Tissue distribution and abuse potential of prucalopride: findings from non-clinical and clinical studies

BACKGROUND: Prucalopride is a selective serotonin type 4 (5-HT(4)) receptor agonist indicated for treatment of chronic idiopathic constipation (CIC) in adults (2 mg orally, daily). 5-HT(4) receptors are present in the central nervous system; therefore, non-clinical and clinical assessments were performed to evaluate the tissue distribution and abuse potential of prucalopride. METHODS: In vitro receptor-ligand binding studies were performed to assess the affinity of prucalopride (≤1 mM) for peptide receptors, ion channels, monoamine neurotransmitters and 5-HT receptors. The tissue distribution of (14)C-prucalopride (5 mg base-equivalent/kg) was investigated in rats. Behavioural assessments in mice, rats and dogs after treatment with single or repeated (up to 24 months) subcutaneous or oral doses of prucalopride (0.02–640 mg/kg across species) were performed. Treatment-emergent adverse events possibly indicative of abuse potential during prucalopride CIC clinical trials were evaluated. RESULTS: Prucalopride showed no appreciable affinity for the receptors and ion channels investigated; its affinity (at ≤100 μM) for other 5-HT receptors was 150–10,000 times lower than that for the 5-HT(4) receptor. In rats, <0.1% of the administered dose was found in the brain and concentrations were below the limit of detection within 24 hours. At supratherapeutic doses (≥20 mg/kg), mice and rats exhibited palpebral ptosis, and dogs exhibited salivation, eyelid tremors, decubitis, pedalling movements and sedation. All clinical treatment-emergent adverse events, possibly indicative of abuse potential, except dizziness, occurred in <1% of patients treated with prucalopride or placebo. CONCLUSION: This series of non-clinical and clinical studies suggest low abuse potential for prucalopride.