Animal Model PKPD A Tool for Drug Development

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

Pharmacokinetics Parameters of Interest: • Time > MIC • Cmax/MIC ratio • AUC/MIC ratio Cmax Concentration (Peak) Area under the curve: AUC MIC Time > MIC Time (hours) 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), P 50 (dose giving 50% of Emax) and slope (N) of the dose-response relationship CFU= (Emax) Dose. N + P 50 N

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 40 th and 41 st ICAAC, 2000 and 2001

Pharmacodynamic Goals (T>MIC as percent of Interval) with Beta-Lactams Class Cephalosporins Organism GNR, pneumo Staph Stasis 40 -50 20 -30 Maximum Killing 70 -80 40 -50 Penicillins GNR, pneumo Staph 30 -40 20 -30 60 -70 40 -50 Carbapenems GNR, staph Pneumo 20 -30 10 -20 40 -50 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 19 th ICC, 1995

Relationship Between T>MIC and Efficacy for Amoxicillin against S. pneumoniae in Murine Pneumonia and Thigh-Infection Models Craig CID 33(Suppl 3): S 233, 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 2 Aminoglycosides 4 B-lactams K. pneumoniae P. aeruginosa S. pneumoniae Thigh Lung

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 Andes, Craig Int J Antimicrob Agents, 2002 Forrest et al. AAC 37: 1073, 1993

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