Abstract
Patients with chronic constipation benefit from treatment with 5-hydroxytryptamine 4 (5-HT4) receptor agonists. However, the first-generation 5-HT4 receptor agonists cisapride and tegaserod were withdrawn from the market owing to rare cardiovascular adverse events that were not 5-HT4-receptor-related but due to the lack of selectivity of these drugs. Here we report the nonclinical cardiovascular profile of the selective 5-HT4 receptor agonist prucalopride. To assess its non-5-HT4 receptor-mediated effects on cardiovascular electrophysiological parameters, in vitro studies were performed in human ether-à-go-go-related gene-transfected cells, guinea pig ventricular myocytes and papillary muscle preparations, rabbit and dog Purkinje fibers, and the Langendorff rabbit heart. In vivo experiments were performed in a rabbit model for drug-induced proarrhythmogenesis, in anesthetized guinea pigs, and anesthetized and conscious dogs. In addition, human platelet aggregation and coronary artery contraction were studied to exclude interactions that have been suggested to mediate the cardiovascular effects of tegaserod. Effects at 5-HT4 receptors were evaluated in piglet and human atrial myocardium, and in anesthetized pigs. Finally, cardiovascular endpoints were investigated in chronic, repeated-dose toxicology studies at very high prucalopride doses in rats and dogs. No relevant effects were observed in any of the cardiovascular studies at concentrations at least 50 times the therapeutic plasma level. Only in pigs were minor and transient increases in heart rate and blood pressure noted upon first exposure to prucalopride, at plasma levels at least 10 times higher than human therapeutic plasma levels. Prucalopride may thus provide therapeutic benefit without the cardiovascular risks reported for other 5-HT4 receptor agonists.
Highlights
Chronic constipation is a common and often debilitating problem that impacts health-related quality of life and imposes a substantial economic burden (Bosshard et al, 2004; Dennison et al, 2005; Wald et al, 2007)
AoPd, diastolic aortic blood pressure; AoPs, systolic aortic blood pressure; CO, cardiac output; HR, heart rate; PRP, platelet-rich plasma; PRU, prucalopride; PVR, pulmonary vascular resistance; QTcB, Bazett-corrected QT interval; QTcF, Fridericia-corrected QT interval; QTcV, Van de Water-corrected QT interval; SOL, solvent; SV, stroke volume; SVR, systemic vascular resistance. aMaximum plasma concentrations ranged from 6.7 ng/ml (0.02 mg/kg) to 79.8 ng/ml (0.16 mg/kg). bMaximum plasma concentrations ranged from 70 ng/ml (0.16 mg/kg) to 757 ng/ml (1.25 mg/kg)
Since previously reported adverse cardiovascular events associated with 5-hydroxytryptamine 4 (5-HT4) agonists were attributed to off-target pharmacology, a broad set of studies was implemented to fully exclude all non-5-HT4 receptor-mediated potential cardiovascular interactions
Summary
Chronic constipation is a common and often debilitating problem that impacts health-related quality of life and imposes a substantial economic burden (Bosshard et al, 2004; Dennison et al, 2005; Wald et al, 2007). Adverse cardiovascular events that were not 5-HT4 receptor-related have been observed with these compounds (http:// www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/ UCM279736.pdf). Tegaserod may be associated with rare occurrences of serious cardiovascular ischemic events such as unstable angina, heart attack, or stroke (http://www.fda.gov/Drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm051284.htm). Possible explanations for this include the effect of tegaserod on 5-HT1 or 5-HT2 receptor activity, which may lead to coronary artery constriction or platelet aggregation (De Maeyer et al, 2008). Published data are limited, neither agent has yet demonstrated significant cardiovascular safety concerns (Smith et al, 2008; http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM279736.pdf; Tack et al, 2012). Throughout this article, safety margins for prucalopride are estimated on the basis of comparisons of doses and plasma levels in various animal species with the therapeutic dose and plasma level in humans
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