title: Mode of action associated with development of hemangiosarcoma in mice given pregabalin and assessment of human relevance.
abstract: Pregabalin increased the incidence of hemangiosarcomas in  carcinogenicity studies of 2-year mice but was not tumorigenic in rats. Serum bicarbonate increased within 24 h of pregabalin administration in mice and rats. Rats compensated appropriately, but mice developed metabolic alkalosis and increased blood pH. Local tissue hypoxia and increased endothelial cell proliferation were also confirmed in mice alone. The combination of hypoxia and sustained increases in endothelial cell proliferation, angiogenic growth factors, dysregulated erythropoiesis, and macrophage activation is proposed as the key event in the mode of action (MOA) for hemangiosarcoma formation. Hemangiosarcomas occur spontaneously in untreated control mice but occur only rarely in humans. The International Programme on Chemical Safety and International Life Sciences Institute  developed a Human Relevance Framework (HRF) analysis whereby presence or absence of key events can be used to assess human relevance. The HRF combines the MOA with an assessment of biologic plausibility in humans to assess human relevance. This manuscript compares the proposed MOA with Hill criteria, a component of the HRF, for strength, consistency, specificity, temporality, and dose response, with an assessment of key biomarkers in humans, species differences in response to disease conditions, and spontaneous incidence of hemangiosarcoma to evaluate human relevance. Lack of key biomarker events in the MOA in rats, monkeys, and humans supports a species-specific process and demonstrates that the tumor findings in mice are not relevant to humans at the clinical dose of pregabalin. Based on this collective dataset, clinical use of pregabalin would not pose an increased risk for hemangiosarcoma to humans.
authors.affiliation: Pfizer Worldwide Research & Development, Drug Safety Research & Development, Groton, Connecticut 06340, USA. kay.criswell@pfizer.com
authors.forename: Kay A
authors.initials: KA
authors.lastname: Criswell
authors.forename: Jon C
authors.initials: JC
authors.lastname: Cook
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Wojcinski
authors.forename: David
authors.initials: D
authors.lastname: Pegg
authors.forename: James
authors.initials: J
authors.lastname: Herman
authors.forename: David
authors.initials: D
authors.lastname: Wesche
authors.forename: John
authors.initials: J
authors.lastname: Giddings
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Brady
authors.forename: Timothy
authors.initials: T
authors.lastname: Anderson
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D006394:Hemangiosarcoma / Q000139:chemically induced* / Q000473:pathology; D006801:Humans; D008262:Macrophage Activation; D051379:Mice; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid