Carcinogenesis

In a 2-year carcinogenicity study in mice, prucalopride was given by daily oral gavage at doses of 10, 20, and 80 mg/kg. An increased incidence of mammary gland adenocarcinomas was observed in female mice at 80 mg/kg/day. The finding is considered rodent-specific. No significant neoplastic changes were seen in male mice dosed up to 80 mg/kg/day and in female mice dosed up to 20 mg/kg/day (exposure ratio of 219 and 24 times the human dosage of 2 mg per day in male and female mice, respectively, based on AUC).

In a 2-year carcinogenicity study in rats, prucalopride was given by daily oral gavage at doses of 5, 20, and 80 mg/kg in males and 5, 10, and 40 mg/kg in females. In male and female rats there was a significant increase in the incidences of benign tumors, including hepatocellular adenomas, thyroid follicular adenomas, and mammary gland fibroadenomas. An increased incidence of pituitary adenomas, pancreas islet cell adenomas, and adrenal gland benign pheochromocytomas was also seen in male rats. The increases in neoplastic changes occurred primarily at the high dose of 80 mg/kg/day in male rats and 40 mg/kg/day in female rats (exposure ratios 556 times (males) and 495 times (females) the human dosage of 2 mg per day, based on AUC). There was no significant increase in tumor incidence at doses up to 20 mg/kg/day in male rats and up to 10 mg/kg/day in female rats (exposure ratios of 63 and 40 times the human dosage of 2 mg per day in male and female rats, respectively, based on AUC).

In a 12-month carcinogenicity study in neonatal mice, prucalopride was administered by oral gavage at total dosages of 75, 150, and 300 mg/kg given across 2 doses on day 8 of age (one-third of total dosage) and day 15 of age (two-thirds of total dosage). Prucalopride was not tumorigenic at doses up to 300 mg/kg (>1600 times the human exposure at 2 mg per day, based on AUC).

Mechanistic studies demonstrated that the increase in tumor incidence in rodents related to stimulation of prolactin in endocrine tissues was associated with dopamine D2 antagonist activity. The hepatic and thyroid tumors were due to induction of enzymes in liver and subsequent disruption of thyroid homeostasis.

Mutagenesis

Prucalopride was tested in a battery of assays, including the Ames bacterial mutation assay in Salmonella typhimurium and Escherichia coli, mouse lymphoma assay, chromosomal aberration assays in human lymphocytes, micronucleus test in mice, Vitotox test, and in vitro Unscheduled DNA Synthesis (UDS) studies. Prucalopride tested positive in the Ames bacterial mutation assay in the S. typhimurium TA100 strain, at concentrations ≥500 mcg/plate, both in the presence and absence of metabolic activation. Prucalopride was negative in other assays evaluating mutagenesis, including in vitro mammalian-based assays (e.g., mouse lymphoma assay, chromosomal aberration assays in human lymphocytes) and in vivo tests (e.g., micronucleus test in mice, a UDS test, a gene mutation assay in Big Blue transgenic rats, and a 32P-postlabeling study in target tissues identified in the carcinogenicity studies, including liver, mammary gland, thyroid, and adrenal tissues). Based on the weight of evidence, prucalopride does not appear to have a mutagenic potential.

Impairment of Fertility

In an oral fertility and early embryonic development study performed in rats at doses of 5, 20, and 80 mg/kg/day, there was no evidence of adverse effects on fertility at doses up to 20 mg/kg. At the highest dose of 80 mg/kg (about 390 times the recommended human dose of 2 mg/day, based on body surface area), an increase in pre-coital interval, pseudo-pregnancies, and pre-implantation loss were seen. These effects could be secondary to increased prolactin secretion with prucalopride treatment.