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: email@example.com).
Received 20 September, 2012
Accepted 18 March, 2013
http://www.clinicaltrials.gov 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.