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

• Type of Material: Article
• Authors: Hari Krishna Ananthula, University of Cincinnati; Scott Parker, St Louis University; Erin Touchette, St Louis University; R. Mark Buller, St Louis University; Gopi Patel, Emory University; Daniel Kalman, Emory University; Johanna S. Salzer, Centers for Disease Control and Prevention; Nadia Gallardo-Romero, Centers for Disease Control and Prevention; Victoria Olson, Centers for Disease Control and Prevention; Inger Damon, Emory University; Tessa Moir-Savitz, Battelle Memorial Institute; Larry Sallans, University of Cincinnati; Milton H. Werner, Inhibikase Therapeut Inc; Catherine M. Sherwin, University of Utah; Pankaj B. Desai, University of Cincinnati
• Language: English
• Date: 2018-12-04
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s40360-018-0270-x
• Title of Journal or Parent Work: BMC Pharmacology and Toxicology
• ISSN: 2050-6511
• Volume: 19
• Issue: 1
• Start Page: 80
• End Page: 80
• Grant/Funding Information: 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.; The work was funded by the Defense Threat Reduction Agency under Contract #HDTRA112C0051 to Inhibikase Therapeutics, Inc.
• Keywords: PRAIRIE DOGS; PLASMA; Allometry; Tyrosine kinase inhibitor; Pharmacology & Pharmacy; ANIMAL-MODELS; ABSORPTION; Animal rule; Science & Technology; Toxicology; PATHOGENESIS; Life Sciences & Biomedicine; VIRUS-INFECTION; US FOOD; EFFICACY; ST-246; METABOLISM; Pharmacokinetics
• Research Categories: Health Sciences, Toxicology; Health Sciences, Pharmacology; Health Sciences, Immunology

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.