WHICH PK-PD MEASURE FOR WHICH DRUG?

Sujata M. Bhavnani, Pharm.D, MS Institute for Clinical

Pharmacodynamics Ordway Research Institute Latham, New York

The Life and Times of Dr. William A. Craig

ROAD MAP Objectives

• To provide a review of the PK-PD measure associated with efficacy in animal infection models

• To review an example where consideration of the PK-PD measure most closely associated with efficacy did not completely tell the entire story

THINGS DR. CRAIG HAS TAUGHT US Factors that Influence the Magnitude of the PK-PD Measure

Associated with Efficacy

Major Effect Minor Effect

Infecting pathogen Resistant organisms

Drug class Dosing regimen

Protein binding

Site of infection

Presence or absence of neutrophils

Starting inoculums

Data by WA Craig, shamelessly stolen by PG Ambrose and given to SM Bhavnani

Z

EXPOSURE & RESPONSE IN MICE Ceftazidime and Klebsiella

pneumoniae

Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosing regimens for broad spectrum cephalosporins. Diagn Micro Infect Dis 1995;22:89-96.

EXPOSURE & RESPONSE IN MICE Amoxicillin and Pneumococci

Andes DR and Craig WA. In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations. Antimicrob Agents Chemother. 1998;42:2375-2379.

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Andes DR and Craig WA. Pharmacodynamic activity of dorpenem against multiple bacteria in a murine-thigh infection model. 2003 ICAAC, Abstract A-308.

EXPOSURE & RESPONSE IN MICE Doripenem Against Pneumococci

EXPOSURE & RESPONSE IN MICE Impact of β-Lactams on % Time > MIC

One of hundreds of Dr. Craig’s slides for which I cannot find the correct reference.

THE PK-PD GOAL OF THERAPY(% T>MIC) Beta-Lactams

Class Organism Stasis Maximum Kill

Penicillin Gram-negative 30-40 60-70

Pneumococci 25-35 35-50

Staphylococci 20-30 40-50

Cephalosporin Gram-negative 40-50 70-80

Pneumococci 35-40 40-50

Staphylococci 20-30 40-50

Carbpenem Gram-negative 20-30 40-50

Pneumococci 15-25 30-45

Staphylococci 10-20 25-40

Data by WA Craig, yet another slide shamelessly stolen by PG Ambrose and given to SM Bhavnani

EXPOSURE & RESPONSE IN MICE Impact of ESBL-Producing

Enterobacteriaciae on % Time > MIC for Cephalosporins1

Time Above MIC (percent)

0 20 40 60 80 100

Cha

nge

in L

og10

CF

U/T

high

over

24

Hou

rs

-3

-2

-1

0

1

2

3

0 20 40 60 80 100

-3

-2

-1

0

1

2

3ESBLs Non-ESBLs

Ambrose PG, Bhavnani SM, Jones RN, Craig WA, Dudley MN. Use of PK-PD and Monte Carlo simulation as decision support for the re-evaluation of NCCLS cephem susceptibility breakpoints for Enterobacteriaceae. 44th ICAAC, Washington, DC, October 30-November 2, 2004 [Abstract No. A-138].

1. Ceftazidime, ceftriaxone, cefepime and cefotaxime.

EXPOSURE & RESPONSE IN MICE Aminoglycosides and Pseudomonas

aeruginosa & Serratia marcescens

Q 6 hr Q 12 hr Q 24 hr Control

1 10 100 1000 10000-4

-2

0

2

4

AUC:MIC Ratio

Ch

ang

e i

n L

og

(C

FU

/g)

ove

r 24

hrs R2=0.852

0.1 1 10 100 1000

Cmax:MIC Ratio

R2=0.826

% Time > MIC

R2=0.766

0 20 40 60 80 100

Craig WA, Andes DR, Bhavnani SM, Drusano GL, Ambrose PG. Pharmacokinetics-pharmacodynamics of amikacin against gram-negative Bacilli in a murine-thigh infection model and examination of the PK-PD variance in humans. 44th Annual Meeting of the Infectious Diseases Society of America, Toronto, Ontario, Canada, October 12-15, 2006.

• Neutropenic mice were inoculated with 106 CFU/thigh of either P. aeruginosa (MIC = 4 mg/L) or S. marcescens (MIC = 8 mg/L)

EXPOSURE & RESPONSE IN MICE Quinolones vs. Gram-Negative Bacilli

AUC0-24:MIC Ratio

2.5 10 25 100 250 1000

Mort

ality

(%

)

0

20

40

60

80

100

Craig WA. Pharmacodynamics of Antimicrobials: General Concepts and Applications. In: Nightingale CH, Murakawa T, Ambrose PG ed. Antimicrobial Pharmacodynamics in Theory and Practice. New York, Marcel Dekker Publishers, 2002.

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EXPOSURE & RESPONSE IN MICE Levofloxacin vs. Pneumococci

Andes & Craig, Int J Antimicrob Agents, 2002

24-Hr AUC/MIC

10 100 1000

Log

10 C

FU /

Thig

h at

24

Hrs

0

2

4

6

8

10

Peak/MIC

1 10 100 1000

Time Above MIC

0 25 50 75 100

PRE-CLINICAL PK-PD ANALYSESResults of Dose-Fractionation Studies

Cmax:MIC Ratio0.1 1 10

ΔL

og1

0 C

FU

/Thi

gh

-4

-3

-2

-1

0

1

2

3

AUC0-24:MIC Ratio1 10 100

% Time>MIC0 20 40 60 80 100

R2 = 87% R2 = 89%R2 = 96%

van Ogtrop ML, Andes D, Stamstad TJ, Conklin B, Weiss WJ, Craig WA, and Vesga O. In vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) against various gram-positive and gram-negative bacteria. Antimicrob. Agents Chemother. 2000 44: 943-949.

EXPOSURE & RESPONSE IN MICE Tigecycline versus Staphylococcus

aureus

Ambrose PG, Forrest A, Craig WA, Rubino CM, Chavnani SM, Drusano GL, Heine HS. Pharmacokinetics-Pharmacodynamics of Gatifloxacin in a Lethal Murine Bacillus anthracis Inhalation Infection Model. Antimicrob Agents Chemother. 2007;51:4351-4355

EXPOSURE & RESPONSE IN VIVO Gatifloxacin Against Bacillus anthracis

• 6-8 week old non-neutropenic female BALB/c mice received aerosol challenges of 50 to 100 times the established 50% lethal dose (3.4 x 104 CFU) of B. anthracis (Ames strain, gatifloxacin MIC = 0.125 mg/L)

THE PK-PD GOAL OF THERAPY Various Drug Classes That I Did Not Have

Time to Mention

Class Organism Bacterial endpoint

Net bacterial stasis

Maximum kill

Macrolides Pneumococci 20-35 40-50

Clindamycin Pneumococci 20-35 40-50

Staphylococci 30-40 60-80

Tetracyclines

Staphylococci 60-80 90-120

Linezolid Staphylococci 80-90 100-150

Vancomycin Staphylococci 150-320 400-800

• We evaluated the effect on H. influenzae of delivering the same cumulative dose three different ways:

o Simulated sustained release single dose

o Simulated divided doses over 3 days

o Simulated divided doses over 5 days

• The pharmacokinetic profile in gerbils was humanized to better reflect the human pharmacokinetic profile

• Two strains were studied, MIC values of 0.5 and 2 mg/L

AZITHROMYCINMongolian Gerbil-Otitis Infection Model

Okusanya OO, Forrest A, Booker BM, Bhavnani SM, Girard D, Ambrose PG. Pharmacokinetics and pharmacodynamics of azithromycin in gerbils with Haemophilus influenzae middle ear infection. Presented at 106th American Society for Clinical Pharmacology and Therapeutics, 2005

AZITHROMYCIN IN THE GERBIL-OTITIS MODEL

Exposure-Response Relationship: Single Dose

Okusanya OO, Forrest A, Booker BM, Bhavnani SM, Girard D, Ambrose PG. Pharmacokinetics and pharmacodynamics of azithromycin in gerbils with Haemophilus influenzae middle ear infection. Presented at 106th American Society for Clinical Pharmacology and Therapeutics, 2005

H.flu Strain 54A1325: Sustained Release Azithromycin Regimen

Time (hrs)

0 20 40 60 80

Con

c (m

g/L)

0

2

4

6

8

10

LogC

FU

0

2

4

6

8

AZITHROMYCIN IN THE GERBIL-OTITIS MODEL

Exposure-Response Relationship: 3-Day Regimen

Okusanya OO, Forrest A, Booker BM, Bhavnani SM, Girard D, Ambrose PG. Pharmacokinetics and pharmacodynamics of azithromycin in gerbils with Haemophilus influenzae middle ear infection. Presented at 106th American Society for Clinical Pharmacology and Therapeutics, 2005

H.flu Strain 54A1325: 3-Day Azithromycin Regimen

Time (hrs)

0 20 40 60 80

Con

c (m

g/L)

0

2

4

6

8

10

LogC

FU

0

2

4

6

8

AZITHROMYCIN IN THE GERBIL-OTITIS MODEL

Exposure-Response Relationship: 5-Day Regimen

Okusanya OO, Forrest A, Booker BM, Bhavnani SM, Girard D, Ambrose PG. Pharmacokinetics and pharmacodynamics of azithromycin in gerbils with Haemophilus influenzae middle ear infection. Presented at 106th American Society for Clinical Pharmacology and Therapeutics, 2005

H.flu Strain 54A1325: 5-Day Azithromycin Regimen

Time (hrs)

0 20 40 60 80

Con

c (m

g/L)

0

2

4

6

8

10

LogC

FU

0

2

4

6

8

IMPLICATIONSAzithromycin in the Gerbil-Otitis Model

• Front-loading the exposure results in a more rapid and complete bacterial kill

• Extending the therapy duration increases the exposure intensity required to effect bacterial eradication

• Having the highest exposure at the time of greatest bacterial count results in the greatest kill possible Optimizes the likelihood of positive clinical outcome, This reduces the likelihood of spontaneous mutation, and Should eliminate a preexisting resistant subpopulation

CONCLUSIONSApplications and Path Forward

• By understanding the PK-PD measure and magnitude associated with efficacy, we have been able to assess the translational value of these data • Non-clinical and clinical are generally concordant!

• Identification of the PK-PD measure associated with efficacy early in drug development provides the opportunity to positively impact the selection of dosing regimens for further clinical study• Decreases risk of drug development failure

• Application of these principles has provided a paradigm for the evaluation of susceptibility breakpoints• Better definitions of susceptibility will better

influence prescribing

Thank you Dr. Craig for all that have you done!!!

EXPOSURE & RESPONSE IN MICE Penicillin and Pneumococci

Dose (mg/kg/6h)

1 10 100 1000

Lo

g 10

CF

U/T

hig

h a

t 2

4 H

rs

-6

-4

-2

0

2

4

SP 10813SP 145SP 146Starting CFU

Forrest A, Rubino CM, Craig Craig WA. Andes DR. Sorgel F, Kinzig-Schippers M, Rodamer M, Jones RN, Ambrose PG. Use of Pharmacokinetics-Pharmacodynamics and Monte Carlo Simulations as Decision Support for Determination of Penicillin VK Susceptibility Breakpoints for Streptococcus pneumonia. 2007 ICAAC, Abstract A-782.

Studied Strain of S. pneumoniae

Effect ExposureSP ATCC 10813

SP CDC 145

SP CDC 146

Stasis f%T>MIC 23.9 20.0 20.3

mg/kg/6h 26 96 1102 log10

Kill f%T>MIC 35.6 32.3 31.2

mg/kg/6h 87.8 736 567

EXPOSURE & RESPONSE IN MICE Linezolid and

Staphylococcus aureus

Andes D, van Ogtrop ML, Peng J, Craig WA, In vivo pharmacodynamic of a new oxazolidinone (linezolid. Antimicrob. Agents Chemother. 2000 46: 3484-3489.

EXPOSURE & RESPONSE IN MICE Doxycycline and Streptococcus pneumoniae

Andes D, Craig WA. In: Nightingale CH, Murakawa T, Ambrose PG, Drusano GL. ed. Antimicrobial Pharmacodynamics in Theory and Practice. New York, Marcel Dekker Publishers, 2nd Ed. 2006.