FC 077LONG-TERM SAFETY OF TENAPANOR FOR THE CONTROL OF SERUM PHOSPHORUS IN PATIENTS WITH CKD ON DIALYSIS

Background and Aims Tenapanor, a first-in-class, phosphate absorption inhibitor blocks the paracellular absorption of phosphate in the GI tract by local inhibition of the sodium-hydrogen exchanger (NHE3). It therefore provides a novel, non-binder approach for managing hyperphosphatemia. Tenapanor is dosed as one small pill twice daily. In three pivotal trials, tenapanor met its primary phosphorus-lowering outcome. This report evaluates long-term safety data from the longest of these trials. Method This 52-week study consisted of a 26-week, open-label, randomized treatment period with a 12-week placebo-controlled randomized withdrawal period, followed by a 14-week open label safety extension period. Maintenance dialysis patients with serum phosphorus ≥ 6.0 mg/dL and a 1.5 mg/dL increase in serum phosphorus following phosphate binder washout were randomized 3:1 to receive tenapanor 30 mg twice daily or sevelamer carbonate, dosed per package insert. At end of the randomized treatment period all patients in the tenapanor arm were re-randomized 1:1 to either tenapanor or placebo for the randomized withdrawal period followed by tenapanor for the safety extension period. Sevelamer was used as a safety control for comparisons of serious adverse events/hospitalizations to tenapanor. Results Tenapanor was generally well tolerated, with diarrhea the only adverse event reported by >5% of patients during the randomized treatment period. Diarrhea was typically mild-to-moderate in severity, transient, and occurred more commonly during the randomized treatment period than the randomized withdrawal or safety extension periods. Rates of serious adverse events leading to hospitalization were higher in patients treated with sevelamer than tenapanor (35.8% vs 24.6%). The highest reported percentages of serious adverse events were infections and infestations (16.1% vs 9.3%) cardiac disorders (8.0% vs 5.7%), respiratory, thoracic and mediastinal disorders (8.8% vs 5.5%), and metabolism and nutritional disorders (7.3% vs 3.6%) for sevelamer and tenapanor, respectively. Adverse events leading to death were higher in patients treated with sevelamer than tenapanor (3.6% vs 2.9%). Conclusion Among maintenance dialysis patients with hyperphosphatemia, tenapanor, a novel, non-binder, phosphate absorption inhibitor that blocks paracellular absorption of phosphorus with a one tablet twice daily dose, has an acceptable safety profile, and, if approved, may offer a new approach to the treatment of hyperphosphatemia.

Drinking and Water Handling in the Medaka Intestine: A Possible Role of Claudin-15 in Paracellular Absorption?

When euryhaline fish move between fresh water (FW) and seawater (SW), the intestine undergoes functional changes to handle imbibed SW. In Japanese medaka, the potential transcellular aquaporin-mediated conduits for water are paradoxically downregulated during SW acclimation, suggesting paracellular transport to be of principal importance in hyperosmotic conditions. In mammals, intestinal claudin-15 (CLDN15) forms paracellular channels for small cations and water, which may participate in water transport. Since two cldn15 paralogs, cldn15a and cldn15b, have previously been identified in medaka, we examined the salinity effects on their mRNA expression and immunolocalization in the intestine. In addition, we analyzed the drinking rate and intestinal water handling by adding non-absorbable radiotracers, 51-Cr-EDTA or 99-Tc-DTPA, to the water. The drinking rate was >2-fold higher in SW than FW-acclimated fish, and radiotracer experiments showed anterior accumulation in FW and posterior buildup in SW intestines. Salinity had no effect on expression of cldn15a, while cldn15b was approximately 100-fold higher in FW than SW. Despite differences in transcript dynamics, Cldn15a and Cldn15b proteins were both similarly localized in the apical tight junctions of enterocytes, co-localizing with occludin and with no apparent difference in localization and abundance between FW and SW. The stability of the Cldn15 protein suggests a physiological role in water transport in the medaka intestine.

Intestinal Absorption Profile of Three Polygala Oligosaccharide Esters in Polygalae Radix and the Effects of Other Components in Polygalae Radix on Their Absorption

Oligosaccharide esters, which are among the main active components of Polygalae Radix (PR), demonstrate significant pharmacological activities in the human nervous system. In our previous research, some other constituents in PR were able to improve the bioavailability of oligosaccharide esters such as sibiricose A5 (SA5), sibiricose A6 (SA6), and 3,6′-disinapoyl sucrose (DISS), but the related components and their underlying mechanisms remain unknown. The present study aimed to investigate the intestinal absorptive profile of SA5, SA6, and DISS and the absorptive behavior influenced by the coadministration of polygalaxanthone III and total saponins of PR (TS) using an in vitro everted rat gut sac model, along with the possible mechanisms that may influence absorption. The results showed that TS could significantly enhance the absorption of SA5, SA6, and DISS monomers. Verapamil, a P-glycoprotein inhibitor, was able to elevate the absorption of SA5 and SA6, and an absorption experiment using Rho123 led us to conclude that TS influenced the absorption of SA5 and SA6 in a manner similar to that of a P-glycoprotein inhibitor. Sodium caprate, a paracellular absorption enhancer, was found to increase the absorption of SA5, SA6, and DISS. Results showed that the absorption mechanisms of SA5 and SA6 may combine active transport with paracellular passive penetration, while DISS’s absorption was dominated by paracellular passive penetration. However, the relationship between polygala saponins and the absorption of SA5, SA6, and DISS by paracellular passive penetration remain to be examined. This is the direction of our future research.

177 Influence of the level of dietary digestible Ca on growth performance, bone ash, plasma Ca, and abundance of genes involved in Ca absorption in 11- to 25-kg pigs fed different levels of digestible P

A 21-d experiment was conducted to test the hypothesis that the Ca requirement to maximize growth performance expressed as the standardized total tract digestible (STTD) Ca to STTD P ratio is less than 1.40:1. The second hypothesis was that increasing dietary Ca increases plasma Ca and downregulates abundance of genes related to Ca absorption (TRPV6 and S100G) and tight junction proteins (OCLN, CLDN1, and ZO1). Twenty corn-soybean meal diets were formulated using a 4 5 factorial design (0.16, 0.33, 0.42, or 0.50% STTD P and 0.14, 0.29, 0.44, 0.59, or 0.74% STTD Ca), and 640 pigs (11.1 ± 1.4 kg) were allotted to the 20 diets in a randomized complete block design. On d 21, weights of pigs and feed left in feeders were recorded and blood, duodenal tissue, ileal mucosa, and the right femur were collected from 1 pig per pen. Abundance of mRNA was determined in duodenum and ileum via quantitative RT-PCR. Data were analyzed using a response surface model by removing the terms in the model that were not significant. Interactions (P < 0.01) between dietary Ca and P for average daily gain (ADG), gain to feed ratio (G:F), and bone ash were observed (Table 1). The predicted maximum ADG (614 g), G:F (0.65), and bone ash (11.68 g) at 0.33% STTD P was obtained at STTD Ca:STTD P ratios of 1.39:1, 1.25:1, and 1.66:1, respectively. There was a linear negative effect (P < 0.05) of Ca on the abundance of S100G, TRPV6, OCLN, and Z01 in the duodenum and on CLDN and ZO1 in the ileum. In conclusion, the STTD Ca:STTD P ratio needed to maximize growth performance of 11- to 25-kg pigs is less than 1.40:1, if P is at the requirement. Increasing dietary Ca reduces transcellular but increases paracellular absorption of Ca.