application of pk/pd in new anti- infective drug development
TRANSCRIPT
Application of PK/PD in New Anti-Infective Drug Development:
Current Challenges and Future Perspectives
Seong Jang, Ph.D. Reviewer, Office of Clinical Pharmacology,
OTS/CDER/FDA
Disclaimer
The views presented here do not necessarily reflect those of the US Food and Drug Administration.
2
Outline
• Summarize PK/PD principles for anti-infective drugs: Current application
• Describe potential application of PK/PD in new anti-infective drug development
• Discuss current challenges and future perspectives
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Why is PK/PD information important?
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HOST
DRUG
BUG
Drug class/MOA PK characteristics PD behavior Dose and regimen
Immunocompetence Comorbidities Previous treatment Colonization
Susceptibility Resistance mechanisms MIC
FID~ U.S. Food and Drug Administration Protecting and Promoting Public Health
www.fda.gov
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MIC T>MIC
Cmax/MIC
AUC/MIC Ratio
Time
Dru
g C
on
cen
trat
ion
Aminoglycosides Daptomycin Metronidazole Quinolones
Aminoglycosides Clindamycin Daptomycin Vancomycin Macrolides Metronidazole Linezolid Quinolones Tetracyclines
Β-Lactams Oritavancin
Cmax
Tmax
AUC
PK/PD index: Determinant of drug response
Identifying the PK/PD index that best correlates with efficacy
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• In vitro hollow-fiber system • Animal model of infection
11 10 R2 = 93% R2- 81%
11 R2 ,. 47.5%
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24-Hour AUC/MIC Peak LeveJ/MIC Time Above MIC(%)
Determination of PK/PD Target PK/PD target: The magnitude of PK/PD index required
for desired efficacy in animal models of infection
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PK/PD target determined from animal models is used as the target for humans.
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AUC 24 /.MIC (F1r e.e. Drug) AUC 24 /MI C (Free Drug)
Current Utility of PK/PD target Dose selection for clinical studies:
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Time
200 mg • AUC24 = 15 μg·hr/mL
Target AUC24/MIC Ratio = 30
500 mg • AUC24 = 40 μg·hr/mL
100 mg • AUC24 = 8 μg·hr/mL
Co
nce
ntr
atio
n
0 24 0 24 0 24
MIC = 0.5 μg/mL
Current Utility of PK/PD target: Probability of Target Attainment (PTA)
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PK/PD target & Human (Patients) PK
AUC (n=1000) AUC/MIC (n=1000) MIC=1 MIC=2 MIC=4 MIC=8
10 (P1)…. 10 5 2.5 1.25
20 (P10)…. 20 10 5 2.5
30 (P25)…. 30 15 7.5 3.75
40 (P40)…. 40 20 10 5
….. ….. …… ……. ……. 200 (P100) 200 100 50 25
% PTA
Target AUC24/MIC Ratio = 5 Dose: 100 mg QD
~100% 99% 90% 60%
-CJ -C J -lJ
Probability of Target Attainment
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MIC (mg/L) 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32
% P
roba
bilit
y of
Tar
get A
ttain
men
t
0
20
40
60
80
100
MIC (mg/L) 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32
% P
roba
bilit
y of
Tar
get A
ttain
men
t
0
20
40
60
80
100
Perc
ent a
t MIC
0
10
20
30
40
• To determine susceptibility criteria • To evaluate the clinical dose proposed
Potential Application of PTA as an Evidence of Drug Efficacy When a clinical efficacy trial is not feasible or is limited for infections or pathogens of low occurrence,
11 Quality of data for PK/PD target and human PK simulation are critical.
MIC (mg/L) 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32
% P
roba
bilit
y of
Tar
get A
ttain
men
t
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20
40
60
80
100
Perc
ent a
t MIC
0
10
20
30
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too rare to evaluate clinical efficacy
PTA as an Evidence of Drug Efficacy: Limitations and Challenges PK/PD target determined in animal model
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• PD endpoints vs. Clinical Response: stasis, 1-log kill, 2-log kill, or survival in animals • Role of immune system: Immunocompromised animals • Concentrations in infection sites Animals ≤ Human
Q
8 0 ' -
8 Q
1 10 100 1000 AUC 24 /MIC (Free Drug)
PTA as an Evidence of Drug Efficacy: Limitations and Challenges
Human PK simulations
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• Monte Carlo Simulation: Observed PK variability
• Different variability b/w healthy subjects vs. patients with infection
35±8.5 (HS) vs. 33±23 (Pts)
• Covariates of Pop. PK: Comorbidities, Infection itself, and etc
0 0
PTA as an Evidence of Drug Efficacy: Future Perspective
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• Intensive animal studies with better animal models • PK/PD target using clinical exposure-response data • PK, MIC, and clinical outcomes from Phase 2 dose-ranging studies • PK, MIC, and clinical outcomes from Phase 3 studies:
To apply to other infection sites
AUC/MIC0 10 20 30 40
Clin
ical
Res
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