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

Abstract

BackgroundSeveral 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.MethodsTo 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.ResultsMarked 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.ConclusionsOur 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.

Drug Repurposing to Identify Nilotinib as a Potential SARS-CoV-2 Main Protease Inhibitor: Insights from a Computational and In Vitro Study

“…We have picked nilotinib because it had a binding free energy of above −25 kcal/mol with the M pro protein, and it has been reported to have antiviral activity. 89 Moreover, nilotinib has shown strong predicted binding interactions with the SARS-CoV-2 papain-like protease (PL pro ) active site in our preliminary study ( Figure S7 ). Recently, nilotinib was demonstrated to be efficacious against SARS-CoV-2 in vitro, strengthening our computational calculation.…”

“…We have used remdesivir as a positive control and tested three native ligands, 6LU7, 5R80, and 5R7Y (Table S6) for direct comparison against the drug candidates. We have picked nilotinib because it had a binding free energy of above −25 kcal/mol with the M pro protein, and it has been reported to have antiviral activity . Moreover, nilotinib has shown strong predicted binding interactions with the SARS-CoV-2 papain-like protease (PL pro ) active site in our preliminary study (Figure S7).…”

SARS‐CoV‐2 and SARS‐CoV: Virtual screening of potential inhibitors targeting RNA‐dependent RNA polymerase activity (NSP12)

“…Nilotinib, a second‐generation small‐molecule tyrosine kinase inhibitor, is widely used in the treatment of chronic myeloid leukemia 18 . Studies have shown that Nilotinib has a potential antiviral effect 19 . Our docking results showed that Nilotinib was mainly combined with the interface between NSP12 and NSP7 of SARS‐CoV‐2 through van der Waals potential energy and hydrogen bonds, involving LYS‐411 (Figure 2A).…”

“…18 Studies have shown that Nilotinib has a potential antiviral effect. 19 Our docking results showed that Nilotinib was mainly combined with the interface between NSP12 and NSP7 of SARS-CoV-2 through van der Waals potential energy and hydrogen bonds, involving LYS-411 ( Figure 2A). Nilotinib could bind to the interface active pockets of the SARS-CoV-2 NSP12 and NSP7 ( Figure 2B).…”

Chronic myeloid leukaemia and the use of tyrosine kinase inhibitors in the days of COVID‐19 pandemic

“…One patient had confirmed COVID‐19 and cured after treatment. Some preclinical data showed that imatinib and nilotinib may have therapeutic efficacy in the management of some viral diseases, 12 and future research in the field of SARS‐CoV‐2 evaluating the efficacy of TKIs might be of interest.…”