title: Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part I. Biotherapeutics.
abstract: Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment.
authors.affiliation: GlaxoSmithKline-Safety Assessment, King of Prussia, Pennsylvania, USA kendall.s.frazier@gsk.com.
authors.forename: Kendall S
authors.initials: KS
authors.lastname: Frazier
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Engelhardt
authors.affiliation: WIL Research Europe, Saint-Germain-Nuelles, France.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Fant
authors.affiliation: MedImmune, Cambridge, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guionaud
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Henry
authors.affiliation: Pfizer-Drug Safety Research and Development, Andover, Massachusetts, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Leach
authors.affiliation: Raritan, Somerset, New Jersey, USA.
authors.forename: Calvert
authors.initials: C
authors.lastname: Louden
authors.affiliation: GlaxoSmithKline-Safety Assessment, King of Prussia, Pennsylvania, USA.
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Scicchitano
authors.affiliation: FDA, CDER, Silver Spring, Maryland, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Weaver
authors.forename: Tanja S
authors.initials: TS
authors.lastname: Zabka
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D057772:Vascular System Injuries / Q000139:chemically induced*
keywords: biomarkers; biotherapeutics; cardiovascular system; nonhuman primate; pharmaceutical development/products; preclinical safety–assessment/risk management; vascular injury