Rational Dosing: The Use of Plasma Concentrations vs.

Tissue Concentrations

Hartmut Derendorf, PhDUniversity of Florida

Drug Delivery

Pharmacokinetics

Pharmacodynamics

Biopharmaceutics

PK-PD-Modelling

?

?

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

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)

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 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

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

• Skin Blister Studies• Microdialysis

Experimental Determination of Free Tissue Concentrations

Skin Blister

Kiistala (1968)

Skin Blister

Kiistala (1968)

Ampicillin

Cloxacillin

Serum Free blister fluid

MicrodialysisDialysate

Perfusate(Ringer’s)

Tissue

Interstitium

CapillaryCell

PerfusateDialysate

No net flux method

TissueCT

DialysateCout

PerfusateCin

If Cin > CT, then Cout < Cin

If Cin < CT, then Cout > Cin

No Net Flux Method

Recovery: 37 ± 5 %

n = 4

0 20 40 60 80 100 120100

101

102

103

con

cen

trat

ion

[µ

g/m

l]

time [min]

Piperacillin

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

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

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.

ExampleDevelopment of an Oral Sustained Release Formulation for Cefaclor

NH2

HN

O N

O

HS

OH

O

Cl

M uscle

Lung

H um an S tud ies

M uscle Lung

Anim al S tud ies

Pharm acokinetics

Microdialysis in Muscle

Lung Microdialysis

Cefaclor in RatsTotal plasma and free tissue levels

50 mg/kg 75 mg/kg

Plasma Cf muscle Cf lung

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 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

Probe insertion

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

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 studiessteady state

dilution models

diffusion models

•animal studies

•clinical studies

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

Filter

Kill Curves

1) Inoculum

2) Dose

3) Sample

Dilution

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

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

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

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

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

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

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

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

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.

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

AcknowledgementsMarkus Müller

Arno Nolting

Teresa Dalla Costa

Andreas Kovar

Amparo de la Peña

Ping Liu

Kenneth Rand

Alistair Webb