Pharmacokinetic/pharmacodynamic (PK/PD) studies are important for understanding how an investigational drug is distributed within the body and metabolized. In particular, such studies can help to identify the most appropriate dose and dosing schedule for a drug about to enter a clinical trial.

PK/PD studies have a range of uses:

  • Providing data on binding to plasma proteins, which can trap a drug within the bloodstream and prevent it reaching a site of infection.
  • Providing proof-of-concept data in animal models, where a human dose has not been validated; for infections such as urinary tract, skin and bone (osteomyelitis), drug efficacy will depend not just on whether a drug has been shown to inhibit a target but also on its ability to gain access to the site of infection.
  • Providing insights into the relationship between exposure to a drug and the response achieved; these studies are normally carried out in a validated animal model for a particular type of infection, such as the murine thigh model (for soft tissue infections) or the murine pneumonia model (for lung infections).

By studying the effects of different doses (dose fractionation studies), developers can establish which pharmacokinetic parameter – such as exposure or peak concentration – best correlates with efficacy against target pathogens. Measurements of this parameter can then be used to establish an optimal dose.

In addition, exposure data can be placed in the context of toxicity data to establish a preliminary non-clinical safety margin – the difference between the dose effective at treating an infection and that causing unacceptable safety concerns.

Although low safety margins are not necessarily predictive of failure in human trials, they are associated with an increased risk of failure.

Phase 1 trials are often dose-finding studies – based on administration of increasing doses of a drug to assess safety and tolerability. Starting a phase 1 trial with low doses will reduce the risk of harm, but will make a trial longer and more expensive, as more dose groups will be needed.

As well as providing valuable insights into safety and the maximum tolerated dose, dose-finding studies can also provide additional data for PK/PD analyses to inform dosing and dosing schedules.