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