Erlotinib in a once-daily high-dose oral regimen could mitigate Chikungunya virus titer in mice

Chikungunya virus (CHIKV) is a re-emerging arbovirus that causes debilitating inflammatory arthritis, for which no approved antiviral therapy currently exists. This study investigated the potential of repurposing erlotinib, a tyrosine kinase inhibitor, as an anti-CHIKV agent. Erlotinib demonstrated promising in vitro antiviral activity, with EC50 values in the low micromolar range and a favorable selectivity index. However, in vivo evaluation in C57BL/6 mice revealed pharmacokinetic limitations, characterized by rapid absorption and clearance, resulting in insufficient drug exposure under standard dosing regimens. Escalation to an intensive four-times-daily (QID) regimen successfully maintained plasma concentrations above the in vitro therapeutic threshold but led to significant body weight loss and failed to reduce viral titers or viral RNA levels in infected tissues. However, a once-daily (OD) regimen improved tolerability and significantly reduced footpad and serum viral titers relative to vehicle-treated controls. Notably, despite the lack of virological control in the QID regimen, erlotinib treatment reduced leukocyte infiltration and tissue inflammation in both treatment regimens, indicating a host-directed immunomodulatory effect. Overall, these findings highlight the critical role of dosing frequency in determining erlotinib's in vivo antiviral efficacy against CHIKV and suggest that once-daily (OD) administration may represent a more viable dosing strategy for further evaluation of erlotinib as a host-directed antiviral against CHIKV. Future strategies should also explore combination approaches with direct-acting antivirals to achieve more viral suppression and mitigation of disease pathology, as well as Structure-Activity Relationship (SAR)-guided scaffold optimization to improve in vivo pharmacokinetic profiles.