed across treatment groups with the exception of diarrhea, which occurred more frequently with tenapanor treatment.Conclusions Tenapanor treatment increased stool sodium and weight over placebo in patients undergoing hemodialysis. However, over 4 weeks of treatment, there was no difference in interdialytic weight gain between patients treated with tenapanor and those receiving placebo.

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

“…In patients with CKD, limited sodium excretion owing to impaired kidney function can lead to fluid overload and hypertension and accelerated renal and cardiovascular dysfunction . A study in patients with CKD on dialysis showed no significant differences in interdialytic weight gain (an assessment of fluid overload) between tenapanor‐ and placebo‐treated patients, although the pharmacodynamic effect of tenapanor was confirmed in this patient group, as evidenced by a significant increase in stool sodium and weight in patients treated with tenapanor versus placebo …”

“…By diverting a portion of dietary sodium to the stool, tenapanor treatment results in an increase in stool fluid content and promotes gastrointestinal motility and is therefore being evaluated for the treatment of constipation‐predominant irritable bowel syndrome (IBS‐C) . In patients with CKD, impaired sodium excretion can contribute to fluid overload and accelerated CKD progression; the effect of tenapanor on these processes has been investigated in an additional 2 clinical trials …”

Effect of Tenapanor on Serum Phosphate in Patients Receiving Hemodialysis

“…Studies in healthy volunteers and patients with CKD stage 5D have shown that tenapanor treatment increased stool sodium 23,25,26 and phosphorus 26 content, and concomitantly, it reduced urinary sodium 23,26 and phosphorus content, 26 consistent with reduced sodium and phosphate absorption. The precise mechanism by which tenapanor reduces intestinal phosphate absorption is currently under investigation and may allow for a multifaceted approach to reducing phosphate absorption in the future.…”

“…Tenapanor acts in the gut to reduce the absorption of sodium and phosphate, with minimal systemic drug exposure. [23][24][25][26] In healthy volunteers, increases in stool phosphorus up to 14.2 mmol/d relative to placebo were observed with tenapanor dosing, with concomitant reductions in urinary phosphorus. 26 The mechanism by which tenapanor reduces GI phosphate uptake is under active investigation; it does not seem to involve direct inhibition of intestinal phosphate transporters type 1 or sodium-dependent phosphate transport protein 2B (NaPi2b, also known as NPT2b).…”

Effects of Tenapanor on Cytochrome P450‐Mediated Drug‐Drug Interactions

“…As part of the drug development process, it is important to evaluate potential drug‐drug interactions caused by inhibition or induction of cytochrome P450 enzymes (CYPs) by the investigational agent. Tenapanor has been shown to have minimal systemic availability in all clinical studies to date, including in healthy volunteers and patients with CKD stage 5D treated with dialysis . After oral administration of a single dose of tenapanor 180 mg or tenapanor 15‐90 mg twice daily to healthy Japanese volunteers for 7 days, serum levels of tenapanor were below the lower limit of quantification (0.5 ng/mL) in 567 of 570 postdose samples .…”