PK/PD studies in advance of a phase 2 trial

Pharmacokinetic/pharmacodynamic (PK/PD) data will be available from pre-clinical and phase 1 studies, as summarized in the phase 1 trial section.

Pharmacodynamics: Analyses of these data can be used to determine the exposure required to cover the target bacterial population. Phase 1 PK and safety data can then be used to select a dose and dosing regimen that will be adequate to treat 90% of expected pathogens.

Pharmacodynamic variability and target attainment: There is a need to take into account both the variability in sensitivity of different pathogens (PD variability) and the variability in drug metabolism in patients (PK variability), which will affect exposure. This variability can be explored using statistical methods such as Monte-Carlo simulations, using phase 1 PK data. These simulations can be used to predict the exposure required to suppress at least 90% of infections based on the antibiotic susceptibility profiles (MIC values) of clinical isolates.

Other influences on dosing: It may also be necessary to take into account the need to suppress the development of resistance. This can be assessed in in vitro studies, for example using the hollow-fibre model. Informative data may also be obtained from PK/PD studies in additional animal models. It is also important that in vivo modelling incorporates multiple, geographically diverse strains.