Download - Kill Curve Analysis
Kill Curve Analysis
Hartmut Derendorf, PhDUniversity of Florida
Drug Delivery
Pharmacokinetics
Pharmacodynamics
Biopharmaceutics
PK-PD-Modeling
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Biomarker vs. Surrogate Endpoint
Biomarker
Drug- or disease-induced measurable physiological, pathophysiological or biochemical change
Surrogate Endpoint
Biomarker that has predictive value for therapeutic outcome
Emax - model
E = intensity of effect
Emax = maximum effect
C = concentration
EC50 = concentration at 0.5 Emax
CEC
CEE
50
max
EC50
Emax - model
Emax - model
ln EC50 - 2
Sigmoid Emax - model
E = intensity of effect
Emax = maximum effect
C = concentration
EC50 = concentration at 0.5 Emax
n = shape (slope) factor
nn50
nmax
CEC
CEE
Sigmoid Emax - model
normal plot semilogarithmic plot
Pharmacodynamics of Anti-infective Agents
•in vitro studiessteady state
dilution models
diffusion models
•animal studies
•clinical studies
NoncompartmentalPK-PD Models
•Time above MIC
•Cmax/MIC
•AUC24/MIC
•Area under the inhibitory curve (AUIC)
- based on reciprocal serum inhibitory titers
- calculated as AUC24/MIC for C>MIC
•AUC above MIC
0 6 18 2412
Con
cent
ratio
n (µ
g/m
L)
0
8
12
16
4
MIC
CmaxAUC > MIC
t > MIC
Time (hours)
•Time above MIC•Cmax/MIC•AUC24/MIC •AUIC •AUC above MIC
CeftazidimeK. pneumoniae in neutropenic mice
Craig 2002
TemafloxacinS. pneumoniae in neutropenic mice
Craig 2002
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
Concentration-dependent vs. Time-dependent
Craig 1991
Auto-dilution system
flaskreservoir
tubingconnector
pump
waste
Kill Curves
NCEC
Ckk
dt
dN
f
f
50
max
Maximum Growth Rate Constant k
Maximum Killing Rate Constantk-kmax
PK-PD Model
Initially, bacteria are in log growth phase
PK-PD ModelIn animals
Bacterial survival fraction of P. aeruginosa in a neutropenic mouse model at different doses (mg/kg) of piperacillin (Zhi et al., 1988)
Single DosePiperacillin vs. E. coli
0 2 4 6 8 10
Time (h)
100
101
102
103
104
105
106
107
108
109
1010
1011
1012
1013
1014C
FU
/mL
control
2g
8g
4g
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
FDA Draft-Guidance for Industry (1997)Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products
New Dosage Form of a Previously Studied Drug
In some cases, modified release dosage forms may be approved on the basis of pharmacokinetic data linking the new dosage form from a previously studied immediate-release dosage form. Because the pharmacokinetic patterns of controlled-release and immediate release dosage forms are not identical, it is generally important to have some understanding of the relationship of blood concentration to response to extrapolate to the new dosage form.
Plasma and free tissue levels
n = 12 (means +/- S.D.) total plasma concentrations free tissue concentrations
500 mg IR
Plasma and free tissue levels
n = 12 (means +/- S.D.) total plasma concentrations free tissue concentrations
500 mg MR 750 mg MR
0 2 4 6 8
Time (hours)
102
103
104
105
106
107
108
109
CF
U/m
L
S. pneumo: 5 µg/mL
0 2 4 6 8
Time (hours)
102
103
104
105
106
107
108
109
CF
U/m
L
S. pneumo: 5 µg/mL, 2-dose
750 mg MR bid vs 500 mg IR tid
time (h)
0 6 12 18 24
Streptococcus pneumoniae
CF
U/m
l
101
102
103
104
105
106
107
108
109
1010
1011
1012
1013
500 mg MR bid vs 500 mg IR tid
time (h)
0 6 12 18 24
CF
U/m
l
101
102
103
104
105
106
107
108
109
1010
1011
1012
1013
Streptococcus pneumoniae
Conclusion
Microdialysis has opened the door to get better information about the drug concentrations at the site of action.
This, in combination with appropriate PK/PD-models, will allow for better dosing decisions than traditional approaches based on blood concentrations and MIC.
PK/PD in Drug Development
StreamliningRational Approach
Cost SavingTime Saving
Questions• What are some of the limitations of MICs?• What is the difference between AUC/MIC vs. AUIC?• Should one use total or unbound concentrations to
calculate PK/PD-indices?• Why do peak concentrations correlate with
aminoglycoside activity but not with beta-lactam activity?• Is AUC/MIC a reasonable PK/PD-index for a macrolide?