Repurposing avermectins as new potential TB therapies

Background: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. Co-infection with HIV and the emergence of drug-resistant Mycobacterium tuberculosis strains (MDR-and XDR-TB) has reaffirmed TB as a global public health threat. New therapies are urgently needed. An alternative approach to generate new TB treatment options in a timely and cost-effective manner is “repurposing” clinically used drugs with known pharmaceutical properties. In the course of a screening program [PMID: 21576426], we identified the in vitro anti-tuberculosis activity of the anthelmintic avermectins (ivermectin, selamectin, moxidectin and doramectin) [PMID: 23165468]. Methods & Materials: We performed a literature search on the pharmacological properties of the avermectins. We integrated this information with our in vitro data and calculated a theoretical pharmacodynamic value (AUC/MIC; a measure of drug exposure) to define potential in vivo efficacy. We validated our analysis by evaluating avermectins in an in vivo model of M. tuberculosis infection. Results: An AUC/MIC ratio of 10 to 15 was calculated for bactericidal activity of the avermectins. Due to tolerability and pharmacokinetic issues the low maximal plasma concentrations of ivermectin (ng/mL range) resulted in a low calculated exposure (AUC/MIC < 1). Moxidectin had a longer half-life than ivermectin and, therefore, the calculated AUC/MIC ratios increased. However, this was still not enough to provide theoretical in vivo activity. In contrast, selamectin's pharmacokinetic properties suggest that it might be effective in vivo against M. tuberculosis; high plasma concentrations (μg/mL range), low toxicity (LD50 >1,600 mg/kg bw), and theoretical AUC/MIC ratios are consistent with potential in vivo activity. Interestingly, reported concentrations of selamectin in the lungs (the main site where M. tuberculosis resides) were ca. 2-fold higher than in plasma, suggesting even higher AUC/MIC ratios at the site of infection. We therefore tested ivermectin and selamectin for in vivo activity against M. tuberculosis. Our predictions were consistent with the in vivo data; while ivermectin at the highest possible safe dose did not have anti-mycobacterial activity in vivo, selamectin was active. Conclusion: This theoretical data analysis supports the potential of selamectin for TB therapy, including MDR- and XDR-TB, and warrant further in vivo testing in mouse infection models.

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