New pharmacokinetic and PK/PD drug development methodologies for cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is a vector-borne neglected tropical disease caused by over 15 species of the intracellular Leishmania parasite. This skin infection is the most common and widely distributed form of leishmaniasis, with an estimated 0.7-1.2 million new cases annually, mainly in the Middle East and Latin America. CL is rarely fatal, but the ulcerative skin lesions often leave lifelong scars, disfigurement, and social stigma. Current treatment of CL is far from optimal. The pentavalent antimonials remain the standard of care since their discovery in the 1940s, but typically require three weeks of painful, toxic injections into the lesions. An alternative therapeutic option is liposomal amphotericin B, but cure rates are variable, access is problematic and invasive drug administration is required. Basic research tools that could accelerate the successful discovery and development of much needed new drugs are currently limited. This thesis aims to provide a coherent set of R&D methodologies to evaluate (i) the penetration of drugs into the infected skin lesions (pharmacokinetics, PK), (ii) the ability to kill the causative Leishmania parasites (pharmacodynamics, PD) and (iii) the interaction between PK and PD (PK/PD) parameters. In chapter 3.1, the limitations of the current in vitro models to predict in vivo drug activity were confirmed. Additionally, combination therapy of standard antileishmanial drugs with chloroquine was found unlikely to be a successful new treatment strategy for CL. In chapter 3.2, we demonstrated a clear relationship between PK and PD parameters for the standard liposomal amphotericin B formulation AmBisome in a mouse model of CL, providing a PK/PD basis for the rational design of better clinical dose regimens. In chapter 3.3, we compared the in vivo effects of AmBisome with Fungisome, an alternative liposomal amphotericin B formulation on the market in India. Fungisome was less efficacious than AmBisome due to lower drug accumulation in skin lesions and had a narrower therapeutic index in the treatment of murine CL. In chapter 3.4, we showed that the CL infection and associated local skin inflammation has a profound effect on the PK of AmBisome and can contribute to its variable therapeutic efficacy against Old and New World Leishmania species. The increased vascular permeability of the dermal capillaries might be exploited for enhanced delivery of small (< 500 Da) oral drugs to the infected skin. Finally, in chapter 3.5, we evaluated a new drug candidate from the Drugs for Neglected Diseases Initiative (DNDI) for visceral leishmaniasis. Our PK and PD data, based on innovative skin microdialysis and qPCR techniques, support the further preclinical development of the nitroimidazole DNDI-0690 as a promising new oral treatment for CL. Overall, the strategies, lessons and research tools provided in this PhD thesis could contribute to the development of safe, effective, affordable and patient-friendly new drugs for the treatment of CL.