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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

Animal Model PK/PD: A Tool for Drug Development

David Andes, MD

University of Wisconsin

Madison, WI USA

pharmacokinetics

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

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?

The Primary Animal Model Pharmacodynamic Questions
slide4

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
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

slide6

PD Magnitude Variables

  • Drug class
  • Dosing regimen
  • Protein binding
  • Site of infection
  • Infecting pathogen
  • Resistance in the infecting pathogen
  • Immune system
  • Treatment endpoint
slide7

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

slide8
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

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
slide10
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

slide11
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
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
slide13

3 Quinolones K. pneumoniae Thigh

2 Aminoglycosides P. aeruginosa Lung

4 B-lactams S. pneumoniae

slide15

NL

Neut

NL

Neut

slide16
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

slide17

Correlation of PK/PD Parameters with Efficacy for Ceftazidime against Pseudomonas aeruginosa

in a Murine Thigh-Infection Model