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

van Schaick E, Benninga MA, Levine A, Magnusson M, Troy S

Pharmacol Res Perspect 4 (4) e00236 [2016-08-00; online 2016-06-01]

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.

PubMed 27891230

DOI 10.1002/prp2.236

Crossref 10.1002/prp2.236

pmc: PMC5114692
pii: PRP2236
ClinicalTrials.gov: NCT01330381