prof. hartmut derendorf university of florida the role of pharmacological predictors in drug...
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Prof. Hartmut Derendorf
University of Florida
The Role of Pharmacological
Predictors in Drug Development
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Resistance Development
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Approved Antibacterial Agents1983-2004
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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
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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
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Pharmacokinetics
Problems:
• Protein Binding
• Tissue Distribution
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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
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AzithromycinTissue Concentrations
tonsil (t)prostate (P)lung (L) serum (S)
500 mg p.o. from Foulds et al. (1990)
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Tissue can be looked at as an aqueous dispersed system of biological material. It is the concentration in the water of the tissue that is responsible for pharmacological activity.
Total tissue concentrations need to be interpreted with great care since they reflect hybrid values of total amount of drug (free + bound) in a given tissue
‘Tissue-partition-coefficients’ are not appropriate since they imply homogenous tissue distribution
Tissue Concentrations
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The free (unbound) concentration of
the drug at the receptor site should be
used in PK/PD correlations to make
prediction for pharmacological activity
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Blister Fluid
• Blister fluid is a ‘homogenous tissue fluid’
• Protein binding in blister fluid needs to be considered
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Ampicillin
Cloxacillin
Serum Free blister fluid
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Interstitium
CapillaryCell
PerfusateDialysate
Microdialysis
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S
NO
NH
CH
COOH
C
O
CS
NNH2 N O CH2COOH
CH2
S
NO
NH
CH2
COOH
C
O
CS
NNH2 N O CH3
O CH3
Cefixime (Protein binding 65%)
Cefpodoxime(Protein binding 17-30%)
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M uscle
Lung
H um an S tud ies
M uscle Lung
Anim al S tud ies
Pharm acokinetics
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i.v. 20 mg/kg in rats
Time (min)
Concentr
ation (
mg/L
)
0 50 100 150 200 250 300
100
101
102
103
iv dose of 20 mg/kg of cefpodoxime (n=6)
plasma lung muscle
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Clinical study Cefpodoxime and
Cefixime
• To compare the soft tissue distribution of these two antibiotics after 400mg oral dose in healthy male volunteers by microdialysis
• Two way cross-over, single oral dose study
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Microdialysis
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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)
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Pharmacokinetics
Cefpodoxime Cefixime
AUCP [mg*h/L] 22.4 (8.7) 25.7 (8.4)
AUCT [mg*h/L] 15.4 (5.2) 7.4 (2.1)
Cmax, P [mg/L] 3.9 (1.2) 3.4 (1.1)
Cmax,T [mg/L] 2.1 (1.0) 0.9 (0.3)
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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
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CeftazidimeK. pneumoniae in neutropenic mice
Craig 2002
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TemafloxacinS. pneumoniae in neutropenic mice
Craig 2002
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Pharmacodynamics
Problems:
• 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)
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Auto-dilution system
flaskreservoir
tubingconnector
pump
waste
Kill Curves
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H. influenzae ATCC10211
MIC: 5 ng/mLS. pneumoniae ATCC6303
MIC: 20 ng/mL
Kill Curves of Ceftriaxone
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S. pneumoniae ATCC6303
MIC: 20 ng/mL H. influenzae ATCC10211
MIC: 5 ng/mL
Kill Curves of Ceftriaxone
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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
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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
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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
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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)
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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.
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Plasma and free tissue levels
n = 12 (means +/- S.D.) total plasma concentrations free tissue concentrations
500 mg IR
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Plasma and free tissue levels
n = 12 (means +/- S.D.) total plasma concentrations free tissue concentrations
500 mg MR 750 mg MR
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Cefaclor 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
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Resistance Modeling
• Pre-existing subpopulations
• Emerging subpopulations
• Adaptive resistance (transporters)
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Drug (C)
fs(C)
Growth
( k0)fr(C)
Bacteria (R)
Bacteria (S)
Bacteria pool
Killing
Two sub-population model
OBS: same growth rate for sensitive (S) and resistant (R)
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tzs
s
tz
r
r
eNsCEC
CKk
dt
dNs
eNrCEC
CKk
dt
dNr
1
1
50
max0
50
max0
NsNrN t
Two sub-population Emax model
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tzr
r
eNCEC
CkCIC
Ck
kdt
dN
1
1
50
250
1
laglage ttttkr eeCC
0
Dose
ka
Cp ke
kill (-) Cr
k0 kecr
Bacteria2
501max 1 k
CrIC
CrkK
Comparing to Emax model:
Modified Emax Model:
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control
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (hours)
100
101
102
103
104
105
106
107
108
109
1010
1011
1012
CF
U/m
L
0.03 0.06 0.13 0.25 0.5
E. coli (MIC=0.013 mg/L)
t (h)
CF
U/m
L
0 12 24 36 4810-5
10-4
10-3
10-2
10-1
100
101
102
103
104
105
106
107control 0.03 0.25 0.50.130.06
E. coli
Two sub-population model
(simultaneous fit)
Modified Emax model
(simultaneous fit)
Model Comparison – E. coli
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• 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
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Proposal
Wild Card Patent Extension
A company that receives approval for a new antibiotic, or a new indication for an existing
antibiotic, that treats a targeted pathogen would be permitted to extend the market exclusivity period for
another of the company’s FDA-approved drugs.
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ISAPInternational Society of Anti-
Infective Pharmacology• Workshops at ECCMID and ICAAC• Symposia at ECCMID and ICAAC• Joint Symposium with FDAand IDSA• Website with slides, presentations and tons of
information
www.isap.org
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AcknowledgementsEdgar Schuck
Qi Liu
Ping Liu
Teresa Dalla Costa
Amparo de la Peña
Ariya Khunvichai
Arno Nolting
Wanchai Treeyaprasert
Stephan Schmidt
Elizabeth Potocka
Martin Brunner
Markus Müller
Kenneth Rand
Alistair Webb
Maria Grant
Andreas Kovar
Olaf Burkhardt
Vipul Kumar
Yanjun Li
Oliver Ghobrial
April Barbour