hartmut derendorf, ph.d. university of florida improvement in dose selection through clinical...
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Hartmut Derendorf, Ph.D.
University of Florida
Improvement in Dose Selection Through Clinical Applications of
PK/PD in Antimicrobial Drug Development
Pharmacokineticsconc. vs time
Co
nc.
Time0 250.0
0.4
PK/PDeffect vs time
Time
Eff
ect
0
1
0
Pharmacodynamicsconc. vs effect
10-3Conc. (log)
Eff
ect
0 6 18 2412
Con
cent
ratio
n (µ
g/m
L)
0
8
12
16
4
MIC
Cmax
Time (hours)
Cmax/MIC
0 6 18 2412
Con
cent
ratio
n (µ
g/m
L)
0
8
12
16
4
MIC
Cmax
Time (hours)
Cmax/MIC
0 6 18 2412
Con
cent
ratio
n (µ
g/m
L)
0
8
12
16
4
MIC
t > MIC
Time (hours)
Time above MIC
0 6 18 2412
Con
cent
ratio
n (µ
g/m
L)
0
8
12
16
4
MIC
t > MIC
Time (hours)
Time above MIC
0 6 18 2412
Con
cent
ratio
n (µ
g/m
L)
0
8
12
16
4
MIC
Time (hours)
AUC24/MIC
0 6 18 2412
Con
cent
ratio
n (µ
g/m
L)
0
8
12
16
4
MIC
Time (hours)
AUC24/MIC
PK PD
Serum MIC
Pharmacokinetics
Problems:
• Protein Binding
• Tissue Distribution
vascular space extravascular space
plasma protein binding
blood cell binding,
diffusion into blood cells,
binding to intracellular biological material
tissue cell binding,
diffusion into tissue cells,
binding to intracellular biological material
binding to extracellular biological material
Microdialysis
0
1
2
3
4
5
6
0 2 4 6 8 10
Time (h)
Co
nce
ntr
ato
in (
mg
/L) plasma muscle free plasma
0
1
2
3
4
5
6
0 2 4 6 8 10
Time (h)
Co
nc
en
tra
tio
n (
mg
/L)
plasma muscle free plasma
Cefixime400 mg po
Cefpodoxime400 mg po
Clinical Microdialysis
Liu & Derendorf, JAC 50, 19 (2002)
PharmacodynamicsProblems:
• MIC is imprecise
• MIC is monodimensional
• MIC is used as a threshold
• When MIC does not explain the data, patches are used(post-antibiotic effect, sub-MIC effect)
Auto-dilution system
flaskreservoir
tubingconnector
pump
waste
Kill Curves
0 5 10 15 20 25102
103
104
105
107
108
109
1010
1011
CF
U/m
L
106
Time (h)
50µg/mL q24h
0 5 25102
103
104
105
106
107
108
109
1011
10 2015
CF
U/m
L
1010
100µg/mL q24h
Time (h)
0 5 10 15 20 25102
103
104
105
106
107
108
109
1011
1010
CF
U/m
L
50µg/mL q8h
Time (h)
0 5 10 15 20 25102
103
104
105
106
107
108
109
1010
1011
CF
U/m
L
100µg/mL q8h
Time (h)
0 5 10 15 20 25102
103
104
105
106
107
108
109
1010
1011
CF
U/m
L
50µg/mL q4h
Time (h)
0 5 10 15 20 25102
103
104
105
106
107
108
109
1010
1011
CF
U/m
L
100µg/mL q4h
Time (h)
Dosing IntervalPiperacillin (2g and 4g) vs. E. coli
q24h q8h q4h
Nolting & Derendorf, Pharm. Res. 13, 91 (1996)
H. influenzae ATCC10211
MIC: 5 ng/mLS. pneumoniae ATCC6303
MIC: 20 ng/mL
Kill Curves of Ceftriaxone
S. pneumoniae ATCC6303
MIC: 20 ng/mL H. influenzae ATCC10211
MIC: 5 ng/mL
Kill Curves of Ceftriaxone
0 5 10 15 20 25
Time (hour)
101
102
103
104
105
106
107
108
CFU
/mL
0
50
100
150
200
250
Ant
ibio
tic C
onc
(ng/
mL)
0 5 10 15 20 25
Time (hour)
101
102
103
104
105
106
107
108
CFU
/mL
0
50
100
150
200
250
Ant
ibio
tic C
onc
(ng/
mL)
PK-PD Modeling Based on Kill Curves
Control (CFU/mL)Treated (CFU/mL)Antibiotic concentration
• Same PK• Same MIC• Same t>MIC• Same AUC/MIC• Same Cmax/MIC• Same k (Growth Rate)
• Different EC50 (Sensitivity)
• Different kmax (Maximum Kill Rate)
02468
101214
0 20 40 60 80
t (h)
C (
mg
/L)
0.0001
0.001
0.01
0.1
1
10
100
1000
10000
100000
0 20 40 60 80
t (h)
CF
U C
ha
ng
e
No
N
02468
101214
0 20 40 60 80
t (h)
C (
mg
/L)
0.0001
0.001
0.01
0.1
1
10
100
1000
10000
100000
0 20 40 60 80
t (h)
CF
U C
ha
ng
e
No
N
Faropenem Daloxate300 mg q12h S. pneumo.
Fed
Fasted
Khunvichai & Derendorf, ICAAC 2001
Piperacillin in patients
Piperacillin serum and muscle levels in healthy patients and intensive care patients after single iv dose of 4g
Brunner et al, 2000
Piperacillin in patients
Sauermann et al, 2003
Piperacillin kill curves (MIC: = 2 mg/l and =4 mg/l)
• A simple comparison of serum concentration and MIC is usually not sufficient to evaluate the PK/PD-relationships af anti-infective agents.
• Protein binding and tissue distribution are important pharmacokinetic parameters that need to be considered. Microdialysis can provide information on local exposure.
• PK-PD analysis based on MIC alone can be misleading.
• Microbiological kill curves provide more detailed information about the PK/PD-relationships than simple MIC values.
Summary
Conclusions
• Intelligent PK/PD can help to streamline rational clinical dose selection
• The final dose needs to be confirmed in a clinical trial
AcknowledgementsMarkus Müller
Edgar Schuck
Qi Liu
Ping Liu
Teresa Dalla Costa
Amparo de la Peña
Ariya Khunvichai
Arno Nolting
Andreas Kovar
Kenneth Rand
Alistair Webb
Maria Grant