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Animal Model PK/PD: A Tool for Drug Development

Animal Model PK/PD: A Tool for Drug Development. David Andes, MD University of Wisconsin Madison, WI USA. Parameters of Interest:. C max (Peak). Time > MIC . C max /MIC ratio. AUC/MIC ratio. Area under the curve:. Concentration. AUC. MIC. Time > MIC. Time (hours).

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Animal Model PK/PD: A Tool for Drug Development

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  1. Animal Model PK/PD: A Tool for Drug Development David Andes, MD University of Wisconsin Madison, WI USA

  2. Parameters of Interest: Cmax (Peak) • Time > MIC • Cmax/MIC ratio • AUC/MIC ratio Area under the curve: Concentration AUC MIC Time > MIC Time (hours) Pharmacokinetics Pharmacodynamics Antimicrobial PK + MIC + Outcome

  3. 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? The Primary Animal Model Pharmacodynamic Questions

  4. Correlation of PK/PD Parameters with Efficacy for Ceftazidime against Pseudomonas aeruginosa in a Murine Thigh-Infection Model Andes & Craig, Int J Antimicrob Agents, 2002

  5. 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 (Emax) DoseN CFU= DoseN + P50N

  6. PD Magnitude Variables • Drug class • Dosing regimen • Protein binding • Site of infection • Infecting pathogen • Resistance in the infecting pathogen • Immune system • Treatment endpoint

  7. Relationship Between T>MIC and Efficacy for Carbapenems (Red), Penicillins (Aqua) and Cephalosporins (Yellow)

  8. 24-Hr AUC/MIC with Total and Free Drug for the Static Dose of Different Fluoroquinolones with S. pneumoniae ATCC 10813 Andes & Craig 40th and 41st ICAAC, 2000 and 2001

  9. Maximum ClassOrganism StasisKilling 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 Pharmacodynamic Goals (T>MIC as percent of Interval) with Beta-Lactams

  10. Relationship Between MIC and T>MIC for the Static Dose for Amoxicillin and Cefpodoxime with strains of S. pneumoniae Andes & Craig AAC 42:2375, 1998; Urban, Andes, Craig 19th ICC, 1995

  11. Relationship Between T>MIC and Efficacy for Amoxicillin against S. pneumoniae in Murine Pneumonia and Thigh-Infection Models Craig CID 33(Suppl 3):S233, 2001

  12. Literature Review for T>MIC for Beta-Lactams Versus Mortality in Animal Models Streptococcus pneumoniae • At least 48 hours of treatment • Mortality 80-100% in untreated controls • Pharmacokinetics provided to calculate magnitude of PK/PD parameter • Mortality recorded within 24 hrs after last dose of drug • Data from 3 animal species and 4 sites of infection

  13. 3 Quinolones K. pneumoniae Thigh 2 Aminoglycosides P. aeruginosa Lung 4 B-lactams S. pneumoniae

  14. NL Neut NL Neut

  15. Comparison of the Relationships Between Efficacy and 24-Hr AUC/MIC for Fluoroquinolones in Animal Models and Infected Patients Animals - Literature Review Seriously ill patients + Ciprofloxacin 24-Hr AUC/MIC Forrest et al. AAC 37:1073, 1993 Andes, Craig Int J Antimicrob Agents, 2002

  16. Correlation of PK/PD Parameters with Efficacy for Ceftazidime against Pseudomonas aeruginosa in a Murine Thigh-Infection Model

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