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

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

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?

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

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

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

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

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

Pharmacodynamic Goals (T>MIC 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 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

Magnitude of PK/PD Parameter for Free Drug Required 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 T>MIC and Efficacy for Amoxicillin against S 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

Literature Review for T>MIC for Beta-Lactams Versus Mortality in Animal Models 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 Streptococcus pneumoniae

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

NL Neut NL Neut

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

Time Above MIC (Percent of Dosing Interval) Time Above MIC Required for a Static Effect After 24-hrs of Therapy with Three ß-Lactam Classes Time Above MIC (Percent of Dosing Interval) Drug q1-3 h q4-6h q8-12h q24h Cephalosporins 35 ± 5 34 ± 6 36 ± 5 33 ± 6 Penicillins 30 ± 6 31 ± 5 30 ± 7 29 ± 6 Carbapenems 21 ± 5 20 ± 5 22 ± 6 20 ± 7

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