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![Page 1: Rational Dosing: The Use of Plasma Concentrations vs. Tissue Concentrations Hartmut Derendorf, PhD University of Florida.](https://reader036.fdocuments.us/reader036/viewer/2022062314/56649ec85503460f94bd4666/html5/thumbnails/1.jpg)
Rational Dosing: The Use of Plasma Concentrations vs.
Tissue Concentrations
Hartmut Derendorf, PhDUniversity of Florida
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Drug Delivery
Pharmacokinetics
Pharmacodynamics
Biopharmaceutics
PK-PD-Modelling
?
?
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Pharmacokineticsconc. vs time
Co
nc
.
Time0 25
0.0
0.4
PK/PDeffect vs time
Time
Eff
ec
t
0
1
0 25
Pharmacodynamicsconc. vs effect
0
1
10-4 10-3Conc (log)
Eff
ec
t
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0 6 18 24
12
Con
cent
ratio
n (µ
g/m
L)
0
8
12
16
4
MIC
CmaxAUC > MIC
t > MIC
Time (hours)
•Time above MIC•AUC above MIC•Cmax/MIC•AUC24/MIC (AUIC)
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FDA Bioequivalence Definition
„ ... rate and extent … and becomes available
at the site of action.“
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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.“
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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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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
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• Skin Blister Studies• Microdialysis
Experimental Determination of Free Tissue Concentrations
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Skin Blister
Kiistala (1968)
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Skin Blister
Kiistala (1968)
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Ampicillin
Cloxacillin
Serum Free blister fluid
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MicrodialysisDialysate
Perfusate(Ringer’s)
Tissue
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Interstitium
CapillaryCell
PerfusateDialysate
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No net flux method
TissueCT
DialysateCout
PerfusateCin
If Cin > CT, then Cout < Cin
If Cin < CT, then Cout > Cin
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No Net Flux Method
Recovery: 37 ± 5 %
n = 4
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0 20 40 60 80 100 120100
101
102
103
con
cen
trat
ion
[µ
g/m
l]
time [min]
Piperacillin
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co
nc
en
trat
ion
[µ
g/m
l]
time [min]
measured tissue conc.
measured plasma conc.
calculated conc.
fitted line
0 50 100 150 200 250 300
dose 1
10-1
100
101
102
103
50 mg/kg
Ceftriaxone
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Ceftriaxone
fitted line
calculated conc.
measured plasma conc.
measured tissue conc.
0 50 100 150 200 250 300
100
101
102
103
dose 1co
nce
ntr
atio
n [
µg
/ml]
time [min]
100 mg/kg
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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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ExampleDevelopment of an Oral Sustained Release Formulation for Cefaclor
NH2
HN
O N
O
HS
OH
O
Cl
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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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Microdialysis in Muscle
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Lung Microdialysis
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Cefaclor in RatsTotal plasma and free tissue levels
50 mg/kg 75 mg/kg
Plasma Cf muscle Cf lung
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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.
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Human study
12 healthy male human volunteersPO Doses:
500 mg IR (immediate release)500 mg MR (modified release)750 mg MR (modified release)
Tissue: muscleTotal sampling time: 12 hours
microdialysis every 20 minutes
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Probe insertion
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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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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.
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Pharmacodynamics
•in vitro studiessteady state
dilution models
diffusion models
•animal studies
•clinical studies
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MICThe 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
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Filter
Kill Curves
1) Inoculum
2) Dose
3) Sample
Dilution
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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
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)
Betalactam antibiotics kill time-dependentPiperacillin vs. E. coli
4g q8h 2g q4h
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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
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Moraxella catarrhalis
time (h)
CF
U/m
l
0 6 12 18 24
10-1
100
101
102
103
104
105
106
107
108
109
1010
1011
750 mg MR bid vs 500 mg IR tid
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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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500 mg MR bid vs 500 mg IR tid
10-1
100
101
102
103
104
105
106
107
108
109
1010
1011
CF
U/m
l
Moraxella catarrhalis
time (h)
0 6 12 18 24
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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
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ConclusionsCefaclor-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.
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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.
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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
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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
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AcknowledgementsMarkus Müller
Arno Nolting
Teresa Dalla Costa
Andreas Kovar
Amparo de la Peña
Ping Liu
Kenneth Rand
Alistair Webb