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

2. 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

3. 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?

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. Pharmacodynamic Goals (T>MIC as percent of Interval) with Beta-Lactams
Maximum
Class Organism Stasis Killing
Cephalosporins GNR, pneumo
Staph
Penicillins GNR, pneumo
Staph
Carbapenems GNR, staph
Pneumo

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. 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
Gyrase, PAR C or E
Efflux
Craig & Andes ICAAC 2000; Craig NCCLS, 2003

12. 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

13. Literature Review for T>MIC for Beta-Lactams Versus Mortality in Animal Models
At least 48 hours of treatment
Mortality % 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

14. 3 Quinolones K. pneumoniae Thigh
2 Aminoglycosides P. aeruginosa Lung
4 B-lactams S. pneumoniae

16. NL
Neut NL
Neut

17. 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

18. 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 ± ± ± ± 6
Penicillins ± ± ± ± 6
Carbapenems 21 ± ± ± ± 7

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