Physiological based pharmacokinetic/pharmacodynamic modelling of Vivia009 and its novel delivery system

Resumen

The work presented in this thesis describes the application of the population modelling approach in the drug development process, mainly focusing on the preclinical stage, and how to overcome the leap forward the clinics. For that purpose, data from a drug (Vivia009) at preclinical stage for Non-Hodgking¿s Lymphoma (NHL) is collected from the company Vivia Biotech, and modelling is applied with the aim of assist in predicting an outcome for humans. In Chapter 1, rat data from intravenous (iv) bolus administration of Vivia009 is collected from various tissues and at different time points. Here, the objective was to develop two different type of models, compartmental and physiological based pharmacokinetic (PBPK), capable to describe simultaneously the biodistribution of the parent drug and its main metabolite (MET). In Chapter 2, a new delivery system (particle) for Vivia009 has being developed and its pharmacokinetic properties are studied with the final aim of comparing to the non-encapsulated drug. For that reason, a new PBPK model is fitted to data of rats administered iv with the new delivery system. In Chapter 3, ex vivo pharmacodynamic data is collected from patients suffering Chronic Lymphocityc Leukemia (CLL), a subtype of NHL. Here, the pharmacological effect of Vivia009 and MET, alone or in combination, is studied in a patient population. The interaction between both drugs is analysed through the response surface modelling approach. Finally, a clinical trial is simulated where either Vivia009 or its new delivery system is administered to a patient population following a general leukemia treatment protocol.