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A Comparative Oncology Study of Iniparib Defines Its Pharmacokinetic Profile and Biological Activity in a
Corey Saba1, Melissa Paoloni2, Christina Mazcko2
1College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of America.
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.
Insights
This veterinary trial found iniparib was well-tolerated in dogs, but parent drug and metabolite concentrations were undetectable in tumors, hindering anti-cancer efficacy. Comparative oncology studies remain valuable for drug development.
Area of Science:
- Comparative Oncology
- Pharmacokinetics
- Drug Development
Background:
- Iniparib's anti-cancer development faced challenges due to unclear mechanism of action and metabolite activity.
- Similarities in iniparib metabolism between humans and dogs supported a comparative veterinary trial.
Purpose of the Study:
- To assess pharmacokinetic exposures and tolerability of iniparib in pet dogs with spontaneous cancers.
- To determine dose-limiting toxicities (DLT) and achievable drug exposures in normal and tumor tissues.
Main Methods:
- Nineteen dogs received iniparib intravenously (IV) alone or with carboplatin, at doses from 10-70 mg/kg.
- Plasma, tumor, and normal tissue samples were analyzed for iniparib and metabolite concentrations.
- Pharmacokinetic and biologic analyses were performed to characterize drug exposure and toxicity.
Main Results:
- Iniparib was generally well-tolerated, with toxicities often attributed to carboplatin.
- High variability in plasma exposure of iniparib and metabolites was observed.
- Clinically relevant concentrations of iniparib and metabolites were not detected in canine tumor tissues.
Conclusions:
- Iniparib demonstrated good tolerability in dogs, but lack of tumor penetration limits efficacy expectations.
- The study highlights the value of comparative oncology trials in addressing drug development questions.
- Despite trial outcomes, the comparative approach provided valuable insights into drug behavior.
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