Pharmacokinetics I: PK-PD approaches - antibiotic drug development

Abstract

The success of antibiotic therapy depends on complex interplay between the administered drug, its mechanism of action, concentration at site of infection, and complexity or severity of infection. Therapeutic response to an anti-infective agent or its pharmacological effect is often associated with high variability in clinical situations. Pharmacokinetics (PK) and pharmacodynamics (PD) contribute to a better understanding of the relationship between drug concentrations in biological fluids and its pharmacological effect. PK-PD studies can provide a means for exploring important pharmacological and toxicological properties of a drug in animals and humans. An integrated PK-PD approach, linking the exposure of a drug and the modulation of pharmacological targets, physiological pathways and ultimately disease systems, can be used to develop unified understanding of the data collected during different stages of drug discovery, which can also be applied in the drug development process. PK-PD relationships can be expressed by numerous mathematical models which have been increasingly demonstrated to be predictive of therapeutic outcomes during the development process. The PK-PD modelling and simulation approaches can streamline drug development and help make crucial decisions. These decisions include but not limited to planning clinical trials and designing optimal dosing strategies, both of which can be extremely costly and critical to the compound being developed if incorrect decisions are made. The purpose of this chapter is to discuss how PK-PD correlations and modelling and simulation process can be applied to drug development emphasizing antibiotic drug development.