Importance of relating efficacy measures to unbound drug concentrations for anti-infective agents

Abstract

For the optimization of dosing regimens of anti-infective agents, it is imperative to have a good understanding of pharmacokinetics (PK) and pharmacodynamics (PD). Whenever possible, drug efficacy needs to be related to unbound concentrations at the site of action. For anti-infective drugs, the infection site is typically located outside plasma, and a drug must diffuse through capillary membranes to reach its target. Disease- and drug-related factors can contribute to differential tissue distribution. As a result, the assumption that the plasma concentration of drugs represents a suitable surrogate of tissue concentrations may lead to erroneous conclusions. Quantifying drug exposure in tissues represents an opportunity to relate the pharmacologically active concentrations to an observed pharmacodynamic parameter, such as the MIC. Selection of an appropriate specimen to sample and the advantages and limitations of the available sampling techniques require careful consideration. Ultimately, the goal will be to assess the appropriateness of a drug and dosing regimen for a specific pathogen and infection.

Fig 1

Pictorial representation of a microdialysis probe inserted into a medium containing an analyte of interest and a drug binding protein.

Fig 2

Azithromycin concentration versus time in uninfected and infected (S. aureus) tissue in a rat thigh infection model. (Reprinted from reference .)

Fig 3

Clarithromycin concentration versus time in plasma, subcutis, and skeletal muscle after a 250-mg single dose (A) and 500 mg twice daily for 3 to 5 days (B). (Reprinted from reference .)

Fig 4

Application of PK/PD modeling and simulation to integrate in vitro and in vivo data and guide drug and dosage selection. Dosage recommendations are further supported by determination of inflection points (a and b) in the MIC distribution obtained from clinical surveillance data and estimates of target drug exposure. (Adapted from reference [Fig. 12.5] with kind permission from Springer Science+Business Media B.V.)