Tenapanor

Limits on what this shows

• Null findings: Block 2017 randomized phase 2 in hemodialysis (162 randomized, 4 weeks): "no clinically relevant treatment-related changes" in serum calcium, potassium or sodium; PTH change did not differ (P=0.31) [6]. The 52-week Japanese study reported no clinically significant laboratory changes other than serum phosphorus and a bicarbonate decrease [9]. Interdialytic weight gain did not differ from placebo [14].
• At-risk subgroups: Children (contraindicated under 6; avoid 6 to under 12) [1][2]; dialysis patients with severe diarrhea; anyone with severe or persistent diarrhea. Other volume-depleting co-medications are a plausible but unsourced amplifier and are not graded here.

Regulatory status

Xphozah label sec 5.1: "In clinical trials, diarrhea was reported in up to 53% of patients, reported as severe in 5%, and associated with dehydration and hyponatremia in less than 1% of patients. Treatment with XPHOZAH should be discontinued in patients who develop severe diarrhea" [2]. Ibsrela label: diarrhea 16% versus 4% placebo in one trial, severe diarrhea 2.5% versus 0.2%, contraindicated under 6 years, avoid at 6 to under 12 years because of serious dehydration risk, with the instruction to suspend dosing and rehydrate in severe diarrhea [1]. Label text read via a summarizing fetch tool; the Xphozah sentence was confirmed by a second targeted query.

Population evidence

FDA multidisciplinary review [3]: hyponatremia was reported as non-serious in two patients in Study 401 and not reported in Study 402; dehydration was reported in three patients in Study 401; the safety analysis centers on diarrhea and temporally related events. PHREEDOM, 52-week randomized phase 3 (564 randomized, tenapanor versus sevelamer): loose stools 53% in the first phase [8]. Japanese 52-week open-label study (212 enrolled): diarrhea 63.7% (135 patients), 74.8% of events mild, 9 discontinuations for diarrhea [9]. Peritoneal dialysis, 54 enrolled: diarrhea 74.1%, 5.6% discontinued [10]. Meta-analysis of 8 short randomized hemodialysis trials (1,001 patients): pooled diarrhea RR 4.34 (95% CI 3.36 to 5.59) [11]. IBS-C trials: T3MPO-1 (n=606 ITT) diarrhea discontinuation 6.5% versus 0.7% [12]; T3MPO-2 (n=593) diarrhea 16.0% versus 3.7% [13]. Serum sodium values and hyponatremia thresholds were not retrieved; counts above are adverse-event reports.

Mechanism

Present and intended. NHE3 inhibition reduces intestinal sodium absorption and increases luminal water [1]. Block 2016 phase 2 (72 outpatients, 37 tenapanor): stool sodium significantly higher than placebo, equivalent to about 2 g/day lower salt intake, stool weight 173 versus 86 g/day (p less than 0.01) [14].

Counter-evidence held on record

Counter-evidence and confounding Hyponatremia and dehydration are adverse-event counts attached to diarrhea, so this entry measures a consequence of the drug's own intended gut effect (Hard Rule 2) rather than a nutrient deficit independent of it. Dialysis patients have baseline volume and sodium shifts driven by dialysis and interdialytic weight gain. Two of the sources in this entry (label and FDA review) describe the same Xphozah trials, so they are one evidence base, not independent confirmations. The 4-week randomized trial measured sodium without a clinically relevant change [6]. Framing caution This is a fluid and sodium loss risk from diarrhea, not a dietary sodium deficiency. It does not mean intake should increase, and no salt or electrolyte supplement is recommended here. Severe diarrhea is a label instruction to stop dosing and contact the prescriber.

Limits on what this shows

• Null findings: As above [6], with the limits that the trial was short, in a different population from the 52-week study, and the table was not read.
• At-risk subgroups: Not defined. Dialysis patients have dialysate-driven bicarbonate and pre-dialysis timing effects.

Regulatory status

Neither the Ibsrela nor the Xphozah label contains the words bicarbonate or acidosis in the text searched [1][2].

Population evidence

Phase 3 open-label single-arm study, hemodialysis, 212 enrolled and 154 completed 52 weeks, tenapanor 5 to 30 mg twice daily: "A decrease in bicarbonate levels was observed." Baseline and endpoint values and effect size were not reported in the text retrieved [9]. Block 2017 4-week randomized trial (162): bicarbonate listed in Table 4; the summarizing fetch reported no treatment-related change, but the table values were not retrieved [6]. No acidosis event was retrieved from any source.

Mechanism

Not stated in the sources opened. A candidate explanation is diarrheal loss of bicarbonate, but no retrieved source tests it, so it is not claimed here.

Counter-evidence held on record

Counter-evidence and confounding Single arm, open label, no comparator, so confounding by dialysis prescription, diet and time is presumed (Hard Rule 6). Graded yellow rather than orange because the magnitude and clinical meaning are unknown and the source was read only through a summarizing tool. The same study also found no clinically significant change in other laboratory values [9]. Framing caution A monitoring prompt for nephrology care, not a deficiency claim. Bicarbonate is an acid-base marker, not a supplement target; no alkali or bicarbonate supplement is recommended from this entry.

Limits on what this shows

• Null findings: Mean phosphorus stayed in the target range over 52 weeks [9]; no hypophosphatemia signal was retrieved, but its frequency was not searched in primary tables.
• At-risk subgroups: Not applicable as a deficiency; the Xphozah population is dialysis patients with hyperphosphatemia.

Regulatory status

Xphozah indication: reduce serum phosphorus in adults with CKD on dialysis as add-on therapy for inadequate response to or intolerance of phosphate binders [2]. Label trials: serum phosphorus fell 0.7 mg/dL versus placebo in the add-on study (95% CI 0.3 to 1.0), and rose 0.7 mg/dL on placebo in two withdrawal studies [2]. Ibsrela label contains no phosphate statement in the text searched [1].

Population evidence

Block 2017: dose-dependent least-squares mean reductions of 0.47 to 1.98 mg/dL (placebo 0.54, P=0.01) in 162 hemodialysis patients [6]. Block 2018: FGF23 fell 9.1 to 27.9% with tenapanor versus a 21.9% rise on placebo, in the same 162-patient trial [7]. PHREEDOM: -1.4 mg/dL versus placebo in the withdrawal analysis [8]. Japanese long-term study: serum phosphorus stayed within 3.5 to 6.0 mg/dL (5.24 mg/dL baseline, 5.11 at week 52) [9]. Meta-analysis: -1.39 mg/dL versus placebo (p less than 0.0001) [11]. Rates of hypophosphatemia were not retrieved from any source.

Mechanism

Present, intended. Tenapanor increased stool phosphorus and reduced urinary phosphorus in Block 2017, per a summarizing fetch [6]. The paracellular-permeability mechanism paper (King 2018) could not be opened and is not relied on.

Counter-evidence held on record

Counter-evidence and confounding Hard Rule 2: a drug's own intended pharmacologic effect is not a nutrient deficiency. Hard Rule 5: this is a lowering of an elevated value, and increasing phosphate intake would defeat the therapy. Entered so readers asking about tenapanor and phosphate see the direction stated explicitly. Framing caution Not a deficiency claim. Do not recommend phosphate supplementation or loosening phosphate dietary advice; phosphate targets in dialysis are set by the nephrology team.

Limits on what this shows

• Null findings: Tenapanor in rats (Tier B, tenapanor in the cohort): cecal concentrations of calcium and magnesium were not significantly affected (P above 0.05), described by the authors as specificity for phosphate [21]; this measures luminal concentration, not flux or balance. Healthy volunteers, two phase 1 trials: no clinically relevant difference from placebo in serum calcium and no impact on urinary calcium excretion [20]. Block 2017: no clinically relevant change in serum calcium and no difference in PTH change (P=0.31) over 4 weeks in 162 hemodialysis patients [6]. A narrative review states that tenapanor does not affect the balance of potassium, calcium and magnesium, without primary data [24]. The Karger meta-analysis [11] makes a similar statement without numbers.
• At-risk subgroups: Not defined. Children: label restriction and juvenile rat tibial growth reduction are toxicity findings of the drug and are not calcium measurements (Hard Rule 2) [1][3].

Regulatory status

The Xphozah label mentions calcium only in a binding or phosphate-binder context and neither label states an effect on calcium absorption in the text searched [1][2]. The FDA review records no in vitro binding between tenapanor and calcium carbonate or calcium acetate [3].

Population evidence

None for tenapanor on calcium absorption or balance. CLASS EXTRAPOLATION (target level). Pan 2012 [18]: NHE3-null versus wild-type mice, n at least 7 per group for most measures (some groups n=6). Duodenal Ca2+ flux was decreased (P below 0.05) and 45Ca absorption 1 minute after gavage was decreased (P below 0.05). Serum Ca2+ and PTH did not differ, fractional urinary Ca2+ excretion was higher (19 +/- 5% versus 8 +/- 1%), and 1,25(OH)2D3 was more than four times higher. Rievaj 2013 [19], from a reference-listing page (abstract level; full text not opened): in murine cecum in Ussing chambers, NHE3-null tissue had a greater than 60% decrease in luminal-to-serosal Ca2+ flux, and the NHE inhibitor 5-(N-ethyl-N-isopropyl) amiloride at 100 micromolar reduced luminal-to-serosal and increased serosal-to-luminal Ca2+ movement. That compound is a non-selective amiloride analog, not tenapanor. Cohort test: tenapanor was NOT in the cohort of either source. The test fails, so the entry is capped at yellow.

Mechanism

Plausible only. In [18] an NHE3-generated osmotic gradient was enough to more than double paracellular Ca2+ flux in vitro, and [19] reports reduced transcellular and secondarily active paracellular absorption in NHE3-null cecum. Tenapanor inhibits NHE3 [1][21], so a partial version of this effect is conceivable but is not shown for the drug.

Counter-evidence held on record

Counter-evidence and confounding Global knockout mice also show renal calcium wasting and low bone density [18]; those are outcomes of complete NHE3 loss in kidney and gut and are not filed here as calcium deficiency (Hard Rule 2). Serum calcium is tightly regulated and unchanged in the knockout, so a normal serum value would not refute reduced absorption, and no validated functional marker for tenapanor has been shown to move (Hard Rule 3), which is why this stays a flag. Dialysis patients have calcium handled by diet, binders and vitamin D analogs, which confounds any human signal. Overlap: [18] also supplies the Vitamin D entry. Framing caution Not a deficiency claim and not evidence that tenapanor lowers calcium. No calcium supplement is recommended from this entry; calcium targets in dialysis are set by the nephrology team.

Limits on what this shows

• Null findings: Tenapanor in people: two phase 1 trials in healthy volunteers found no consistent effect on mean daily urinary potassium excretion and no clinically relevant difference in serum potassium versus placebo [20]; Block 2017 found no clinically relevant change in serum potassium over 4 weeks in hemodialysis [6]; a narrative review states one phase 1 study found no effect on potassium excretion [25]. Tenapanor in rats: luminal potassium concentration decreased, which the authors attribute to dilution and which is not a systemic measure [21]. No hypokalemia event was retrieved from any tenapanor source.
• At-risk subgroups: Not defined. Dialysis patients and anyone on potassium-sparing or potassium-binding therapy are the groups where potassium is routinely monitored; no source ties tenapanor to a change in them.

Regulatory status

Neither label mentions potassium status or hypokalemia or hyperkalemia as an effect in the text searched [1][2]. The Xphozah label separates dosing from sodium polystyrene sulfonate (a potassium binder) by at least 3 hours, which is a drug-interaction instruction and not a potassium finding [2].

Population evidence

None for tenapanor. CLASS EXTRAPOLATION (target level). Xue 2022 [15], introduction (secondary statement, citing Xue 2020, which was not opened): intestine-specific NHE3 knockout mice show persistent alkaline diarrhea, metabolic acidosis, hyponatremia and hyperkalemia with drastically elevated plasma aldosterone and increased mortality. A Physiological Society conference abstract [22] (peer review status not stated; abstract only) reports the same phenotype in intestinal-epithelium NHE3 knockout mice, with roughly 25% mortality within three weeks. Schultheis 1998 [23], abstract only: global NHE3-null mice are mildly acidotic with slight diarrhea, reduced blood pressure and raised plasma aldosterone; the abstract summary did not state a potassium value. No numeric potassium values were retrieved from any source. Cohort test: tenapanor was NOT in the cohort of any of these. The test fails, so the entry is capped at yellow. [15] and [22] describe the same knockout model and are one evidence line, not two.

Mechanism

Plausible only. Loss of intestinal sodium absorption causes volume depletion and aldosterone elevation, and the sources link the hyperkalemia to the raised aldosterone. Tenapanor produces a milder, partial version of the sodium and water effect [1][14], but no source shows it causing the aldosterone or potassium change.

Counter-evidence held on record

Counter-evidence and confounding Complete genetic ablation in the intestinal epithelium, with about a quarter of mice dying within three weeks [22], is far more severe than a minimally absorbed inhibitor given to patients. Hyperkalemia in the knockout runs with severe volume and sodium loss and high aldosterone, a state not seen in the tenapanor trials read. Dialysis patients have baseline potassium shifts driven by dialysis timing and diet, so confounding is presumed (Hard Rule 6). Overlap: [15] and [22] also underlie the Gut microbiome entry (same knockout model). Framing caution This is an excess or retention direction (Hard Rule 5), not a dietary deficiency. Do not read it as a reason to restrict or add potassium, and no potassium supplement or restriction is recommended from this entry. Potassium in dialysis is managed by the nephrology team.

Limits on what this shows

• Null findings: No tenapanor source reports 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D. Serum calcium and PTH were unchanged with tenapanor in the 4-week randomized trial [6].
• At-risk subgroups: Not defined.

Regulatory status

Neither label contains the word vitamin in the text searched [1][2]. The 2022 sponsor briefing document mentions vitamin D once, in a general description of phosphorus physiology [26].

Population evidence

None for tenapanor. CLASS EXTRAPOLATION (target level). Pan 2012 [18]: NHE3-null versus wild-type mice, n at least 7 per group for most measures; serum 1,25(OH)2D3 was significantly increased by more than four times (P below 0.05) while serum Ca2+ and PTH did not differ, alongside reduced intestinal Ca2+ absorption and higher urinary calcium excretion. Cohort test: tenapanor was NOT in the cohort. The test fails, so the entry is capped at yellow. Tenapanor lowers FGF23 in dialysis patients [7], but no vitamin D metabolite result is reported there in the portion read. The 52-week Japanese study did not report 25-hydroxyvitamin D [9]; a first-pass summary claiming no vitamin D change was discarded earlier because the text did not support it.

Mechanism

Not stated in the source summary. A compensatory response to reduced intestinal calcium absorption is a candidate explanation but was not tested in any source opened, so it is not claimed. Transit-time acceleration with diarrhea is a theoretical route for fat-soluble vitamins; no source tests it for tenapanor.

Counter-evidence held on record

Counter-evidence and confounding This is a reverse-direction finding in a complete gene knockout, filed as a context flag so readers asking about tenapanor and vitamin D see the direction stated. It rests on the same single mouse paper as the Calcium entry [18] and adds no independent line of evidence. An elevated active hormone is not a nutrient deficiency (Hard Rule 2), and in dialysis the vitamin D axis is dominated by kidney disease and by vitamin D analog therapy. Framing caution Not a deficiency claim and not an indication to supplement vitamin D. No vitamin D dose is recommended from this entry.

Limits on what this shows

• Measured parameters (null): Tenapanor in rats (tenapanor in the cohort): cecal magnesium concentration not significantly affected, P above 0.05 [21]; this is a luminal concentration, not systemic magnesium status or absorption flux. A 2021 narrative review states that tenapanor does not affect the balance of potassium, calcium and magnesium [24], and the Karger meta-analysis [11] says tenapanor does not affect serum calcium, sodium, potassium or magnesium; neither statement is accompanied by magnesium data in the text read, so they are not treated as measurements.
• Why no grade: Dual condition met: no Tier B or C evidence and no circulating claim. A disclosed gap, not a finding of safety.

What was searched

The potassium and magnesium web query above; label text searched for "magnesium" (not found in either label); Block 2017 queried: magnesium not discussed in the text read [6]. Repair 2026-10-07: web searches on NHE3-null mouse calcium, magnesium and vitamin D phenotypes and on NHE3-deficient mouse acid-base and potassium phenotypes (results led to the sources now cited in the Calcium, Vitamin D and Potassium entries; none reported magnesium); the FDA review and sponsor briefing document returned no magnesium mention (summarizing tool); the healthy-volunteer phase 1 paper did not analyze magnesium per its summary [20].

Channel outcomes

Genuine gap for human magnesium status and for any NHE3-deficiency magnesium phenotype; the intestine-specific knockout abstract [22] mentions no magnesium. Partly tooling-limited: the search budget ran out a second time.