Prucalopride: A Recently Approved Drug by the Food and Drug Administration for Chronic Idiopathic Constipation

Abstract

On December 14, 2018, the Food and Drug Administration (FDA) approved prucalopride (trade name Motegrity) for chronic idiopathic constipation.[1] Prucalopride is a selective 5-hydroxytryptamine receptor 4 agonist (5-HT4 agonist), which was introduced to the market in 2009 and has been commercially available in Europe since 2010[2] and in Canada since 2011.[3] The main effect of prucalopride is to stimulate colonic motility, which explains its efficacy to treat constipated patients unresponsive to other regimens.[2] Chemically, prucalopride is 4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide, butanedioic acid, with molecular formula of C22H32ClN3O7.[4] In vivo and in vitro studies revealed that prucalopride enhances the peristaltic reflex and propulsive motor patterns in the gastrointestinal tract via 5-HT4 receptor activation. In experimental studies, prucalopride has been shown to be highly selective for the 5-HT4 receptor showing a receptor affinity (Ki) of 8.7 nM, with in vitro affinity for other receptors and ion channels at least 150 times lower, suggesting a low potential for off-target effects.[3] In a range of in vitro studies on isolated gastrointestinal tissues from mouse, rat, guinea pig, dog, pig, and man, prucalopride facilitated the release of neurotransmitters. Depending on the location of the 5-HT4 receptor, these were acetylcholine from myenteric neurons leading to enhanced amplitude of contractions, calcitonin gene-related peptide and acetylcholine from intrinsic sensory neurons leading to stimulation of peristalsis, and nitric oxide from myenteric nerves leading to improved relaxation. All these actions resulted in improved propulsion in gastrointestinal tract. In several in vivo gastrointestinal motility studies, prucalopride was shown to stimulate gastrointestinal motility, with a pronounced effect on the large bowel.[3] The peak plasma concentration of prucalopride is attained within 0.3–1.5 h, with low plasma protein binding of 27%–37%. Prucalopride achieved highest tissue concentrations in the gastrointestinal tract, liver, kidney, adrenal gland, and lungs (>10 times than in plasma) in animal studies. Main metabolic pathways are through hydroxylation, O-demethylation, and N-glucuronide conjugation.[3] In three clinical trials, 12 weeks of prucalopride 2 and 4 mg/day treatment resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements compared to placebo. There was also significantly improved bowel habit and associated symptoms, and patient satisfaction with bowel habit and treatment, including patients with refractory constipation (>80% of trial patients).[5 6 7] Prucalopride (Motegrity) has been approved as 1 mg/2 mg once daily dose by the FDA. In clinical trials, suicide, suicide attempts, and suicide ideation have been reported, though no causal relationship could be established. Headache, abdominal pain, nausea, and diarrhea were the most common adverse effects reported in the clinical trials. Hypersensitivity; intestinal perforation or obstruction due to structural or functional disorder of the gut wall; obstructive ileus; and severe inflammatory conditions of the intestinal tract such as Crohn's disease, ulcerative colitis, and toxic megacolon/megarectum are some of the contraindications to the use of prucalopride.[8] Prucalopride works similarly in men and women, without any racial or age difference. Even the occurrence of side effects was similar between patients younger than 65 years and 65 years or older.[9] In vitro studies have documented low potential of prucalopride in inhibition or induction of cytochrome enzymes and transporters.[8] Due to its few side effects, the lack of cardiovascular effects, and interactions with other drugs, prucalopride may be safely used in elderly people as well.[2]