AbstractsBiology & Animal Science

Cancer is one of the leading causes of death worldwide. Therefore, the onset and behavior of cancer is studied by many research groups. Nowadays a focus is on targeted therapy and potential targets for new compounds, although rediscovery and improvement of old anticancer agents can also result in new strategies. An example of such is the development of new oral formulations of taxanes, a group of widely used anticancer agents that are currently administered intravenously (i.v.). A major limitation in the concept of oral administration of the taxanes paclitaxel (Taxol®)and docetaxel (Taxotere®), is the low oral availability. Paclitaxel and docetaxel have poor aqueous solubility and upon oral administration, intestinal uptake can be seriously hampered by drug efflux through P-glycoprotein (P-gp/MDR1/ABCB1) and by drug metabolism via Cytochrome P450 (CYP) 3A. Several studies by our group have shown that the oral bioavailability of paclitaxel and docetaxel can be enhanced by combining the taxanes with the CYP3A4 inhibitor ritonavir (Norvir®). The aim of this thesis was to obtain mechanistic insights in the boosting effect of ritonavir on orally administered taxanes and to support clinical development of oral formulations of paclitaxel and docetaxel. Therefore, multiple aspects involved in the development of oral formulations of taxanes are described. In the first part of this thesis, the development of bioanalytical assays for quantification of taxanes was addressed. Bioanalytical assays for the combined quantification of taxanes and ritonavir in human plasma, feces and urine were developed and validated. Moreover, an approach was described to quantify docetaxel metabolites by LC-MS/MS using docetaxel calibration samples, which can be applied to other metabolites when chemically pure substances are not available. The second part of this thesis addressed preclinical studies on taxanes. Roles of drug metabolizing and transporting enzymes after oral administration of taxanes were studied using knock-out and humanized mouse models. It was also observed that co-administration of docetaxel and ritonavir caused increased anti-tumor efficacy of docetaxel in a mouse model for hereditary breast cancer. The third and final part of this thesis addressed clinical studies on taxanes. Plasma concentrations of metabolites of docetaxel were studied since both the oral route of administration of docetaxel and co-administration with ritonavir might alter docetaxel metabolite concentrations in plasma, compared with standard intravenous administration. In the first studies with oral docetaxel, the most common and dose-limiting toxicity was diarrhea. The onset of severe diarrhea in patients after administration of oral formulations of docetaxel with ritonavir were explained by combining preclinical and clinical data.