An Interdisciplinary Approach to Investigating Drug Distribution During Experimental Visceral Leishmaniasis

Visceral leishmaniasis (VL) is a neglected tropical disease caused by various Leishmania spp. It poses a threat throughout the world with 200,000-400,000 new cases annually. During VL, large scale localised immune responses are mounted which fail to contain the parasite and morbidity ensues, leading to death if untreated. A hallmark of this immune response to visceral infection in experimental models of VL is the development of hepatic granulomas, comprised of inflammatory leukocyte aggregates surrounding a central parasitized core of macrophages. Liposomal Amphotericin B (LAmB) is a frontline treatment for VL but the interaction of LAmB with different leukocyte subsets is poorly characterised and the dependency of therapeutic outcome on processes such as leukocyte migration is largely unknown. In this thesis, an interdisciplinary approach, combining immunological investigations, mass spectroscopy analysis and mathematical modelling, was employed to investigate the sub-tissue distribution of Amphotericin B in the liver of L. donovani-infected mice treated with LAmB. Utilising fluorescence activated cell sorting coupled with liquid chromatography tandem mass spectroscopy, we defined the sub-tissue description of Amphotericin B for the first time. Following from this, a mathematical model was developed that described the hepatic immune response to infection with L. donovani, accounting for both intracellular and extracellular populations of parasite, with the aim of extending this model using pharmacological data. The mathematical model describing both the immune response to infection and the pharmacokinetic and pharmacodynamic activities of LAmB within the liver allows for investigation into the influence of immunological processes on drug accumulation.