AnimalModelPKPDAToolforDrugDevelopment.pptVIP

Animal Model PK/PD: A Tool for Drug Development David Andes, MD University of Wisconsin Madison, WI USA Pharmacokinetics The Primary Animal Model Pharmacodynamic Questions Predictive PD Parameter – What PK characteristic do I optimize? Magnitude of PD Parameter – How much drug do I need? PD Magnitude Variables – What factors impact how much drug I need? Study PD Correlation in humans – Can this help predict outcome in clinical disease? Mathematical Analysis of Dose-Response Data from Animal Models after 24 Hours of Therapy Nonlinear regression and Hill equation to estimate Emax (difference from untreated control), P50 (dose giving 50% of Emax) and slope (N) of the dose-response relationship 24-Hr AUC/MIC with Total and Free Drug for the Static Dose of Different Fluoroquinolones  with S. pneumoniae ATCC 10813 Pharmacodynamic Goals (TMIC as percent of Interval) with Beta-Lactams Maximum Class Organism Stasis Killing Cephalosporins GNR, pneumo 40-50 70-80 Staph 20-30 40-50 Penicillins GNR, pneumo 30-40 60-70 Staph 20-30 40-50 Carbapenems GNR, staph 20-30 40-50 Pneumo 10-20 25-40 Relationship Between MIC and TMIC for the Static Dose for Amoxicillin and Cefpodoxime with strains of S. pneumoniae Magnitude of PK/PD Parameter for Free DrugRequired for Static Dose of Gemifloxacin Against S. pneumoniae in Thighs of Neutropenic Mice Drug MIC Mean AUC/MIC Susceptible 0.015 28.3 Gyrase, PAR C or E 0.03-2.0 31.3 Efflux 0.12-0.25 5.8 Craig Andes ICAAC 2000; Craig NCCLS, 2003 Relationship Between TMIC and Efficacy for Amoxicillin against S. pneumoniae in Murine Pneumonia and Thigh-Infection Models Literature Review for TMIC for Beta-Lactams Versus Mortality in Animal Models At least 48 hours of treatment Mortality