Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2021 Publisher: Janssen-Cilag (New Zealand) Ltd, Auckland, NEW ZEALAND Telephone: 0800 800 806 Fax: (09) 588 1398 Email: medinfo@janau.jnj.com
Pharmacotherapeutic group: Other drugs for constipation
ATC code: A06AX05
Prucalopride is a dihydrobenzofurancarboxamide with enterokinetic activities. Prucalopride is a selective, high affinity serotonin (5-HT4) receptor agonist, which likely explains its enterokinetic effects. In vitro, affinity for other receptors was detected only at concentrations exceeding its 5-HT4 receptor affinity by at least 150-fold. In rats in vivo, prucalopride at doses above 5mg/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.
The efficacy of RESOTRANS was established in three multicentre, randomised, double-blind, 12-week placebo-controlled studies in subjects with chronic constipation (n=1,279 on RESOTRANS, 1,124 females, 155 males) namely PRU-INT-6, PRU-USA-11 and PRU-USA-13. The RESOTRANS doses studied in each of these three studies included 2 mg and 4 mg dosing once daily. Table 2 provides a summary of the constipation history (prior to study enrolment) demonstrating that the patients enrolled were chronically constipated. Over 70% of patients had ≤1 SBM at baseline and more than 80% indicated that prior therapy was inadequate. The primary efficacy endpoint was the proportion () of patients that reached normalisation of bowel movements defined as an average of three 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 three 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 RESOTRANS that reached an average of ≥ 3 SCBM per week was 27.8 (week 4) and 23.6% (week 12), versus 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 RESOTRANS versus 23.4% (week 4) and 24.6% (week 12) of placebo patients.
In all three studies, treatment with RESOTRANS 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. A significant benefit on a number of Quality of Life measures, such as degree of satisfaction with treatment and with bowel habits, physical and psychosocial discomfort and worries and concerns, was also observed at both the 4 and 12 week assessment time points.
Table 2. History of constipation for Phase III pivotal studies (PRU-INT-6, PRU-USA-11, PRUUSA-13) in patients with chronic constipation – ITT population:
| Placebo | PRU* 2 mg | PRU 4 mg | All PRU | |
|---|---|---|---|---|
| Parameter | N=645 | N=640 | N=639 | N=1,279 |
| Duration of constipation, years | ||||
| Mean (SE) | 20.44 (0.616) | 19.84 (0.622) | 20.18 (0.643) | 20.01 (0.447) |
| Median (min;max) | 20 (0.5; 77) | 16 (0.5; 70) | 17 (0.3; 82) | 16 (0.3; 82) |
| Average freq./week spontaneous bowel movement over previous 6 months, n (%) | ||||
| No spontaneous BMa | 259 (40.2) | 251 (39.2) | 262 (41.0) | 513 (40.1) |
| >0 and ≤1 | 224 (34.7) | 224 (35.0) | 206 (32.2) | 430 (33.6) |
| >1 and ≤3 | 153 (23.7) | 153 (23.9) | 155 (24.3) | 308 (24.1) |
| >3 | 9 (1.4) | 12 (1.9) | 16 (2.5) | 28 (2.2) |
| Subject main complaint, n (%) | ||||
| Infrequent defaecation | 185 (28.7) | 202 (31.6) | 184 (28.8) | 386 (30.2) |
| Abdominal bloating | 163 (25.3) | 152 (23.8) | 159 (24.9) | 311 (24.3) |
| Abdominal pain | 98 (15.2) | 102 (15.9) | 85 (13.3) | 187 (14.6) |
| Feeling not completely empty | 95 (14.7) | 83 (13.0) | 97 (15.2) | 180 (14.1) |
| Straining | 68 (10.5) | 65 (10.2) | 80 (12.5) | 145 (11.3) |
| Hard stools | 36 (5.6) | 36 (5.6) | 34 (5.3) | 70 (5.5) |
| Laxative takenb, n (%) | ||||
| No | 89 (13.8) | 92 (14.4) | 98 (15.3) | 190 (14.9) |
| Yes | 556 (86.2) | 548 (85.6) | 541 (84.7) | 1089 (85.1) |
| Overall therapeutic effect, n (%) | ||||
| Adequate | 106 (17.0) | 115 (18.5) | 100 (16.2) | 215 (17.4) |
| Inadequate | 516 (83.0) | 507 (81.5) | 517 (83.8) | 1024 (82.6) |
* PRU = Prucalopride
a BM = bowel movement
b many patients had also been treated with diet and bulking agents
Study PRU-INT-6 was a multicentre, randomised, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy, safety, and effect on quality of life of RESOTRANS 2 and 4 mg including 716 male and female patients (mean age 43.9 [17−89] years) with chronic constipation.
The study consisted of 2 phases: a 2-week drug-free run-in phase followed by a randomised, 12-week, double-blind, placebo-controlled treatment phase. The trial population had long standing chronic constipation with a mean duration of 17.6 years (1−79 years).
The primary efficacy parameter was the proportion of patients with an average of ≥3 SCBM per week. Over the 12-week treatment period, 19.5% and 23.6% of patients in the RESOTRANS 2 and 4 mg groups, respectively, had ≥3 SCBM per week, as compared with 9.6% of placebotreated patients (2 mg p≤0.01; 4 mg p≤0.001). Over Weeks 1 through 4, 23.7% and 26.6% of patients in the RESOTRANS 2 and 4 mg groups, respectively, had ≥3 SCBM per week compared with 10.4% of placebo-treated patients (p≤0.001, in both cases).
For the main secondary parameter (the proportion of patients with an average increase of ≥1 SCBM per week from run-in), significant improvements were seen for both RESOTRANS 2 and 4 mg treatment groups compared with placebo. Over the 12-week treatment period, the proportion of patients with an average increase of ≥1 SCBM per week was 38.1% and 44.1% in the 2 and 4 mg groups, respectively, compared with 20.9% of placebo patients (p≤0.001, in both cases). Over Weeks 1 through 4, 41% and 46% of patients in the RESOTRANS 2 and 4 mg groups, respectively, had an increase of ≥1 SCBM per week, compared with 20.9% of placebo patients (p≤0.001, in both cases).
RESOTRANS significantly improved the time to first bowel movement when compared with placebo. The median time required to have the first SCBM in the RESOTRANS 2 and 4 mg groups was 113 and 49.5 hours after the first dose, respectively, compared with 493 hours in the placebo group (p≤0.001, in both cases).
Study PRU-USA-11 was a multicentre, randomised, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy, safety, and effect on quality of life of 2 and 4 mg RESOTRANS including 570 male and female patients (mean age 48.3 [18−85] years) with chronic constipation. The study consisted of 2 phases: a 2-week drug-free run-in phase followed by a randomised, 12-week, double-blind,placebo-controlled treatment phase. The trial population had long-standing chronic constipation, with a mean duration of 21.1 years (1−79 years).
The primary efficacy parameter was the proportion of patients with an average of ≥3 SCBM per week. Over the 12-week treatment period, 28.9% of patients in the RESOTRANS 2 and 4 mg groups had ≥3 SCBM per week as compared with 13% of placebo-treated patients (p≤0.001, in both cases). Over Weeks 1 through 4, 32.1% and 37.4% of patients in the RESOTRANS 2 and 4 mg groups, respectively, had ≥3 SCBM per week compared with 9.8% of placebo-treated patients (p≤0.001, in both cases).
For the main secondary parameter (the proportion of patients with an average increase of ≥1 SCBM per week from run-in), significant improvements were seen for both the RESOTRANS 2 and 4 mg treatment groups compared with placebo. Over the 12-week treatment period, the proportion of patients with an average increase of ≥1 SCBM per week was 50.3% and 51.1% in the 2 and 4 mg groups, respectively, compared with 25.9% of placebo patients (p≤0.001, in both cases). Over Weeks 1 through 4, 56.5% and 58.8% of patients in the RESOTRANS 2 and 4 mg groups, respectively, had an increase of ≥1 SCBM per week, compared with 24.3% of placebo patients (p≤0.001, in both cases).
RESOTRANS significantly improved the time to first bowel movement when compared with placebo. The median time required to have the first SCBM in the RESOTRANS 2 and 4 mg groups was 32.5 and 25 hours after the first dose, respectively, compared with 297 hours in the placebo group (p≤0.001, in both cases).
Study PRU-USA-13 was a multicentre, randomised, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy, safety, and effect on quality of life of 2 and 4 mg RESOTRANS including 641 male and female patients (mean age 47.9 [18−95] years) with chronic constipation.
The study consisted of 2 phases: a 2-week drug-free run-in phase followed by a randomised, 12-week, double-blind, placebo-controlled treatment phase. The trial population had longstanding chronic constipation, with a mean duration of 22 years (1−82 years).
The primary efficacy parameter was the proportion of patients with an average of ≥3 SCBM per week. Over the 12-week treatment period, 23.4% and 22.3% of patients in the RESOTRANS 2 and 4 mg groups, respectively, had ≥3 SCBM per week as compared with 11.8% of placebotreated patients (p≤0.01, in both cases). Over Weeks 1 through 4, 29.2% and 28.9% of patients in the prucalopride 2 and 4 mg groups, respectively, had ≥3 SCBM per week compared with 11.5% of placebo-treated patients (p≤0.001, in both cases).
For the main secondary parameter (the proportion of patients with an average increase of ≥1 SCBM per week from run-in), significant improvements were seen for both the RESOTRANS 2 and the 4 mg treatment groups compared with placebo. Over the 12-week treatment period, the proportion of patients with an average increase of ≥1 SCBM per week was 42.6% and 46.6% in the 2 and 4 mg groups, respectively, compared with 27.5% of placebo patients (p≤0.001, in both cases). Over Weeks 1 through 4, 48.8% and 51.5% of patients in the RESOTRANS 2 and 4 mg groups, respectively, had an increase of ≥1 SCBM per week, compared with 25.5% of placebo patients (p≤0.001, in both cases).
RESOTRANS significantly improved the time to first bowel movement when compared with placebo. The median time required to have the first SCBM in the RESOTRANS 2 and 4 mg groups was 55 and 46 hours after the first dose, respectively, compared with 311 hours in the placebo group (p≤0.001, in both cases).
Over 600 elderly subjects were investigated in double-blind placebo-controlled Phase II and III studies comparing the 1mg, 2mg and 4mg doses of RESOTRANS with placebo. Results demonstrated that the 1 mg daily dose is the lowest effective dose in achieving the primary endpoint of ≥ 3 SCBM per week and the secondary endpoint of increase ≥ 1 SCBM per week.
It has been shown that RESOTRANS does not cause rebound phenomena or induce dependency. A thorough double-blind QT study was performed to evaluate the effects of RESOTRANS on the QT interval at therapeutic (2mg) and supratherapeutic doses (10mg) and compared with the effects of placebo and a positive control. This study did not show significant differences between RESOTRANS and placebo at either dose, based on mean QT measurements and outlier analysis. This confirmed the results of two placebo controlled QT studies. In double blind clinical studies, the incidence of QT-related adverse events and ventricular arrhythmias was low and comparable to placebo.
Data from open label studies up to 2.6 years offer some evidence for longer-term safety and efficacy; however, no placebo controlled efficacy data for treatments longer than 12 weeks duration are available.
Prucalopride is rapidly absorbed; after a single oral dose of 2mg, Cmax was attained in 2-3 hours. The absolute oral bioavailability is >90%. Concomitant intake of food does not influence the oral bioavailability of prucalopride.
Prucalopride is extensively distributed and has a steady-state volume of distribution (Vdss) of 567 litres. The plasma protein binding of prucalopride is about 30%.
Metabolism is not the major route of elimination of prucalopride. In vitro, human liver metabolism of prucalopride is very slow and only minor amounts of metabolites are found. In an oral dose study with radiolabelled prucalopride in man, small amounts of eight metabolites were recovered in urine and faeces. The major metabolite (R107504, formed by O-demethylation and oxidation of the resulting alcohol function to a carboxylic acid) accounted for less than 4% of the dose. Unchanged active substance made up about 85% of the total radioactivity in plasma and only R107504 was a minor plasma metabolite.
In healthy subjects a large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and approximately 6% in faeces) via both passive filtration and active renal transporters (P-gp and BCRP). The plasma clearance of prucalopride averages 317mL/min. Its terminal half-life is about one day. Steady-state is reached within three to four days. On once daily treatment with 2mg prucalopride steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7ng/mL, respectively. The accumulation ratio after once daily dosing ranged from 1.9 to 2.3. The pharmacokinetics of prucalopride is doseproportional within and beyond the therapeutic range (tested up to 20mg). 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.
After once daily dosing of 1 mg, peak plasma concentrations and AUC of prucalopride in elderly patients were 26% to 28% higher than in young adults. This effect can be attributed to a diminished renal function in the elderly.
Compared to subjects with normal renal function, plasma concentrations of prucalopride after a single 2mg dose were on average 25% and 51% higher in subjects with mild (ClCR 50-79mL/min/1.73m²) and moderate (ClCR 25-49mL/min/1.73m²) renal impairment, respectively. In subjects with severe renal impairment (ClCR ≤ 24mL/min/1.73m²), plasma concentrations were 2.3 times the levels in healthy subjects (see sections 4.2 and 4.4).
Non-renal elimination contributes up to about 35% of total elimination. After a single oral dose of 2mg, Cmax and AUC of prucalopride were on average 10-20% higher in patients with moderate and severe hepatic impairment than in subjects with normal hepatic function.
After a single oral dose of 0.03mg/kg in paediatric patients aged between 4 and 12 years, Cmax of prucalopride was comparable to the Cmax in adults after a single 2mg dose. Unbound Area Under the Curve (AUC) was 30-40% lower than after 2mg in adults. Unbound exposure was similar over the whole age-range (4-12 years). The average terminal half-life in paediatric patients was about 19 hours (range 11.6 to 26.8 hours). RESOTRANS is not recommended in children or adolescents (see section 4.4 – Use in Children and Adolescents).
Non-clinical data reveal no special hazard for humans based on conventional studies of carcinogenic potential.
Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity.
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