Clinical utility of antifungal pharmacokinetics and pharmacodynamics

Historically the anti-infective dose and dosing interval chosen in clinical trials have been based on an arbitrary goal of maintaining drug levels in serum above the minimum inhibitory concentration of infecting pathogens for most if not all of the dosing interval. Subsequent United States Food and Drug Administration approval of a dosing regimen is then based on clinical success in treatment trials. Over the past decade, the emergence of drug resistance has limited the clinical utility of an increasing number of antimicrobial agents. However, early in drug development clinical trials do not often define the impact of infection with these less susceptible pathogens. The field of pharmacodynamics provides analysis tools that can help predict the likelihood of treatment success with various antimicrobial treatment regimens against susceptible and resistant pathogens.

In-vitro and animal model studies have begun to define the pharmacodynamic characteristics of a variety of antifungal compounds. In-vivo studies have demonstrated that the pharmacodynamic target associated with efficacy is similar among antifungal drugs within the same class and have shown the importance of considering protein. Analysis of clinical trial data suggests that the pharmacodynamic target identified in animal model studies is predictive of outcomes in humans.

Antifungal pharmacodynamics can be used to understand the relationship between drug dosing, in-vitro susceptibility and treatment efficacy. Consideration of these relationships can be used to optimize dosing regimens with current antifungal agents, to develop susceptibility breakpoint guidelines, and in the design of dosing regimens for drugs in early development.