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Rational Dosing: The Use of
Plasma Concentrations vs.
Tissue Concentrations
Hartmut Derendorf, PhD
University of Florida
Drug Delivery
?
Biopharmaceutics
Pharmacokinetics
?
PK-PD-Modelling
Pharmacodynamics
Pharmacokinetics
Pharmacodynamics
conc. vs time
0.4
conc. vs effect
Conc.
Effect
1
0.0
Time
0
25
10-4
PK/PD
effect vs time
1
Effect
0
0
0
Time
25
Conc (log)
10-3
Concentration (µg/mL)
16
Cmax
AUC > MIC
12
8
•Time above MIC
•AUC above MIC
•Cmax/MIC
•AUC24/MIC (AUIC)
MIC
4
0
0
6
t > MIC
12
24
18
Time (hours)
FDA Bioequivalence Definition
„ ... rate and extent … and becomes available
at the site of action.“
FDA Guidance for Industry 1997
Part IV „Clinical Issues, Pharmacokinetics“
„... Pharmacodynamics should include relating drug
concentrations at the site of action to the in vitro
susceptibilty of the target microorganism.“
vascular space
plasma
protein
binding
extravascular space
binding to
extracellular
biological
material
blood cell
binding,
tissue cell
binding,
diffusion into
blood cells,
diffusion into
tissue cells,
binding to
intracellular
biological
material
binding to
intracellular
biological
material
Significance of free tissue levels
•Only the free, non-bound drug can be
pharmacologically active
•Hence, total drug concentrations (“tissue levels”)
should not be related to pharmacological activity
•From a pharmacological and clinical point of
view, free tissue levels are most significant with
respect to therapeutic outcome
Experimental Determination of
Free Tissue Concentrations
• Skin Blister Studies
• Microdialysis
Skin Blister
Kiistala (1968)
Skin Blister
Kiistala (1968)
Ampicillin
Cloxacillin
 Serum
 Free blister fluid
Microdialysis
Dialysate
Perfusate
(Ringer’s)
Tissue
Perfusate
Dialysate
Interstitium
Capillary
Cell
No net flux method
Dialysate
Cout
Perfusate
Cin
Tissue
CT
If Cin > CT, then Cout < Cin
If Cin < CT, then Cout > Cin
No Net Flux Method
Cin - Cout
4
n=4
2
0
-2
-4
-6
0
5
10
15
Cin
Recovery: 37 ± 5 %
20
Piperacillin
concentration [µg/ml]
103
102
101
100
0
20
40
60
time [min]
80
100
120
Ceftriaxone
50 mg/kg
dose 1
measured plasma conc.
fitted line
concentration [µg/ml]
103
measured tissue conc.
calculated conc.
102
101
100
10-1
0
50
100
150
time [min]
200
250
300
Ceftriaxone
1
100 dose
mg/kg
103
measured plasma conc.
fitted line
measured tissue conc.
concentration [µg/ml]
calculated conc.
102
101
100
0
50
100
150
time [min]
200
250
300
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.
Example
Development of an Oral Sustained
Release Formulation for Cefaclor
NH2
O
HN
OH
N
O
H
O
S
Cl
Pharmacokinetics
Human Studies
Muscle
Lung
Animal Studies
Muscle
Lung
Microdialysis in Muscle
Lung Microdialysis
Cefaclor in Rats
Total plasma and free tissue levels
50 50mg/kg
mg/kg i.v.
7575mg/kg
mg/kg i.v.
103
Cefaclor (mcg/ml)
Cefaclor (mcg/ml)
103
102
101
100
0
20
40
60
80
100
120
Time (min)
Plasma
102
101
100
0
20
40
60
Time (min)
Cf muscle
Cf lung
80
100
120
Conclusions - Rats
Microdialysis can be used to determine free cefaclor
concentrations in muscle and lung tissue.
Free concentrations of cefaclor in both lung and muscle
tissue have almost identical profiles and are lower than the
respective free plasma concentrations.
Since unbound concentrations in muscle and lungs are
equal in rats, Cf,muscle may be used as an estimate of Cf,lung
in humans.
Human study
12 healthy male human volunteers
PO Doses:
500 mg IR (immediate release)
500 mg MR (modified release)
750 mg MR (modified release)
Tissue: muscle
Total sampling time: 12 hours
microdialysis every 20 minutes
Probe insertion
Plasma and free tissue levels
500mgmg
500
IR IR
- M eans
15
C e fa clo r (mcg /ml)
12
9
6
3
0
0
1
2
3
4
Time (hours)
n = 12 (means +/- S.D.)
 total plasma concentrations
 free tissue concentrations
5
6
Plasma and free tissue levels
500 mg MR
750 mg MR
750 mg AF - Means
12
9
9
Cefac lor (m c g/m l)
Cefaclor (mcg/ml)
500 mg AF - Means
12
6
3
0
6
3
0
0
1
2
3
4
5
6
0
T ime (hours)
n = 12 (means +/- S.D.)
 total plasma concentrations
 free tissue concentrations
1
2
3
Time (hours)
4
5
6
Conclusions - Humans
Oral absorption of cefaclor can be sustained, but only to
about 3h due to the presence of an absorption window
Relative bioavailability of the modified release product is
approximately 80%
Microdialysis can be used to determine free cefaclor
concentrations in human muscle tissue.
Free concentrations of cefaclor in muscle tissue are lower
than respective free plasma concentrations.
Pharmacodynamics
•in vitro studies
steady state
dilution models
diffusion models
•animal studies
•clinical studies
MIC
The Current Paradigm
MIC is a well established laboratory parameter routinely
determined in microbiology
MIC is by far the most common pharmacodynamic
parameter for anti-infective agents
Most PK/PD-approaches for anti-infectives are based on
MIC (e.g. AUIC, t>MIC, Cmax/MIC)
Drug concentrations are compared to MIC to make dosing
decisions
Kill Curves
Dilution
Filter
1) Inoculum
2) Dose
3) Sample
PK-PD Model
k max  C f
dN 
 k
dt 
EC50  C f

 N


Maximum Growth Rate Constant
k
Maximum Killing Rate Constant
k-kmax
Initially, bacteria are in log growth phase
Single Dose
Piperacillin vs. E. coli
1014
control
1013
1012
1011
CFU/mL
1010
2g
109
108
4g
107
8g
106
105
104
103
102
101
100
0
2
4
6
Time (h)
8
10
Betalactam antibiotics kill time-dependent
Piperacillin vs. E. coli
50µg/mL q4h
10 11
10 11
10 10
10 9
10 8
10 7
10 6
10 5
10 4
10 3
10 2
CFU/mL
CFU/mL
100µg/mL q8h
0
5
10
15
Time (h)
4g q8h
20
25
10 10
10 9
10 8
10 7
10 6
10 5
10 4
10 3
10 2
0
5
10
15
Time (h)
2g q4h
20
25
M. cat: 0.5 µg/mL, 2-dose
108
108
107
107
CFU/mL
109
106
105
106
105
104
104
103
103
102
102
0
2
4
6
0
8
2
4
6
8
Time (hours)
T ime (hours)
S. pneumo: 5 µg/mL
S. pneumo: 5 µg/mL, 2-dose
109
109
108
108
107
107
CFU/mL
CFU/mL
CFU/mL
M. cat: 0.5 µg/m L
109
106
105
106
105
104
104
103
103
102
102
0
2
4
Time (hours)
6
8
0
2
4
Time (hours)
6
8
750 mg MR bid vs 500 mg IR tid
Moraxella catarrhalis
10 11
10 10
10 9
10 8
CFU/ml
10 7
10 6
10 5
10 4
10 3
10 2
10 1
10 0
10 -1
0
6
12
tim e (h)
18
24
750 mg MR bid vs 500 mg IR tid
Streptococcus pneumoniae
10 13
10 12
10 11
10 10
CFU/ml
10 9
10 8
10 7
10 6
10 5
10 4
10 3
10 2
10 1
0
6
12
tim e (h)
18
24
500 mg MR bid vs 500 mg IR tid
Moraxella catarrhalis
1011
1010
109
108
CFU/ml
107
106
105
104
103
102
101
100
10-1
0
6
12
time (h)
18
24
500 mg MR bid vs 500 mg IR tid
Streptococcus pneumoniae
10 13
10 12
10 11
10 10
CFU/ml
10 9
10 8
10 7
10 6
10 5
10 4
10 3
10 2
10 1
0
6
12
tim e (h)
18
24
Conclusions
Cefaclor-Study
A suitable PK/PD model was successfully applied to link different cefaclor
dosing regimens to their respective anti-infective activity.
Using PK/PD, different dosing regimens can be compared taking into account
the therapeutically active concentrations at the site of action.
The results show that in spite of a 78-84% relative bioavailability 500 mg MR
bid are equivalent to 500 mg IR tid.
Furthermore, the same total daily dose (1.5 g) is more effective when given in a
sustained way: 750 mg MR bid is more effective than 500 mg IR tid.
Comparison of Emax-model vs. MIC
Emax-model is two-dimensional (Emax, EC50) whereas MIC is
mono-dimensional.
Emax-model allows for gradual changes in pharmacodynamic
activity whereas MIC is a threshold value.
Emax-model can be integrated in PK-PD models to
characterize the complete effect-time-relationship whereas
MIC can only be used in integrated models (AUIC, t>MIC).
Emax-model is more complex than MIC. However, today’s
computer software can handle this with ease.
Emax-model allows for more differentiated dose
recommendation based on microbiological data than MIC.
Conclusion
The free (unbound) concentration of
the drug at the receptor site should be
used in PK/PD correlations to make
prediction for pharmacological activity
Conclusions
• Simple comparisons of serum concentrations and MIC
are not sufficient for proper evaluation of antibiotic
agents and their dosing schemes
• Protein binding and tissue distribution are critical
pharmacokinetic properties that need to be considered
• Pharmacodynamic kill curves can provide more detailed
information about the pharmacodynamics than MICs
Acknowledgements
Markus Müller
Arno Nolting
Teresa Dalla Costa
Andreas Kovar
Amparo de la Peña
Ping Liu
Kenneth Rand
Alistair Webb