Resolor Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Prucalopride, a high affinity selective, serotonin type 4 (5‑HT₄) receptor agonist, is a gastrointestinal prokinetic agent that stimulates colonic peristalsis increasing bowel motility. This peristalsis is referred to as high-amplitude propagating contractions (HAPCs) in humans and giant migrating contractions in dogs.
Prucalopride does not antagonize 5-HT_2A, 5-HT_2B, 5-HT₃, motilin or CCK₁ receptors or hERG ion channels, with affinity for other receptors or ion channels detected in vitro at concentrations exceeding 5‑HT₄ receptor affinity by 150‑fold or greater. Additional in vitro studies demonstrated no effect on either contractile responses in human, canine, and porcine coronary arteries at concentrations up to 10 μM (500 times the human clinical C_max) or on human platelet aggregation at concentrations up to 200 nM (10 times the human clinical C_max).
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.
Pharmacodynamic Effects: High Amplitude Propagating Contractions: The pharmacodynamic effects of prucalopride have been confirmed in human subjects with chronic constipation using manometry in an open-label, randomized, 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.
Pharmacodynamic effects of prucalopride related to prokinetic activity were studied in healthy subjects and in patients with chronic constipation at doses ranging from 0.5‑4 mg once daily. In a double-blind, randomized, placebo-controlled, crossover manometry study in healthy subjects receiving prucalopride 4 mg once daily (2 times the maximum human recommended dose of 2 mg) or placebo for 7 days showed that prucalopride increased the amplitude of HAPCs without affecting colonic phasic activity.
Colonic Transit Times: Prucalopride accelerates colonic transit at a dose of 2 mg. An integrated analysis of 3 randomized, placebo-controlled, dose-finding studies in 280 subjects with chronic idiopathic constipation showed that after treatment with prucalopride at once-daily doses of 2 mg or 4 mg (2 times the maximum human recommended dose), the colonic transit time was reduced by 12 hours and 13.9 hours, respectively, compared to an increase of 0.5 hours in the placebo group. Furthermore, a positive correlation between constipation symptom severity and decreased colonic transit time was found.
Clinical Studies: The efficacy of Prucalopride succinate (Resolor) was established in 3 multicenter, randomized, double-blind, 12-week placebo-controlled studies in patients with chronic constipation (n=1279 on Prucalopride succinate (Resolor): 1124 females, 155 males). The Prucalopride succinate (Resolor) doses studied in each of these 3 studies included 2 mg and 4 mg dosing once daily. The primary efficacy endpoint was the proportion (%) of patients that reached normalization of bowel movements defined as an average of 3 or more spontaneous, complete bowel movements (SCBM) per week over the 12-week treatment period. Both doses were statistically superior (p<0.001) to placebo at the primary endpoint in each of the 3 studies, with no incremental benefit of the 4 mg dose over the 2 mg dose. The proportion of patients treated with the recommended dose of 2 mg Prucalopride succinate (Resolor) that reached an average of ≥3 SCBM per week was 27.8% (week 4) and 23.6% (week 12), vs 10.5% (week 4) and 11.3% (week 12) on placebo. A clinically meaningful improvement of ≥1 SCBM per week, the most important secondary efficacy endpoint, was achieved in 48.1% (week 4) and 43.1% (week 12) of patients treated with 2 mg Prucalopride succinate (Resolor) vs 23.4% (week 4) and 24.6% (week 12) of placebo patients.
In all 3 studies, treatment with Prucalopride succinate (Resolor) also resulted in significant improvements in the Patient Assessment of Constipation Symptoms (PAC SYM), a validated and disease-specific set of symptom measures, including abdominal, stool and rectal symptoms, determined at week 4 and week 12. At the 4- and 12-week assessment time points, significant improvement in several quality of life measures was also observed, such as degree of satisfaction with treatment and bowel habits, physical and psychosocial discomfort and worries and concerns resulting from constipation symptoms. In addition, the efficacy, safety and tolerability of Prucalopride succinate (Resolor) in male patients with chronic constipation were evaluated in a 12-week, multi-center, randomized, double-blind, placebo-controlled study (N=370). The primary endpoint of the study was met: a statistically significantly higher percentage of subjects in the Prucalopride succinate (Resolor) group (37.9%) had an average of ≥3 SCBMs/week compared with subjects in the placebo treatment group (17.7%) (p<0.0001) over the 12-week, double-blind treatment period. The safety profile of Prucalopride succinate (Resolor) was consistent with that seen in female patients.
The safety and efficacy of Prucalopride succinate (Resolor) in adult male and female patients (51 male, 450 female) with chronic constipation in the Asia Pacific region (China 62%, South Korea 19%, Australia 8%, Thailand 6%, Taiwan 5%) was evaluated in a 12-week randomized, double-blind, placebo-controlled multi-center study with parallel group design. The primary endpoint of the study was the proportion (%) of patients achieving ≥3 SCBMs per week during the entire 12 week treatment phase. The key secondary endpoint was the proportion of patients achieving ≥3 SCBMs per week during the first 4 weeks of the treatment phase of the study. Results for the primary endpoint in the ITT analysis set showed that the percentage of responders in the Prucalopride succinate (Resolor) 2 mg group (33.3%) was significantly higher (p<0.001) than that in the placebo group (10.3%). Results for the key secondary endpoint showed that the percentage of responders (34.5%) was significantly higher (p<0.001) than that in the placebo group (11.1%). The overall safety profile in this study was consistent with that established in previous studies with Prucalopride succinate (Resolor) 2 mg in subjects from Western populations. It has been shown that prucalopride does not cause rebound phenomena, or induce dependency.
A thorough placebo- and positive-controlled QT study (N=120) was performed to evaluate the effects of prucalopride on QT interval at therapeutic (2 mg) and supratherapeutic doses (10 mg). This study did not show significant differences between prucalopride succinate (Resolor) and placebo at either dose, based on mean QTc measurements (largest increase in mean double-delta QTc [subject-specific correlation] was 3.83 msec for 2 mg and 3.03 msec for 10 mg) and outlier analysis. This confirmed the results of two earlier, placebo-controlled QT studies which included QT measurements. The three studies confirm that, the incidence of QT-related adverse events and ventricular arrhythmias was low and comparable to placebo.
The efficacy, safety and tolerability of prucalopride in pediatric patients (aged 6 months to 18 years) with functional constipation, were evaluated in an 8-week double-blind, placebo-controlled trial (N=213), followed by a 16 week open-label comparator-controlled (Polyethylene glycol 4000) study of up to 24 weeks (n=197). The starting dose administered was 0.04 mg/kg/day titrated between 0.02 and 0.06 mg/kg/day (to a maximum of 2 mg daily) for children weighing ≤50 kg given as an oral solution of prucalopride or matching placebo. Children weighing >50 kg received 2 mg/day prucalopride tablets or matching placebo. The primary endpoint of the study was not met: there was no difference in the proportion of patients having an average of ≥3 spontaneous bowel movements (SBMs) per week AND an average number of fecal incontinence episodes of ≤1 per 2 weeks during week 5 to week 8 of the double-blind treatment period in the prucalopride and placebo groups, 17% versus 17.8%, respectively, (p=0.9002). Overall, the safety profile in children was similar to that in adults.
The efficacy and safety of Prucalopride succinate (Resolor) in patients (aged 18 years or older) with chronic constipation, were evaluated in a 24 week multi-center, randomized, double-blind, placebo-controlled study (N=361). The proportion of patients with an average weekly frequency of ≥3 Spontaneous Complete Bowel Movements (SCBMs) per week (i.e., responders) over the 24-week double-blind treatment phase was not statistically different (p=0.367) between the Prucalopride succinate (Resolor) (25.1%) and placebo (20.7%) treatment groups. The difference between treatment groups in the average weekly frequency of ≥3 SCBMs per week was not statistically significant over weeks 1-12 which is inconsistent with the 5 other multi-center, randomized, double-blind, 12-week placebo-controlled studies demonstrating efficacy at this timepoint in adult patients. The study is therefore considered to be inconclusive with respect to efficacy.
The totality of the data including the other double-blind placebo-controlled 12 week studies support the efficacy of Prucalopride succinate (Resolor). The safety profile of Prucalopride succinate (Resolor) in this 24 week study was consistent with that seen in the other 12 week studies.
Pharmacokinetics: 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 liters. The plasma protein binding of prucalopride is about 30%.
Metabolism: 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. Cytochrome P450 3A4 has been shown in vitro to be the only enzyme involved in the metabolism of prucalopride. In an oral dose study with radiolabeled prucalopride in man, small amounts of 7 metabolites were recovered in urine and feces. The quantitatively most important metabolite in excreta, R107504, accounted for 3.2% and 3.1% of the dose in urine and feces respectively. Other metabolites identified and quantified in urine and feces 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: In healthy subjects a large fraction of the active substance is excreted unchanged (60-65% of the administered dose in urine and about 5% in feces). 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 1 day. Steady-state is reached within 3-4 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 1.9-2.3. The pharmacokinetics of prucalopride is dose proportional within and beyond the therapeutic range (tested up to 20 mg). Once daily prucalopride displays time independent kinetics during prolonged treatment.
A population pharmacokinetic analysis based on combined data from Phase I, II, and III studies showed that the apparent total clearance of prucalopride correlated with creatinine clearance, but not with age, body weight, gender, or race.
Toxicology: Non-Clinical Information: 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 (including neonatal/juvenile toxicity).