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Oral Prucalopride in Children With Functional Constipation

Winter, Harland S.*; Di Lorenzo, Carlo; Benninga, Marc A.; Gilger, Mark A.§; Kearns, Gregory L.||; Hyman, Paul E.; Vandeplassche, Lieve#; Ausma, Jannie#; Hoppenbrouwers, Mieke#

Journal of Pediatric Gastroenterology and Nutrition: August 2013 - Volume 57 - Issue 2 - p 197–203
doi: 10.1097/MPG.0b013e318292f9ea
Original Articles: Gastroenterology

Background and Objectives: Prucalopride is a selective, high-affinity 5-HT4 receptor agonist with gastrointestinal prokinetic activities. The aim of this study was to evaluate the pharmacokinetics, efficacy, safety, and tolerability of prucalopride oral solution in children, ages 4 years or older to 12 years or younger, with functional constipation.

Methods: A single oral dose of 0.03 mg/kg prucalopride was administered to 38 children to characterize prucalopride pharmacokinetics (NCT01674166). Thereafter, 37 children entered an open-label extension period in which 0.01 to 0.03 mg/kg of prucalopride was administered once per day for 8 weeks to investigate efficacy, safety, and tolerability (NCT01670669).

Results: Mean (standard deviation [SD]) Cmax, tmax, and AUC (area under the plasma concentration-time curve from time 0 to infinity) were 3.8 (0.6) ng/mL, 1.8 (0.9) hour, and 65.3 (10.6) ng · h−1 · mL−1, respectively, with limited (16%) variability in Cmax and AUC. Mean (SD) t1/2 was 19.0 (3.1) hours. On average, mean (SD) renal clearance (0.25 [0.08] L · h−1 · kg−1) accounted for 54% of the apparent total plasma clearance (0.46 [0.07] L · h−1 · kg−1). The apparent volume of distribution was 12.6 (2.6) L/kg. Prucalopride treatment resulted in a mean bowel movement frequency of 6.8/week, normal stool consistency, and reduced frequency of fecal incontinence. During the 8-week extension, 70% of study participants had at least 1 adverse event (all but 1 of mild/moderate intensity, 19% considered related to prucalopride). No children discontinued prucalopride because of adverse events.

Conclusions: The pharmacokinetic profile of a single dose of prucalopride oral solution (0.03 mg · kg−1 · day−1) generally resembled the profile in adults (2-mg tablet) but reflected lower systemic exposure in children. Prucalopride treatment for 8 weeks demonstrated an apparent favorable efficacy and tolerability profile in children with functional constipation.

*MassGeneral Hospital for Children, Boston, MA

Nationwide Children's Hospital, Columbus, OH

Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands

§Texas Children's Hospital, Houston, TX

||Children's Mercy Hospital, Kansas City, MO

Children's Hospital, New Orleans, LA

#Shire-Movetis NV, Turnhout, Belgium.

Address correspondence and reprint requests to Harland S. Winter, MD, MassGeneral Hospital for Children, Pediatric GI Unit, CRPZ 5-560, 175 Cambridge St, Boston, MA 02114 (e-mail:

Received 20 September, 2012

Accepted 18 March, 2013 registration numbers: NCT01670669, NCT01674166.

H.S.W. has current research grants from Janssen, UCB, Nutricia, The Pediatric IBD Foundation, Autism Research Institute, and Warner-Chilcott. He has current consulting agreements with Prometheus Laboratories, Salix, Janssen Pharmaceuticals, and Shire-Movetis NV. C.D. has consulting agreements with Janssen Pharmaceuticals, Abbott Laboratories, Ironwood Pharmaceuticals, and QOL Medical. M.A.B. has consulting agreements with Shire-Movetis NV and Danone. M.A.G. has current research grants from Redhill Biopharma, QOL Medical, Otsuka Pharmaceutical Inc, and the National Institutes of Health (NO1 A1 25465). G.L.K. has active consulting agreements with Upsher-Smith Laboratories, Inc, Solginex, Inc, and Bristol-Myers Squibb. He has current research grants from Bristol-Myers Squibb and the National Institutes of Health. L.V., J.A., and M.H. are employees of Shire-Movetis NV and own stock in Shire. P.E.H. reports no conflicts of interest.

The clinical research was funded by the Janssen Research Foundation, Beerse, Belgium, and Shire-Movetis NV, Turnhout, Belgium. Although Janssen Research Foundation and Shire-Movetis NV were involved in the design, collection, analysis, interpretation, and fact checking of the information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication was made by the authors independently.

The results of the study were presented at Digestive Disease Week 2009, Chicago, IL.

Constipation is a common problem in childhood. Reported prevalence rates for functional constipation in the general pediatric population vary between 0.7% and 29.6%, with a median rate of 12% (1). Functional constipation in children is generally treated by educating the parents and child (when appropriate) about the act of defecation. Fecal impaction if present is removed, followed by maintenance laxative therapy to keep the stools soft and to avoid recurrence of painful bowel movements (2).

Prucalopride (RESOLOR, prucalopride succinate tablets) belongs to the class of dihydro-benzofuran-carboxamide derivatives with gastrointestinal prokinetic activity and is the first of a new generation of selective, high-affinity 5-HT4 receptor agonists that stimulate gastrointestinal motility and act on the lower gastrointestinal tract. The high affinity and selectivity for 5-HT4 receptors differentiates prucalopride from previous-generation compounds such as cisapride and tegaserod by minimizing the potential for target-unrelated adverse effects, such as cardiac effects.

In dogs, prucalopride improved colonic function by stimulating proximal colonic motility, enhancing gastroduodenal motility, and accelerating delayed gastric emptying (3). Prucalopride also induced giant migrating contractions in dogs, which are equivalent to the high-amplitude propagated contractions in humans that provide the main propulsive force for defecation. In human studies, prucalopride stimulated high-amplitude propagated contractions (4) and accelerated colonic transit in healthy volunteers (5) and in patients with constipation (6).

The results of 3 identical pivotal phase III studies demonstrated that treatment of adults with chronic constipation with prucalopride 2 mg once per day for 12 weeks increased the frequency of spontaneous complete bowel movements and improved patient satisfaction with bowel function, perception of constipation, and constipation-related quality of life (7–9). Prucalopride was well tolerated in adults (7–9) and elderly patients (10).

Prucalopride reaches peak plasma concentrations on average between 2 and 3 hours after single-dose oral administration in healthy adults, and food did not affect the rate or extent of absorption (11). The average apparent terminal elimination half-life of prucalopride was approximately 24 hours and steady-state plasma concentrations were achieved after 3 days (12). The pharmacokinetics of the drug were not concentration dependent and appeared similar for healthy adults and adults with chronic constipation (12). Prucalopride is approved in the European Union for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. The recommended dose for adults is 2 mg once per day.

To evaluate the therapeutic potential of prucalopride in treating pediatric patients with chronic constipation, it is essential to assess both the pharmacokinetics and pharmacodynamics of the drug in children. Therefore, we undertook a single-dose (0.03 mg/kg) pharmacokinetic study of the drug in children ages 4 years or older to 12 years or younger with functional constipation. Additionally, we conducted a preliminary study to assess the safety, tolerability, steady-state plasma concentrations, and efficacy after once-per-day dosing of 0.01 to 0.03 mg/kg prucalopride oral solution in these children during an 8-week period. The results of these studies are reported herein.

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Study Population and Design

This was a phase I, open-label, noncontrolled study conducted between November 1998 and July 1999 at 9 centers in the United States. Children were eligible if they were 4 years or older to 12 years or younger, with Tanner stage I–II, and between the 5th and 95th percentile for weight–height proportionality for age. Children had to have a confirmed diagnosis of functional constipation, defined as a history of fecal impaction occurring periodically during at least 2 months (determined by rectal examination or palpable on abdominal examination) plus <3 bowel movements per week and/or a history of fecal incontinence (13). If children were impacted at the first evaluation, they were disimpacted using a clinically acceptable method determined by the investigator before initiation of prucalopride. Children were excluded if they showed abnormal growth (by examination or laboratory tests), had an abnormal neurologic examination, cystic fibrosis, Hirschsprung disease, a history of an anorectal malformation, a chromosomal abnormality, a disease or surgical state known to affect gastrointestinal drug absorption, renal or liver disease, or anemia. Concomitant medication was not allowed, except for acetaminophen as an analgesic. Any laxative used for maintenance therapy of functional constipation was discontinued at least 24 hours before study entry.

The protocol was reviewed and approved by an independent institutional review board and by the institutional review boards of the participating centers. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonisation. Written informed consent was obtained and signed by the child's legal guardian and by the investigator before the initiation of study procedures. Depending on the institution, assent was obtained for children older than 6 or 7 years, and appropriately documented before entry into the study.

All children received a single dose of 0.03 mg/kg prucalopride in oral solution (0.2 mg/mL), together with 30 mL of water. A standardized snack of milk and cookies was served 2 hours after dosing. All of the children consumed age-appropriate meals and fluid volumes. Fluid intake was standardized and strictly monitored.

Before the administration of prucalopride (supervised) by site personnel, all of the children had an indwelling venous cannula placed in a large vein, either on the dorsum of the hand or on the forearm, for pharmacokinetic blood sampling. Immediately before prucalopride administration, a 5.0-mL venous blood sample was obtained: 1 mL of this sample was used as blank plasma sample (0 hours) and the remainder of the sample was used for the determination of prucalopride protein binding. Repeated blood samples of 1.0 mL each were obtained at the following postdose times: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 48, and 72 hours. In addition to blood sampling, urine was collected immediately before prucalopride administration, followed by quantitative collections at 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours after drug administration. The children were hospitalized for the first 24 hours after prucalopride dosing and returned to the hospital for the 48- and 72-hour assessments. Safety was monitored for the 72-hour study period through assessment of adverse events, vital signs (pulse rate, blood pressure, and respiration rate), clinical laboratory tests (hematology, biochemistry, and urine analysis), physical examinations, and electrocardiogram parameters (heart rate, PR interval, QRS width, QT interval, corrected QT interval using Bazett [QTcB] and Fridericia [QTcF] formula).

Children who completed all of the assessments up to 72 hours after dosing were given the option to enroll in an open-label extension study, in which prucalopride oral solution was administered once per day for up to 8 weeks, approximately 2 hours before the evening meal at a starting dose of 0.02 mg/kg. Before entering the open-label extension study, informed consent and assent were obtained according to the procedure described above and any fecal impaction was to be removed. Depending on the child's response to treatment, the daily dose could be adjusted upward or downward for optimal treatment by the child's parent within a range of 0.01 to 0.03 mg/kg. At baseline and at week 4 of the study, prucalopride was dispensed as a solution of prucalopride 0.2 mg/mL in 100-mL bottles. The child's parent kept a dispensing diary, which was checked at each visit. Use of concomitant medication, including laxatives for additional (rescue) therapy, was allowed throughout the 8-week period.

Children were to visit the study center every 2 weeks (ie, at weeks 2, 4, 6, and 8). At each visit, a 1-mL venous blood sample for determination of prucalopride plasma concentrations was obtained. Additionally, a daily diary was used to prospectively collect the following parameters in week 1 through week 8: frequency of bowel movements in the toilet, episodes of fecal incontinence, reimpaction rate (ie, the need for repeated disimpaction), and stool consistency (average number of days per week with liquid stool, loose stool, formed stool, hard stool, or no stool). To evaluate a child's overall improvement, the parents and the investigators were asked at each visit to rate the change in the child's constipation as very much improved, much improved, minimally improved, unchanged, minimally worse, much worse, or very much worse as compared with before treatment. Safety was assessed throughout the 8-week period as described above.

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Analytical Procedures and Pharmacokinetic Analysis

Blood samples were collected in heparinized glass tubes and were centrifuged (10 minutes, 1000g at 4°C) within 30 minutes after collection. Plasma aliquots were aspirated from the cellular fraction, placed into labeled polypropylene vials, and frozen at −18°C until assayed. Each urine sample was mixed, the volume and pH were recorded, and an aliquot (10 mL) was placed in a labeled polypropylene vial, which was subsequently placed at −18°C until assayed. Prucalopride plasma and urine concentrations were measured by a validated, sensitive radioimmunoassay technique. The range of linearity for the method using plasma samples was 0.1 to 55.0 ng/mL and the lower limit of quantification was 0.1 ng/mL. Accuracy and precision were obtained from measuring standardized quality control samples (0.17–10.1 ng/mL): the mean accuracy ranged from 90.8% to 97.7% and overall precision from 5.0% to 13.4% for plasma samples. For urine samples, the lower limit of quantification was 20 ng/mL and the linear concentration range was 20 to 11,110 ng/mL. The mean accuracy ranged from 85.5% to 86.8% and overall precision from 6.2% to 8.2%.

In vitro plasma protein binding was determined by equilibrium dialysis, after fortification of the predose plasma samples with 3H-prucalopride. At the end of the dialysis, prucalopride concentrations in the plasma (C) and buffer (Cu) compartments of the dialysis cells were used to calculate the fraction of unbound prucalopride (fu) as the ratio of the unbound concentration Cu to the total concentration C (Cu/C).

Single-dose pharmacokinetic parameters were determined from prucalopride plasma concentration time profiles with actual sampling times, by noncompartmental analysis using WinNonlin, version 3 (Pharsight Corporation, Sunnydale, CA). The following pharmacokinetic parameters were determined for each subject: peak plasma concentration (Cmax), time to reach peak plasma concentration (tmax), apparent elimination rate constant (λz) and half-life (t1/2), areas under the plasma concentration-time curve (AUC24h, AUClast, AUC), body weight–normalized apparent total clearance (CL/F), and body weight–normalized apparent volume of distribution (Vd/F). The fractions of dose excreted in the urine at 24 hours (fe24h) and body weight–normalized renal clearance (CLR) were determined from the urinary concentrations. The bound fraction of prucalopride (fb) was calculated as fb = 1 − fu, and was expressed as a percentage.

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Statistical Analysis

All of the statistical analyses were performed with Statistical Analysis System software, version 6.12 (SAS Institute Inc, Cary, NC). The efficacy analysis included all of the children who took at least 1 dose of prucalopride and provided any postbaseline data for ≥1 efficacy variable (intent-to-treat population).

Descriptive statistics (mean ± standard deviation [SD], minimum [min], maximum [max]) were calculated for all pharmacokinetic parameters. Steady-state plasma concentrations obtained during the 8-week extension period were normalized to the 0.03 mg/kg starting dose and summarized (mean ± SD) according to treatment duration (weeks 2, 4, and 8) and postdose sampling time interval (0–6 hours, >6–12 hours, >12–18 hours, >18–24 hours, and >24 hours).

Efficacy parameters were summarized using descriptive statistics. The average number of bowel movements in the toilet per week, the average number of episodes of fecal incontinence per week, the reimpaction rate, and stool consistency scores were calculated for each week. Global assessment of improvement was analyzed for each visit.

Adverse events were coded according to World Health Organization–preferred terms and summarized by body system and preferred term. Additional analyses were performed for 5 specific adverse events (abdominal pain, nausea, vomiting, diarrhea, and headache) to assess the percentage of these events with onset in week 1 and the percentage of these events with onset on each day of week 1.

For laboratory tests, the proportion of children with values at baseline within and outside of normal limits during the study was calculated for each visit time point. Descriptive statistics were calculated per visit for vital signs, laboratory data, and electrocardiogram data, for both observed values and changes from baseline.

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Thirty-eight children received a single oral dose of 0.03 mg/kg prucalopride. Most children were white (87%) and boys (66%). The mean age, height, body weight, and body mass index at study entry were 8 years, 129.2 cm, 30.0 kg, and 17.2 kg/m2, respectively (Table 1). All 38 children completed the pharmacokinetic and safety assessments up to 72 hours after dosing.



Thirty-seven of the 38 children entered the 8-week extension study. The total duration from first medication intake through the last contact date in the extension phase was 55 days (range 7–74 days). The mean daily dose per kilogram of body weight increased slightly during the study, from approximately 0.021 to 0.025 mg · kg−1 · day−1. Overall, the mean (SD) daily dose was 0.024 (0.0058) mg/kg.

All of the children had received previous therapy for functional constipation, of which 36 children (97%) received laxative-type medications. Commonly used were mineral oil (27 children, 73%), lactulose (17 children, 46%), senna fruit (16 children, 43%), magnesium hydroxide (14 children, 38%) and Fleet enema (13 children, 35%), and cisapride (9 children, 24%).

Five of the 37 children (14%) discontinued the study prematurely for reasons of insufficient response (2 children, 5%), loss to follow-up, noncompliance, or withdrawal of consent (1 child each, 3%). Twenty-one (57%) children used laxative-type concomitant therapies, with mineral oil (9 children, 24%) and bisacodyl (4 children, 11%) being the most common. Other concomitant laxative-type therapies included enema, Fleet enema, liquid paraffin, polycarbophil calcium, sennoise A + B (2 children each, 5%) and Haley M-O, lactulose, mineral oil emulsion, Philips Laxcaps, senna, and Travad phosphate enema (1 child each, 3%). None of the children discontinued prucalopride because of adverse events.

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Single-dose pharmacokinetic parameters are summarized in Table 2. Prucalopride was rapidly absorbed, with limited interpatient variability in Cmax and AUC (coefficient of variation of 16.4% and 16.3%, respectively). Cmax was generally reached within 2 hours after dosing. Distribution was rapid, followed by a slower apparent elimination phase, which had an average t1/2 of 19 hours. Mean CLR and CL/F were 0.25 and 0.46 L · h−1 · kg−1, respectively (coefficient of variation of 32.4% and 15.7%, respectively). Mean Vd/F was 12.6 L/kg (coefficient of variation of 20.3%). Plasma protein binding averaged 28.6% and was consistent across the cohort of children, all of whom had normal plasma albumin concentrations. No correlations were apparent among CLR, CL/F, Vd/F (all body weight normalized) or λz, and age (Fig. 1). Similarly, there were no apparent associations for body surface area–normalized pharmacokinetic parameters and age (data not shown).

Table 2

Table 2



Dose-normalized (to 0.03 mg/kg) plasma levels of prucalopride measured in each of the sampling windows during the 8-week continuous treatment were of the same order across treatment weeks (Table 3).

Table 3

Table 3

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All 37 children who participated in the 8-week extension study were included in the efficacy analysis. During the 8-week treatment period, 94.3% (33/35) of children achieved an average of ≥3 bowel movements per week. The weekly average number of bowel movements in the toilet normalized within 1 week of treatment to 6.9, and remained relatively stable during the 8-week treatment period (range 5.6–7.2) (Fig. 2). The overall mean for the total treatment period was 6.8 bowel movements in the toilet per week. The average number of episodes of fecal incontinence per week declined from 5.6 in week 1 to 3.4 in week 8 (Fig. 3), with an overall mean for the total treatment period of 4.2 episodes per week.





Reimpaction requiring disimpaction with a treatment of investigator's choice was infrequent. The highest weekly rates were observed in weeks 1 (0.08) and 8 (0.07). The rate remained constant between weeks 2 and 7 (range 0.05–0.06).

Stool consistency normalized during treatment as demonstrated by much higher frequencies of formed stools than hard, loose, or liquid stools. The average number of days with no stools passed per week decreased during the first 3 weeks of treatment from 2.3 to 1.8. For the remainder of the treatment period, the average number of days with no passed stools per week was stable, ranging from 1.9 to 2.1.

The percentage of parents rating their child's improvement as either much or very much improved was 42% at week 2, 65% at week 4, 67% at week 6, and 55% at week 8. The percentage of investigators rating a child's improvement as either much or very much improved was similar, with 41% at week 2, 65% at week 4, 70% at week 6, and 58% at week 8.

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Safety and Tolerability

Safety and tolerability data obtained during the 8-week extension study were consistent with those obtained after single-dose administration. During the 8-week extension, 26 of 37 children (70%) experienced at least 1 adverse event. The most common adverse events, reported in 10% or more of children, were headache (9 children, 24%), abdominal pain (8, 22%), upper respiratory tract infection (7 children, 19%), injury (6 children, 16%), fever, viral infection (5 children each, 14%), coughing, vomiting, and abnormal laboratory values (4 children each, 11%). All 4 children with abnormal laboratory values had a decreased white blood cell count. In 2 of these 4 children, the white blood cell count had normalized by week 8. For the other 2 children, no data were available at week 8 because of premature discontinuation for reasons of noncompliance and loss to follow-up. Of the most common adverse events, abdominal pain, headache, upper respiratory tract infection, coughing, and abnormal laboratory value had a greater frequency of onset in the first 4 weeks of treatment than in the second 4 weeks of treatment. Four of the 15 events of abdominal pain (27%), both events of diarrhea (without fecal incontinence, 100%), and 5 of the 14 events of headache (36%) were reported in week 1. Concomitant medication was used to treat headache in 11 of 14 events. The duration of headache was ≤1 day in 12 of 14 events and all subjects recovered.

All reported adverse events during the 8-week extension were of mild or moderate severity, with the exception of severe abdominal pain in 1 child. Seven (19%) children had adverse events that were considered by the investigators to be probably related to prucalopride treatment (abdominal pain, headache, fecal incontinence). No serious adverse events occurred and none of the adverse events reported led to premature discontinuation from the study. None of the changes at any time point in QTcB, QTcF, QT interval, heart rate, or QRS interval were clinically significant. Two subjects had a QTcB increase of >30 mseconds, with the QTcB intervals classified as normal. In addition, there were no changes or apparent trends over time in vital signs or clinical laboratory parameters.

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In this study, we evaluated the pharmacokinetic profile of prucalopride in children 4 years or older to 12 years or younger with functional constipation and collected preliminary data on its efficacy in the treatment of functional constipation in this population. Single-dose prucalopride was administered as an oral solution at a dose of 0.03 mg/kg, which is equivalent to a 2-mg dose in a 67-kg adult. The approved therapeutic dose in adults is 2 mg once per day. During continuous treatment, the daily dose fluctuated between 0.02 and 0.03 mg/kg.

In adults, the absolute bioavailability of prucalopride is >90%, indicating that absorption after oral dosing is almost complete and that no appreciable first-pass metabolism occurs (12). Therefore, CL/F and Vd/F may be considered reliable estimates of the true CL and Vd of prucalopride. Moreover, a study in healthy adults showed that the oral solution and the tablet formulations of prucalopride used in studies in adults are bioequivalent in rate and extent of absorption (data on file, Shire-Movetis NV).

Prucalopride pharmacokinetic parameters in children determined in this study displayed limited interpatient variability, with coefficients of variation of approximately 16% for Cmax, AUC, and CL/F, 32.5% for CLR, and 20% for Vd/F. Because the fixed dose of 2 mg in adults is close to the 0.03 mg/kg used in this study (ie, 2 mg in a 70-kg subject equals 0.029 mg/kg), a direct comparison with adult Cmax and AUC appeared reasonable. In this comparison, the Cmax in children was approximately 15% lower than in adults, whereas total exposure (AUC) was 30% to 40% lower. Cmax values in this study were attained at a mean tmax of 1.8 hours, indicating that absorption in children may occur somewhat faster than in adults where mean tmax values generally range from 2 to 3 hours (data on file, Shire-Movetis NV). Apparent oral clearance in children 4 to 12 years of age as determined in this study was on average 60% to 75% higher than in healthy adults (14; data on file, Shire-Movetis NV); however, within the 4- to 12-year age range, no correlation between CL/F and age was apparent. Moreover, as in adults, CLR accounted for >50% of apparent total body clearance. Vd was roughly on the same order or somewhat (20%) higher than in adults (14; data on file, Shire-Movetis NV). No correlation was observed between λz and age, and the t1/2 of 19 hours observed in children was at the lower end of the range of similar values reported from adult studies. Protein binding of prucalopride in the children (28.6%) was comparable with values (28%–33%) reported in adults (12,14).

Because the dose was not constant in the 8-week extension phase, plasma samples were dose normalized to 0.03 mg/kg to allow a direct comparison with adult data. Pharmacokinetic samples in the extension phase were taken at different time points postdose (within and between subjects), and dose-normalized steady-state plasma levels of each visit were averaged according to postdose windows. Within each sampling time window, plasma levels were on the same order for all visits, indicating that no further accumulation occurred with longer treatment duration. Samples obtained in the 18- to 24-hour postdose window can be considered near-trough plasma levels. Trough plasma concentrations at steady state in adults treated with 2 mg once per day were on average 2.5 ng/mL (12,14). The near-trough levels in the present study suggest that also at steady state, systemic exposure may be somewhat lower in children than in adults (12); however, the data are too limited to draw quantitative conclusions.

The results for clinical efficacy collected in the 8-week extension study demonstrated that prucalopride improved the frequency of bowel movements in the toilet, as well as the stool consistency. Although this was an open-label study with no baseline assessment, children entering the study were required to have a minimum 2-month history of fecal impaction and >3 bowel movements in the toilet per week and/or fecal incontinence. In addition, children were disimpacted if needed to obtain a similar baseline for all children. During treatment, the average number of bowel movements in the toilet normalized to a mean of 6.8/week, whereas the average number of episodes of fecal incontinence declined considerably from 5.6 in week 1 to 3.4 in week 8. This suggests that during an 8-week period, prucalopride efficacy was apparent, with a benefit seen at week 1 that was maintained during the entire course of treatment. This was corroborated by global assessments performed by both the parent and the investigator with comparable reports of improvement.

This study was initiated before the publication of the first Rome pediatric criteria in 1999. Enrollment into the study was restricted to children 4 years or older to 12 years or younger, an age range at which constipation frequently occurs, with a confirmed diagnosis of functional constipation. The definition of functional constipation in our study reflects important parts of the current Rome III criteria in children 4 years or older (15). Therefore, the results of our study are likely generalizable to most children with functional constipation as presently defined.

No gastrointestinal prokinetic agents are presently approved for the treatment of functional constipation in children. Some years ago, cisapride was investigated as a possible treatment for this condition (16–23). The benefits of this agent did not appear to outweigh the risks of perceived adverse cardiac events associated with the drug (24), which, in many countries, has resulted in its withdrawal from the market. Present guidelines for childhood functional constipation recommend mineral oil (a lubricant) or magnesium hydroxide, lactulose, sorbitol, polyethylene glycol (osmotic laxatives), or a combination of lubricant and laxative when daily medication is necessary (2); however, well-designed placebo-controlled studies that support efficacy of these agents in pediatric patients are limited (25,26). The paucity of evidence-based information to guide treatment options in childhood constipation leaves many clinicians with limited options (27). Polyethylene glycol was only available as a laxative toward the end of the studies and is therefore not listed as concomitant medication.

In the present study, the adverse event profile of prucalopride oral solution in children with functional constipation appeared similar to that observed in adults (7–9). Common adverse events that the investigators considered to be related to prucalopride use included gastrointestinal events (attributable to its pharmacodynamic effects) and headache. The incidence of adverse events appeared highest in the first weeks of treatment and decreased thereafter. No new tolerability signals, previously undetected in adults, were seen in this study.

Because of its selective profile, prucalopride is expected to have a wider safety margin than other 5-HT4 agonists. Prucalopride has been shown to have a high affinity and selectivity for 5-HT4 receptors; its affinity for these receptors is at least 150 times that for other receptors. Prucalopride has a 50% inhibitory concentration (IC50) of 8140 ng/mL in attenuating the potassium current (Ikr) in the human ether-à-go-go–related gene-transfected human embryonic kidney cell model. This is >2000 times the average Cmax value of 3.8 ng/mL observed in the present study. In contrast, other 5-HT4 receptor agonists, such as tegaserod and cisapride, have affinity for other receptors or channels, including the 5-HT1,2 receptor (tegaserod) and human ether-à-go-go–related gene channel (cisapride), which is in the same range as their affinity for the 5-HT4 receptor and may contribute to the less favorable benefit–risk profile of these compounds (28,29). A randomized, double-blind, placebo- and positive-controlled thorough QT study in healthy volunteers showed that prucalopride administered at doses up to 10 mg had no clinically relevant effects on the QT interval (30).

In conclusion, the results of this multicenter, open-label, phase I study show that a dose of 0.02 to 0.03 mg/kg prucalopride oral solution in children 4 years or older to 12 years or younger with functional constipation appeared to be well tolerated and potentially clinically effective. Although the pharmacokinetics of a single 0.03-mg/kg prucalopride dose in children were generally comparable with those observed in adults, our data reflect a lower systemic exposure in children. A possible effect of age on clearance and distribution is to be further explored. Future studies to substantiate the pharmacokinetics and exposure–response relations for prucalopride in children with functional constipation and its efficacy and safety appear warranted.

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We thank the following site co-investigators for their participation in the study: Jeffrey L. Blumer, MD, PhD, University Hospitals of Cleveland, Cleveland, OH; Charles Hodge, MD, University of Missouri-Kansas City School of Medicine, Kansas City, MO; and Colin Rudolph, MD, PhD, Children's Hospital Medical Center, Cincinnati, OH. We thank Anita van den Oetelaar for medical writing assistance, David Pierce (Shire) and Vera Van de Velde for their review of the manuscript, and Slavka Baronikova (Shire-Movetis NV) and Louisa Howard (Oxford PharmaGenesis) for editorial assistance.

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efficacy; functional constipation; pharmacokinetics; prucalopride; tolerability

© 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,