Is Prucalopride the Gastroparesis Treatment We've Been Waiting For?

David A. Johnson, MD


August 20, 2019

This transcript has been edited for clarity.

Hello. I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia.

If you've been taking care of patients in a practice, you'll recognize that gastroparesis is one of the more challenging problems that we face in clinical medicine. Although gastroparesis is associated with diseases like diabetes and hypothyroidism, in the majority of cases it is idiopathic. This condition is accompanied by abnormal gastric emptying, but efforts at trying to stimulate gastric motility have not really been shown to improve emptying or its associated symptoms.

When it comes to treating gastroparesis, one of the first things we can do is to change patients' diets to accommodate it. I most commonly recommend well-cooked, low-fat, small meals to my patients.

However, our ability to successfully intervene has been limited by the fact that we don't have good medications to treat gastroparesis.

Metoclopramide is not without a bevy of problems, certainly as it relates to legal issues surrounding its neurologic side effects. Domperidone is not currently approved by the US Food and Drug Administration (FDA). If you can get it, it will be through a compounding pharmacy in your state or by obtaining it internationally, most often through Canada. Although domperidone does work reasonably well, it has been shown to have some problems. The macrolide erythromycin has been shown to be somewhat efficacious, at least in diabetic gastroparesis. However, enthusiasm surrounding its use has been dampened by long-term side effects and selective resistance to it among certain organisms.

Domperidone and metoclopramide are additionally problematic because they can cause a prolongation in the QT interval. This can result in polymorphic ventricular tachycardia, specifically torsade de pointes, which is obviously a concern. We always have to counsel our patients about this and other potential side effects with these drugs, such as galactorrhea, of which they may not be aware. These drugs may also have adverse interactions with other medications that physicians prescribe. But remember that complications associated with a non-FDA-approved medication won't show up in the cross-check.

Has a New Treatment Option Emerged?

Prucalopride, a highly selective 5-hydroxytryptamine receptor 4 agonist, has been well studied, particularly in the lower gastrointestinal tract, and has been recently approved for idiopathic constipation. Prucalopride has excellent bioavailability, with a 24-hour half-life; it sticks around for a long period of time. Interestingly, when they studied it in colonic motility, they were actually able to demonstrate that it enhanced gastric emptying in dog models, healthy volunteers, and patients with chronic constipation.

According to a recent study from the University of Leuven in Belgium,[1] prucalopride may also hold promise for improving symptoms and gastric emptying in patients with gastroparesis. Researchers behind this randomized, placebo-controlled, crossover, proof-of-concept study enrolled 28 patients with idiopathic gastroparesis and six with diabetic gastroparesis. All patients had abnormal gastric emptying and associated symptoms. The primary endpoint was improvement in symptom severity, as measured by the validated Gastroparesis Cardinal Symptom Index. Gastric emptying was also included among other secondary outcomes.

Patients were randomized to 4 weeks of treatment with prucalopride (2 mg once a day) or placebo, followed by a 2-week washout period, after which they were then crossed over to the other arm. It's very important to recognize that gastric symptoms did not differ at the crossover point. This indicates that there was no carryover effect and that these patients did not persist in being symptomatic.

Prucalopride's Efficacy

This study showed that patients had a significant improvement in their primary outcome after receiving prucalopride. In particular, meal-related symptoms, postprandial fullness, and bloating were significantly lower in the treatment group. Patients receiving prucalopride also experienced significant improvements in the three subscales of the Gastroparesis Cardinal Symptom Index: fullness/satiety, nausea/vomiting, and bloating/distention.

Interestingly, prucalopride significantly improved the gastric half emptying time when compared with placebo and baseline levels. There was, however, no concordance between the degree of improvement of gastric emptying and the degree of improvement in symptoms. This leaves open the question of whether gastric emptying equals gastric symptom improvement. Nonetheless, prucalopride did improve both gastric emptying and symptoms.

The symptoms of gastroparesis are somewhat complex, and we're not exactly sure why this commercially available drug improved them in these patients. It can be related to compliance, gastric emptying, titration, or presentation in the duodenum. We also don't have an absolute answer on why prucalopride showed an improvement here in terms of gastric emptying. There was an acceleration in colonic emptying noted, with stool motility also increasing in the patients on prucalopride. However, this was very transient and was not correlated with improvement in their gastric symptoms.

Take-away Message

When it comes to prucalopride, what do we have? We have a new drug that's available for chronic constipation but that also improves symptoms and gastric emptying in gastroparesis. Prucalopride not only may be safe and effective but also does not change the QT interval. It will also show up when you assess for possible drug-drug interactions, and it doesn't seem to be associated with the concerns surrounding other treatments for gastroparesis. It should be noted that this study is limited by taking place at a tertiary referral center and its proof-of-concept design. However, the fact that it is a randomized controlled trial with a crossover design is, I think, very provocative.

There's certainly more to be said and studied about this drug. It remains to be seen whether it will have the same effectiveness in the diabetic population with neuropathy. Time will tell, and this needs closer analysis. But I'm intrigued by the prospects of having a safe and effective drug that improves the symptoms of gastroparesis and gastric emptying. Prucalopride may be something that clinicians want to potentially try, particularly in their patients with idiopathic gastroparesis.

I'm Dr David Johnson. Thanks again for listening.

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