Nonclinical assessment of carcinogenic risk and tumor growth enhancement potential of prasugrel, a platelet-inhibiting therapeutic agent.

Prasugrel, a thienopyridine ADP receptor antagonist, is an orally administered prodrug requiring in vivo metabolism to form the active metabolite that irreversibly inhibits platelet activation and aggregation mediated by the P2Y12[sub 12] receptor. A comprehensive nonclinical safety assessment including genotoxicity and carcinogenicity studies supported the chronic use of prasugrel in patients with atherothrombotic disease. In addition, a special assessment of the potential for prasugrel to enhance tumor growth was undertaken to address regulatory concerns relating to increases in human cancers. Prasugrel demonstrated no evidence of genotoxicity and was not oncogenic in a 2-year rat carcinogenicity study. In the 2-year mouse study, an increase in hepatocellular adenomas was considered secondary to enzyme induction and not relevant to human safety. Further, the absence of any increase in common background tumors at any other organ site in either rodent study indicated a lack of tumor promoting activity (apart from the CYP450 induction-related increase in mouse liver tumors). Cell culture studies with 3 human tumor cell lines (lung, colon, prostate) demonstrated that exposure of serum-starved cells to prasugrel's active and major circulating human metabolites does not increase cell proliferation relative to starved cells stimulated to proliferate by addition of 10% FBS. Prasugrel also did not increase tumor growth relative to vehicle controls in nude mice implanted with 3 human tumor cell lines. Thus, traditional genotoxicity and 2-year bioassays as well as specially designed tumor growth enhancement studies in human tumor cell lines and mouse xenograft models clearly demonstrated prasugrel's lack of tumorigenic potential.