title: A Comparative Oncology Study of Iniparib Defines Its Pharmacokinetic Profile and Biological Activity in a Naturally-Occurring Canine Cancer Model.
abstract: Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regarding its mechanism of action, the activity of its metabolites, and their potential accumulation in tumors. Due to strong similarities in metabolism of iniparib between humans and dogs, a veterinary clinical trial in pet dogs with spontaneous cancers was designed to answer specific questions pertaining to pharmacokinetic exposures and tolerability of iniparib. Dogs were treated with iniparib alone and in combination with carboplatin chemotherapy. Iniparib doses ranged between 10-70 mg/kg intravenously (IV). Plasma, tumor and normal tissue samples were collected before and at various time points scheduled after exposure for pharmacokinetic and biologic analysis. The primary endpoints included characterization of dose-limiting toxicities (DLT) and determination of the drug exposures that could be achieved in both normal and tumor tissues. Nineteen dogs were treated. DLT included fever, anorexia, diarrhea, neutropenia, and thrombocytopenia; most effects were attributable to carboplatin based on the timing of adverse event onset. The maximum tolerated dose (MTD) of iniparib was not identified. Moderate to high variability in plasma exposure was noted for iniparib and all metabolites between animals. When quantifiable, iniparib and metabolite plasma:tumor ratios were < 0.088 and <1.7, respectively. In this study, iniparib was well tolerated as a single agent and in combination with carboplatin over a range of doses. However, clinically relevant concentrations of the parent drug and selected metabolites were not detectable in canine tumor tissues at any studied dose, thus eliminating expectations for clinical responses in dogs or humans. Negative clinical trials in humans, and the uncertainties of its mechanism of action, ultimately led to the decision to stop clinical development of the drug. Nevertheless, the questions that can be asked and answered within the comparative oncology approach are evident from this successfully executed comparative clinical trial and exemplify the value of such studies in drug development.
authors: College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of America.
authors: Corey
authors: C
authors: Saba
authors: Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Melissa
authors: M
authors: Paoloni
authors: Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Christina
authors: C
authors: Mazcko
authors: College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors: William
authors: W
authors: Kisseberth
authors: College of Veterinary Medicine and Biological Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Jenna H
authors: JH
authors: Burton
authors: College of Veterinary Medicine, Auburn University, Auburn, Alabama, United States of America.
authors: Annette
authors: A
authors: Smith
authors: College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America.
authors: Heather
authors: H
authors: Wilson-Robles
authors: School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
authors: Sara
authors: S
authors: Allstadt
authors: School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors: David
authors: D
authors: Vail
authors: College of Veterinary Medicine, University of Missouri-Columbia, Columbia, Missouri, United States of America.
authors: Carolyn
authors: C
authors: Henry
authors: College of Veterinary Medicine and Biological Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Susan
authors: S
authors: Lana
authors: College of Veterinary Medicine and Biological Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors: E J
authors: EJ
authors: Ehrhart
authors: College of Veterinary Medicine and Biological Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Brad
authors: B
authors: Charles
authors: School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
authors: Michael
authors: M
authors: Kent
authors: College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of America.
authors: Jessica
authors: J
authors: Lawrence
authors: School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, United States of America.
authors: Kristine
authors: K
authors: Burgess
authors: College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America.
authors: Antonella
authors: A
authors: Borgatti
authors: College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Steve
authors: S
authors: Suter
authors: Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
authors: Paul
authors: P
authors: Woods
authors: Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Ira
authors: I
authors: Gordon
authors: Sanofi Aventis, Guesde, Vitry-sur-Seine, 94403 Cedex, France.
authors: Patricia
authors: P
authors: Vrignaud
authors: Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Chand
authors: C
authors: Khanna
authors: Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Amy K
authors: AK
authors: LeBlanc
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001549:Benzamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000662:veterinary*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C090712:iniparib