Transcript 04-Bhavnani

WHICH PK-PD MEASURE FOR
WHICH DRUG?
The Life and Times of Dr. William A. Craig
Sujata M. Bhavnani, Pharm.D, MS
Institute for Clinical Pharmacodynamics
Ordway Research Institute
Latham, New York
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
EXPOSURE & RESPONSE IN MICE
Ceftazidime and Klebsiella pneumoniae
Z
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.
EXPOSURE & RESPONSE IN MICE
Doripenem Against Pneumococci
Z
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
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
Penicillin
Cephalosporin
Carbpenem
Organism
Stasis
Maximum
Kill
Gram-negative
30-40
60-70
Pneumococci
25-35
35-50
Staphylococci
20-30
40-50
Gram-negative
40-50
70-80
Pneumococci
35-40
40-50
Staphylococci
20-30
40-50
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
Change in Log10 CFU/Thigh
over 24 Hours
Impact of ESBL-Producing Enterobacteriaciae on
% Time > MIC for Cephalosporins1
3
ESBLs
3
Non-ESBLs
2
2
1
1
0
0
-1
-1
-2
-2
-3
-3
0
20 40 60 80 100
0
20
40
60
80 100
Time Above MIC (percent)
1. Ceftazidime, ceftriaxone, cefepime and cefotaxime.
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].
EXPOSURE & RESPONSE IN MICE
Change in Log (CFU/g) over 24 hrs
Aminoglycosides and Pseudomonas aeruginosa
& Serratia marcescens
R2=0.852
R2=0.826
R2=0.766
4
2
0
-2
-4
1
10
100
1000
10000
AUC:MIC Ratio
Q 6 hr
•
Q 12 hr
Q 24 hr
0.1
1
10
100
Cmax:MIC Ratio
1000 0
20
40
60
80
% Time > MIC
Control
Neutropenic mice were inoculated with 106 CFU/thigh of either P. aeruginosa (MIC = 4 mg/L)
or S. marcescens (MIC = 8 mg/L)
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.
100
EXPOSURE & RESPONSE IN MICE
Quinolones vs. Gram-Negative Bacilli
Mortality (%)
100
80
60
40
20
0
2.5
10
25
100 250
1000
AUC0-24:MIC Ratio
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.
EXPOSURE & RESPONSE IN MICE
Log10 CFU / Thigh at 24 Hrs
Levofloxacin vs. Pneumococci
10
8
6
Z
4
2
0
10
100
1000 1
24-Hr AUC/MIC
10
100
Peak/MIC
Andes & Craig, Int J Antimicrob Agents, 2002
1000 0
25
50
75 100
Time Above MIC
EXPOSURE
& RESPONSE
IN MICE
PRE-CLINICAL
PK-PD ANALYSES
Tigecycline
StaphylococcusStudies
aureus
Resultsversus
of Dose-Fractionation
ΔLog10 CFU/Thigh
3
R2 = 96%
R2 = 87%
R2 = 89%
2
1
0
-1
-2
-3
-4
0.1
1
10
1
10
100 0 20 40 60 80 100
Cmax:MIC Ratio AUC0-24:MIC Ratio % Time>MIC
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 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)
Ambrose PG, Forrest A, Craig WA, Rubino CM, Chavnani SM, Drusano GL, Heine HS. PharmacokineticsPharmacodynamics of Gatifloxacin in a Lethal Murine Bacillus anthracis Inhalation Infection Model. Antimicrob
Agents Chemother. 2007;51:4351-4355
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
AZITHROMYCIN
Mongolian Gerbil-Otitis Infection Model
• 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
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
H.flu Strain 54A1325: Sustained Release Azithromycin Regimen
10
8
8
6
4
4
LogCFU
Conc (mg/L)
6
2
2
0
0
0
20
40
60
80
Time (hrs)
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: 3-Day Regimen
H.flu Strain 54A1325: 3-Day Azithromycin Regimen
10
8
8
6
4
4
LogCFU
Conc (mg/L)
6
2
2
0
0
0
20
40
60
80
Time (hrs)
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: 5-Day Regimen
H.flu Strain 54A1325: 5-Day Azithromycin Regimen
10
8
8
6
4
4
LogCFU
Conc (mg/L)
6
2
2
0
0
0
20
40
60
80
Time (hrs)
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
IMPLICATIONS
Azithromycin 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
CONCLUSIONS
Applications 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
Log10 CFU/Thigh at 24 Hrs
4
2
Studied Strain of S. pneumoniae
0
-2
SP 10813
SP 145
SP 146
Starting CFU
-4
Effect
Exposure
SP ATCC
10813
SP CDC
145
SP CDC
146
Stasis
f%T>MIC
23.9
20.0
20.3
mg/kg/6h
26
96
110
f%T>MIC
35.6
32.3
31.2
mg/kg/6h
87.8
736
567
2 log10 Kill
-6
1
10
100
1000
Dose (mg/kg/6h)
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.
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.