Skin pharmacokinetics and anti-parasitic pharmacodynamics

Current therapeutics for the protozoan skin disease cutaneous leishmaniasis (CL) are far from optimal, as they require invasive drug administration, long treatment courses or safety monitoring. Our work focusses on the discovery and development of better, more patient-friendly drugs for CL. We here propose a strategy based on the evaluation of skin pharmacokinetics (PK) and anti-parasitic pharmacodynamics (PD) to advance new CL drug candidates from bench to beside. 

Early on in the drug discovery pathway, the activity of experimental compounds is tested against a panel of Leishmania species and in vitro ADME parameters are determined. Drug candidates with favourable properties are advanced into oral and topical dose-response efficacy studies in mouse models of L. major and L. mexicana CL. In addition, we compare pharmacokinetics in infected and uninfected skin to understand how the physiopathology of CL could be exploited for targeted drug delivery. Finally, we combine in vivo skin microdialysis and bioluminescent imaging to assess free drug exposure and rate of parasite kill directly at the dermal site of infection.

By combining such PK and PD approaches, we aim to contribute to the development of new short-course, safe and effective treatments for CL in the form of an oral and/or topical formulation.