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Author Notes:

Correspondence: pankaj.desai@uc.edu

Study design, data collection, analysis, interpretation, and preparation of the manuscript were done independently by the investigators.

HA, MB, DK, VO, DI, CS, MW, PD participated in the conception and design of the study, acquisition of data, and analysis and interpretation of results.

HA, ET, SP, GP, JS, NG, MT, LS participated in the conception of the pharmacokinetic studies.

HA and LS participated in the analysis of plasma samples and interpretation of results.

HA drafted the manuscript, with MW and PD revised it carefully for important intellectual content.

All authors reviewed the manuscript, provided critical feedback and approved the final manuscript.

We are thankful to M. Shannon Keckler, Scott Smith, Jessica Ayers, Julian Jolly, and Paul Hudson for their assistance in sample collection in studies in prairie dogs.

CS is a member of the editorial board (Section Editor) of this journal.

The authors declare that they have no competing interests.

This work was performed under contract HDTRA112C0051 from the Defense Threat Reduction Agency, DoD to Inhibikase Therapeutics. The principal investigator under the contract was Dr. Milton H. Werner who is also the Chief Executive and Chief Scientific Officer of Inhibikase Therapeutics, Inc. Dr. Werner is a substantial shareholder in Inhibikase Therapeutics. The funds provided to the University of Cincinnati under this contract were the sole source of funds to the University provided by Inhibikase Therapeutics. Dr. Werner was actively involved in the design of the study and the interpretation of the data, but was not a principal author of the manuscript.

Subjects:

Research Funding:

The work was funded by the Defense Threat Reduction Agency under Contract #HDTRA112C0051 to Inhibikase Therapeutics, Inc.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Pharmacology & Pharmacy
  • Toxicology
  • Tyrosine kinase inhibitor
  • Pharmacokinetics
  • Allometry
  • Animal rule
  • VIRUS-INFECTION
  • ANIMAL-MODELS
  • PRAIRIE DOGS
  • US FOOD
  • EFFICACY
  • PLASMA
  • ST-246
  • PATHOGENESIS
  • METABOLISM
  • ABSORPTION

Preclinical pharmacokinetic evaluation to facilitate repurposing of tyrosine kinase inhibitors nilotinib and imatinib as antiviral agents

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Journal Title:

BMC Pharmacology and Toxicology

Volume:

Volume 19, Number 1

Publisher:

, Pages 80-80

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: Several tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity due to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs are attractive candidates for "repurposing" as anti-viral agents. However, clinical evaluation of therapeutics against infectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United States Food and Drug Administration formulated the "Animal Rule" to facilitate use of validated animal models for conducting anti-viral efficacy studies. Methods: To enable such efficacy studies of two clinically approved TKIs, nilotinib, and imatinib, we first conducted comprehensive pharmacokinetic (PK) studies in relevant rodent and non-rodent animal models. PK of these agents following intravenous and oral dosing were evaluated in C57BL/6 mice, prairie dogs, guinea pigs and Cynomolgus monkeys. Plasma samples were analyzed using an LC-MS/MS method. Secondarily, we evaluated the utility of allometry-based inter-species scaling derived from previously published data to predict the PK parameters, systemic clearance (CL) and the steady state volume of distribution (Vss) of these two drugs in prairie dogs, an animal model not tested thus far. Results: Marked inter-species variability in PK parameters and resulting oral bioavailability was observed. In general, elimination half-lives of these agents in mice and guinea pigs were much shorter (1-3 h) relative to those in larger species such as prairie dogs and monkeys. The longer nilotinib elimination half-life in prairie dogs (i.v., 6.5 h and oral, 7.5 h), facilitated multiple dosing PK and safety assessment. The allometry-based predicted values of the Vss and CL were within 2.0 and 2.5-fold, respectively, of the observed values. Conclusions: Our results suggest that prairie dogs and monkeys may be suitable rodent and non-rodent species to perform further efficacy testing of these TKIs against orthopoxvirus infections. The use of rodent models such as C57BL/6 mice and guinea pigs for assessing pre-clinical anti-viral efficacy of these two TKIs may be limited due to short elimination and/or low oral bioavailability. Allometry-based correlations, derived from existing literature data, may provide initial estimates, which may serve as a useful guide for pre-clinical PK studies in untested animal models.

Copyright information:

© 2018 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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