title: Development of a population pharmacokinetic model of prucalopride in children with functional constipation.
abstract: A recent phase 3 trial of prucalopride in children with functional constipation (SPD555-303 ClinicalTrials.gov Identifier: NCT01330381) reported negative efficacy results. Here, we developed a population pharmacokinetic (PK) model of prucalopride in children to assess prucalopride exposure in SPD555-303. An initial population PK model in children was developed based on sampled single-dose data from a phase 1 study (PRU-USA-12). This model was subsequently updated with sampled data from SPD555-303 and used to simulate plasma concentration-time profiles for children aged 6 months to 18 years who were treated once daily with prucalopride 0.02, 0.04, or 0.06 mg kg-1(maximum dose, 2 mg). Simulated PK profiles were compared with those of adults at the recommended dose of 2 mg once daily. Data were available from 38 patients (median age, 8.5 years) in PRU-USA-12 and 137 patients (median age, 7.9 years) in SPD555-303. Mean (range) area under the plasma concentration-time curve (AUC) at steady state was 62.3 (40.5-82.7) ng mL-1h (dose, 0.03 mg kg-1) in PRU-USA-12 and 100.3 (22.7-286.0) ng mL-1h (dose, 0.04 mg kg-1; maximum, 2 mg) in SPD555-303. Prucalopride 0.04 mg kg-1once daily in children produced similar maximum plasma concentrations and approximately 10% lower AUC compared with adults receiving 2 mg once daily. This population PK analysis indicates that the PK profile of prucalopride in children in SPD555-303 was similar to that observed in adults. The negative efficacy results of SPD555-303 cannot be explained by differences in prucalopride exposure between children and adults.
authors.affiliation: SGS Exprimo NV Mechelen Belgium.
authors.forename: Erno
authors.initials: E
authors.lastname: van Schaick
authors.affiliation: Division of Pediatric Gastroenterology and Nutrition Emma Children's Hospital/Academic Medical Center Amsterdam Netherland.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Benninga
authors.affiliation: Shire Lexington, Massachusetts USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Levine
authors.affiliation: Pharmetheus AB U-A Science Park Uppsala Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Magnusson
authors.affiliation: Shire Lexington, Massachusetts USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Troy
keywords: Children; constipation; pediatric; population pharmacokinetics; prucalopride