Development of a population pharmacokinetic model of prucalopride in children with functional constipation

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(−1) h (dose, 0.03 mg kg(−1)) in PRU‐USA‐12 and 100.3 (22.7–286.0) ng mL(−1) h (dose, 0.04 mg kg(−1); maximum, 2 mg) in SPD555‐303. Prucalopride 0.04 mg kg(−1) once 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.