Background: Several tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity\ndue to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs\nare attractive candidates for â??repurposingâ? as anti-viral agents. However, clinical evaluation of therapeutics against\ninfectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United\nStates Food and Drug Administration formulated the â??Animal Ruleâ? to facilitate use of validated animal models for\nconducting anti-viral efficacy studies.\nMethods: To enable such efficacy studies of two clinically approved TKIs, nilotinib, and imatinib, we first conducted\ncomprehensive pharmacokinetic (PK) studies in relevant rodent and non-rodent animal models. PK of these agents\nfollowing intravenous and oral dosing were evaluated in C57BL/6 mice, prairie dogs, guinea pigs and Cynomolgus\nmonkeys. Plasma samples were analyzed using an LC-MS/MS method. Secondarily, we evaluated the utility of\nallometry-based inter-species scaling derived from previously published data to predict the PK parameters, systemic\nclearance (CL) and the steady state volume of distribution (Vss) of these two drugs in prairie dogs, an animal model\nnot tested thus far.\nResults: Marked inter-species variability in PK parameters and resulting oral bioavailability was observed. In general,\nelimination half-lives of these agents in mice and guinea pigs were much shorter (1â??3 h) relative to those in larger\nspecies such as prairie dogs and monkeys. The longer nilotinib elimination half-life in prairie dogs (i.v., 6.5 h and\noral, 7.5 h), facilitated multiple dosing PK and safety assessment. The allometry-based predicted values of the Vss\nand CL were within 2.0 and 2.5-fold, respectively, of the observed values.\nConclusions: Our results suggest that prairie dogs and monkeys may be suitable rodent and non-rodent species to\nperform further efficacy testing of these TKIs against orthopoxvirus infections. The use of rodent models such as\nC57BL/6 mice and guinea pigs for assessing pre-clinical anti-viral efficacy of these two TKIs may be limited due to\nshort elimination and/or low oral bioavailability. Allometry-based correlations, derived from existing literature data,\nmay provide initial estimates, which may serve as a useful guide for pre-clinical PK studies in untested animal\nmodels.
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