Pharmacokinetic–Pharmacodynamic Modeling in Drug Development with Special Reference to Oncology
This chapter provides a general overview of the role in drug development of the model based approaches adopted both in the decision making process and to meet the requirements for market authorization and approval. In particular, the complex scenarios that pharmaceutical industries have to face in order to launch new chemical entities are described. Modeling and simulation approaches provide a fundamental contribution in optimizing drug development processes. Models can be used to: (i) quantitatively evaluate the effects and the risk:benefit ratios for a new treatment; (ii) simulate the outcomes of experimentally untested conditions; and (iii) devise the best experimental design, and also providing a reasonable guess of the probability of technical success. In this way, the development of compounds with a low probability of being approved can be stopped, allowing the redirection of resources to projects with higher probabilities of success. Notably, a dedicated pharmacometric division was recently formed at the US Food and Drug Administration (FDA), as the agency considered that it was urgent and crucial to boost the integration of pharmacometric expertise. In this chapter, some achievements in the oncology therapeutic area are illustrated through five paradigmatic semi-mechanistic pharmacokinetic–pharmakodynamic models, covering all phases of drug development from preclinical to clinical. For each model, the discussion ranges from the relevant background and mathematical formulation to application and impact.