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Chapter 1 - Definition: Translational and Personalised Medicine, Biomarkers, Pharmacodynamics

The incorporation of pharmacodynamic biomarkers in early phase drug development can provide important information about the biological effects of the treatment intervention on the patient and tumour. In oncology, “pharmacodynamics” refers to the effect of the drug on the patient and the tumour. This reflects the relationship between exposure to the drug and pharmacological response. Assessing pharmacodynamic parameters allows for the determination of whether a drug administered at a particular dose leads to modulation of the target. This is particularly important in phase I studies, where the goal is to assess the feasibility and safety of new therapeutic agents and to define the maximally-tolerated dose. Usually determination of pharmacodynamic effects requires serial tumour sampling through biopsies. However, acquiring tumour tissue can be challenging, depending on the location of the tumour, as well as the invasiveness and associated risks of the biopsy procedure required. A way to indirectly obtain information on target effects is to use surrogate normal tissues. For example, skin, hair follicles, and peripheral blood mononuclear cells (PBMCs) are all sources of normal tissue that are used for pharmacodynamic assessments in early phase clinical trials. However, there are several limitations to this approach, including the lack of expression of oncogenic targets in normal tissues, such as acquired oncogenic somatic mutations, issues with tumour heterogeneity, as well as differences in drug concentrations between surrogate normal tissues and tumour tissues.

Biomarker Selection and Validation Surrogate Endpoints

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