Pharmacokinetic-pharmacodynamic modelling of therapeutic proteins

Abstract

Pharmacokinetic/pharmacodynamic modelling approach has proven to be an extremely valuable tool in the preclinical and clinical development of a wide range of drugs. However its application to biotechnological medicines, a recent but growing market, is still very scarce, especially at the preclinical level. In this thesis, three examples of mathematical models and their applicability to different therapeutic proteins at early preclinical stages will be given. In Chapter 1 an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to describe and compare kinetic and dynamic behaviour of interferon (IFN) α with a new developed fusion protein obtained by linking IFNα to Apo-AI is presented. Modelling approach enabled the integration of multiple information, as well as the identification and quantification of important differences in the in vivo behaviour of the molecules. Chapter 2 describes a target-mediated drug disposition model developed to jointly characterize interleukin 12 (IL-12) kinetics and its relationship with IFNγ. The model was applied to propose an improved dosing regimen able to achieve sustained IL-12 levels minimising the negative feedback triggered by IFNγ. The final case-study is included in Chapters 3 and 4. First, a semi-mechanistic model accounting for the key biological mechanisms implied in the tumour response triggered by a novel vaccine is presented. In a second step, the model developed was expanded to characterize the pharmacodynamic effects triggered by two co-adjuvant therapies commonly used in combination therapies (cyclophosphamide and CpG).