Oral Prucalopride in Children With Functional Constipation

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]) C-max, t(max), 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 C-max and AUC. Mean (SD) t(1/2) 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.