Animal Model PK/PD: A Tool for Drug Development
David Andes, MD
University of Wisconsin
Madison, WI USA
Pharmacokinetics
Time (hours)
Co
nce
ntr
atio
n
AUCAUC
MIC
Parameters of Interest:
Cmax (Peak)
Time > MIC
Area under the curve:
• Time > MIC • 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 Efficacyfor Ceftazidime against Pseudomonas aeruginosa
in a Murine Thigh-Infection Model
24Hr-AUC/MIC
100 300 1000
Lo
g10
CF
U p
er T
hig
h
-3
-2
-1
0
1
2
Peak/MIC
10 30 100 300 1000
Time Above MIC
20 40 60 80 100
q2h q4h q6h q8h q12h
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
Dose (mg/kg/6 hrs)10 30 100 300
Lo
g1
0 C
FU
pe
r T
hig
h a
t 2
4 H
rs
5
6
7
8
9
Static Dose
1 Log K ill
P50
Emax
CFU=(Emax) DoseN
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
0 20 40 60 80 100
-4
-2
0
2
Lo
g 10
CF
U p
er
Lu
ng
or
Th
igh
Time Above MIC (percent)
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
0
40
80
120
160
Gati Sita Moxi Gemi Garen Levo Cipro
24
-Hr
AU
C/M
IC
Total
Free
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
MIC (mg/L)
0.016 0.06 0.25 1 4 16
Tim
e A
bove
MIC
(%
)
10
20
30
40
50
Amoxicillin (T)Cefpodoxime (T)
Andes & Craig AAC 42:2375, 1998; Urban, Andes, Craig 19th ICC, 1995
Relationship Between T>MIC and Efficacy for Amoxicillin against S. pneumoniae in
Murine Pneumonia and Thigh-Infection Models
Time Above MIC (% of Dosing Interval)
0 20 40 60 80 100
Ch
an
ge
in
Lo
g C
FU
/Th
igh
o
r L
un
g O
ve
r 2
4 o
r 4
8 H
rs
-4
-2
0
2
4
Pneumonia - 48 Hrs
Thigh - 24 Hrs
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
0 20 40 60 80 100
Mor
talit
y (%
)0
20
40
60
80
100
Cephalosporins Penicillins
Time Above MIC (% of Interval)
Streptococcus pneumoniae
Gentamicin Total Dose (mg/kg)
1 10 100
Ch
an
ge
in L
og 1
0 C
FU
/Lu
ng
3
4
5
6
7
8
9
10
Su
rviv
al a
t D
ay
5 (
%)
-20
0
20
40
60
80
100
120
Static Dose
PD50
Correlation Between Bacterial Numbers After 24-hr of Therapyand Survival After 4-5 Days of Therapy
24-hr Static Dose (mg/kg)
1 10 100
Da
y 5
PD
50
1
10
100 R2 = 92%
3 Quinolones K. pneumoniae Thigh2 Aminoglycosides P. aeruginosa Lung4 B-lactams S. pneumoniae
Relationship Between QuinoloneAUC/MIC and Mortality at End of Therapy and 7-12 Days After the End of Therapy
AUC/MIC
3 10 30 100 300
Su
rviv
al (%
)
0
20
40
60
80
100
Impact of Neutrophils on the 24 hr Static Dose of Selected Quinolones
Against S. pneumoniae and K. pneumoniae
24 H
our S
tatic
Dos
e (m
g/kg
)0.1
1
10
100
1000
S. pneumoniae K. pneumoniae
Ciprofloxacin Dose-Response Relationship Against S. pneumoniae in
Both Normal and Neutropenic Mice
Total Dose (mg/kg/24 hr)
10 100 1000 10000
Cha
nge
in L
og10
CFU
/Thi
gh
-6
-4
-2
0
2 NeutropenicNormal
NL Neut NeutNL
Comparison of the Relationships Between Efficacy and 24-Hr AUC/MIC for Fluoroquinolones
in Animal Models and Infected Patients
0
20
40
60
80
100
0-62.5 62.5-125 125-250 250-500 >500
Eff
icac
y
Clinical
Microbiologic
24-Hr AUC/MIC2.5 10 25 100 250 1000
Mor
talit
y (%
)
0
20
40
60
80
100
Animals - Literature Review Seriously ill patients + Ciprofloxacin
24-Hr AUC/MICAndes, 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
24Hr-AUC/MIC
100 300 1000
Lo
g10
CF
U p
er T
hig
h
-3
-2
-1
0
1
2
Peak/MIC
10 30 100 300 1000
Time Above MIC
20 40 60 80 100
q6h q8h
Plot 2 Upper Specification