A combined in-vivo-PK / in-vitro-PD approach to simulate target site pharmacodynamics of antibiotics in humans

Erwin Schrödinger Fellowship J 1895 PK-PD simulations to predict antimicrobial efficacy Markus MÜLLER 26.6.2000 A new approach will be developed to quantify in vivo anti-infective activity by simulating effect-site- pharmacokinetics (PK) of antibiotics in-vitro. This approach is based on i) the in vivo measurement of interstitial drug pharmacokinetics at the target site and ii) a subsequent pharmacodynamic (PD) simulation of the time-versus- drug-concentration-profile in an in vitro setting. To demonstrate the feasibility of this approach, individual time-versus-concentration-profiles of the unbound drug fraction of select antimicrobial agents will be measured in the interstitial space fluid of animals and humans by microdialysis. Thereafter, different bacterial strains will be exposed in vitro to the interstitial drug profile obtained from in vivo experiments. The data will be analyzed with an integrated PK/PD model allowing a more detailed evaluation of the data than using MIC-values. This model employs an Emax relationship to link unbound drug concentrations to bacterial kill rates. The experiments will provide evidence for the effect of pharmacokinetic variability at the target site on therapeutic success and failure in antimicrobial therapy. the proposed in-vivo-PK/ in-vitro-PD approach may provide valuable guidance for drug and dose selection of antimicrobial agents.