The focus of my research work is the optimisation of anti-infective therapy. Commonly, during clinical investigations blood or plasma samples are obtained to determine therein the total concentration of a drug. This procedure has two major drawbacks: first, the blood stream is only rarely the site of the infection and second, only the fraction unbound to plasma proteins is pharmacologically active. Thus, I will use the methodology of microdialysis, which enables to minimally invasively sample the unbound analyte directly at the target site, as only this fraction can diffuse across the microdialysis membrane. To achieve reliable results in in vivo experiments, in vitro investigations are necessary. I therefore examine the feasibility of specific clinical questions as well as influencing factors, e.g. on the relative recovery of an analyte (active agent, metabolite, biomarker) in the microdialysate, in the in vitro microdialysis system.

Thereby I focus on the triazole antifungal voriconazole that is approved for instance in the treatment of invasive aspergillosis and candidiasis in non-neutropenic patients. Voriconazole is nearly completely metabolised in the liver by cytochrome P450 enzymes (CYP) and shows a significant inhibition of those. Moreover, polymorphisms in the gene encoding for CYP2C19 play an important role in the metabolism and as a consequence in the exposure of the body to the drug.

Consequently, for the development of safe and effective dosing regimens it is inevitable to characterise quantitatively and mechanistically the distribution to the target site and the metabolic pathway as well as the contribution of the metabolites to the pharmacokinetics and pharmacodynamics of voriconazole.

In order to reliably analyse the in vitro and in vivo obtained microdialysate and plasma samples, a HPLC-MS/MS will be established for the simultaneous quantification of voriconazole and its metabolites and validated according to the EMA guidelines.