PKPD and disease modeling: Concepts and applications to oncology

Abstract

Despite the transition from chemotherapy with cytotoxic and cytostatic drugs to targeted therapy with monoclonal antibodies, clinical decisions regarding the benefit of pharmacological interventions still rely on the concept of a maximum tolerated dose (MTD). In this chapter, it is shown that a model-based approach can be used in oncology to optimize dose selection and characterize drug effect on tumor growth, overall survival and safety. Furthermore, modeling and simulation also provides insight into the underlying mechanisms of action, enabling translation of the differences in pharmacology, safety and disease processes from preclinical experiments to clinical trials. A paradigm shift is proposed to bring the benefits of model-based drug development to cancer patients, in which biomarkers of safety and prognostic markers of overall survival are assessed to predict treatment outcome and disease progression. © American Association of Pharmaceutical Scientists 2011.