Prucalopride

Prucalopride is a dihydrobenzofurancarboxamide with gastrointestinal prokinetic activities. Prucalopride is a selective, high affinity serotonin (5-HT₄) receptor agonist, which is likely to explain its prokinetic effects. In vitro, only at concentrations exceeding its 5-HT₄ receptor affinity by at least 150-fold, affinity for other receptors was detected.

In rats, prucalopride in vivo, at doses above 5 mg/kg (at and above 30-70 times the clinical exposure), induced hyperprolactinaemia caused by an antagonistic action at the D₂ receptor.

In dogs, prucalopride alters colonic motility patterns via serotonin 5-HT₄ receptor stimulation: it stimulates proximal colonic motility, enhances gastroduodenal motility and accelerates delayed gastric emptying. Furthermore, giant migrating contractions are induced by prucalopride. These are equivalent to the colonic mass movements in humans, and provide the main propulsive force to defecation. In dogs, the effects observed in the gastrointestinal tract are sensitive to blockade with selective 5-HT₄ receptor antagonists illustrating that the observed effects are exerted via selective action on 5-HT₄ receptors.

These pharmacodynamic effects of prucalopride have been confirmed in human subjects with chronic constipation using manometry in an open-label, randomised, crossover, reader-blinded study investigating the effect of prucalopride 2 mg and an osmotic laxative on colon motility as determined by the number of colonic high-amplitude propagating contractions (HAPCs, also known as giant migrating contractions). Compared with a constipation treatment working through osmotic action, prokinetic stimulation with prucalopride increased colonic motility as measured by the number of HAPCs during the first 12 hours after intake of the investigational product. The clinical significance or benefit of this mechanism of action when compared with other laxatives has not been investigated.

Absorption

Prucalopride is rapidly absorbed; after a single oral dose of 2 mg in healthy subjects, C_max was attained in 2-3 hours. The absolute oral bioavailability is >90%. Concomitant intake of food does not influence the oral bioavailability of prucalopride.

Distribution

Prucalopride is extensively distributed, and has a steady-state volume of distribution (Vd_ss) of 567 litres. The plasma protein binding of prucalopride is about 30%.

Biotransformation

Metabolism is not the major route of elimination of prucalopride. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. In an oral dose study with radiolabelled prucalopride in man, small amounts of seven metabolites were recovered in urine and faeces. The quantitatively most important metabolite in excreta, R107504, accounted for 3.2% and 3.1% of the dose in urine and faeces, respectively. Other metabolites identified and quantified in urine and faeces were R084536 (formed by N-dealkylation) accounting for 3% of the dose and products of hydroxylation (3% of the dose) and N-oxidation (2% of the dose). Unchanged active substance made up about 92-94% of the total radioactivity in plasma. R107504, R084536 and R104065 (formed by O-demethylation) were identified as minor plasma metabolites.

Elimination

A large fraction of the active substance is excreted unchanged (60-65% of the administered dose in urine and about 5% in faeces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. The plasma clearance of prucalopride averages 317 ml/min. Its terminal half-life is about one day. Steady-state is reached within three to four days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively. The accumulation ratio after once daily dosing ranged from 1.9 to 2.3. The pharmacokinetics of prucalopride is dose-proportional within and beyond the therapeutic range (tested up to 20 mg). Prucalopride o.d. displays time-independent kinetics during prolonged treatment.

Special populations

Population pharmacokinetics

A population pharmacokinetic analysis showed that the apparent total clearance of prucalopride was correlated with creatinine clearance, but that age, body weight, sex or race had no influence.

Older people

After once daily dosing of 1 mg, peak plasma concentrations and AUC of prucalopride in older people were 26% to 28% higher than in young adults. This effect can be attributed to a diminished renal function in older people.

Renal impairment

Compared to subjects with normal renal function, plasma concentrations of prucalopride after a single 2 mg dose were on average 25% and 51% higher in subjects with mild (Cl_CR 50-79 ml/min) and moderate (Cl_CR 25-49 ml/min) renal impairment, respectively. In subjects with severe renal impairment (Cl_CR ≤24 ml/min), plasma concentrations were 2.3 times the levels in healthy subjects.

Hepatic impairment

Non-renal elimination contributes to about 35% of total elimination. In a small pharmacokinetic study, the C_max and AUC of prucalopride were, on average, 10-20% higher in patients with moderate to severe hepatic impairment compared with healthy subjects.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. An extended series of safety pharmacology studies with special emphasis on cardiovascular parameters showed no relevant changes in haemodynamic and ECG derived parameters (QTc) with the exception of a modest increase in heart rate and blood pressure observed in anaesthetised pigs after intravenous administration, and an increase in blood pressure in conscious dogs after bolus intravenous administration, which was not observed either in anaesthetised dogs or after oral administration in dogs reaching similar plasma levels. A subcutaneous neonatal/juvenile toxicity study performed in rats 7-55 days of age resulted in a NOAEL of 10 mg/kg/day. The AUC_0-24h exposure ratios at the NOAEL versus human children (dosed at approximately 0.04 mg/kg daily) ranged between 21 and 71 providing adequate safety margins for the clinical dose.