Plecanatide may be safely administered with antacid

Acid suppression therapy appears to exert no meaningful effect on the efficacy or safety of plecanatide when administered concomitantly, according to a study.

Pooled data from two 12-week, phase III trials of plecanatide in chronic idiopathic constipation (CIC) showed that the efficacy response rates were significantly greater with the study drug than with placebo, regardless of concomitant acid suppression medication, the study authors said.

The complete spontaneous bowel movement (CSBM) response rates were 23.6 percent with plecanatide 3 mg (the approved dose) and 22.1 percent the 6-mg dose vs 7.6 percent with placebo (p=0.001 and p=0.002, respectively) among acid suppressor users. The corresponding rates among nonusers were 20.4 percent and 19.6 percent vs 12.1 percent (p<0.001 for both comparisons). CSBM response was defined as ≥3 CSBMs in a given week and ≥1 CSBM increase from baseline within a week for ≥9 of 12 weeks (including ≥3 of the last 4 treatment weeks). [Clin Ther 2022;doi:10.1016/j.clinthera.2021.11.009]

Acid suppressor users also saw significant positive changes in secondary and other endpoints, including more regular bowel movements, improved stool consistency, reduced patient-reported constipation symptoms, and greater satisfaction with plecanatide relative to placebo.

“Patients using acid suppression were older (mean age 54.8 years) compared with those not undergoing acid suppression (mean age 43.9 years); however, despite their age difference (gastroesophageal reflux disease is more common with increasing age), the efficacy of plecanatide was unaffected,” the authors pointed out.

In terms of safety, plecanatide carried no new safety signals among acid suppressor users. Serious adverse events occurred in 3.3 percent and 1.0 percent of patients who did vs did not use concomitant acid suppression therapy, respectively.

Most of the patients in the acid suppressor cohort were receiving proton pump inhibitors (PPIs). These drugs have the potential to affect the activity of concomitantly administered oral medications by way of altering gastric pH and drug solubility. However, as previous studies have shown, PPIs do not significantly alter the pH of the duodenum. [Drug Saf 2014;37:201-211; Aliment Pharmacol Ther 2003;17:403-408; Dis Colon Rectum 2001;44:1585-1589]

“The results of this study are congruent with findings that acid suppression therapy does not affect the therapeutic effects of pH-dependent drug activity in the small bowel. In addition, if acid suppression therapy did change the small bowel pH, then native uroguanylin binding to GC-C receptor would have been affected, leading to PPI-related constipation. In fact, PPIs can lead to the development of bowel symptoms, with the most common being diarrhoea,” according to the authors. [Otolaryngol Head Neck Surg 2016;155:547-554; Rev Gastroenterol Mex 2019;84:44-51; Eur J Clin Invest 2011;41:380-386]

The current analysis included 2,639 CIC patients in the intention-to-treat population, of whom 338 (12.8 percent) received concomitant acid suppression medication (plecanatide 3 mg, n=106; 6 mg, n=113; placebo, n=119). Meanwhile, the pooled safety population consisted of 2,627 patients, among whom 337 (12.8 percent) were also users of acid suppressor (plecanatide 3 mg, n=107; 6 mg, n=112; placebo, n=118).

“Although few studies have focused on the pH-dependent pharmacodynamic properties of small bowel–targeted therapies, to our knowledge, this is the first study to investigate the efficacy and safety of concomitant acid suppressive therapy and plecanatide in a large population of patients with CIC,” the authors said. [J Gastroenterol 2020;55:1013-1022]

The current study, despite its limitations, establishes that plecanatide can be safely used with PPIs without affecting efficacy, they added.