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The General Concepts ofPharmacokinetics and

Pharmacodynamics

Hartmut Derendorf, PhDUniversity of Florida


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PHARMACOKINETICS

what the body does to the drug

PHARMACODYNAMICS

what the drug does to the body


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Pharmacokineticsconc. vs time

Conc.

Time0 25

0.0

0.4

PK/PDeffect vs time

Time

Effect

0

1

0 25

Pharmacodynamicsconc. vs effect

0

1

10-4 10-3Conc (log)

Effect


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Pharmacokinetics

the time course of drug and metabolite

concentrations in the body


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Pharmacokinetics helps

to optimize drug therapy:

dose dosage regimen

dosage form


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Right on Target


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Right on Target


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What happens to a drug after its administration ?("Fate of drug")

Liberation

AbsorptionDistribution

Metabolism

Excretion


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Clearance

Volume of distribution

Half-life

Bioavailability

Protein Binding

Pharmacokinetic Parameters


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Clearance

quantifies ELIMINATION

is the volume of body fluid cleared per time

unit (L/h, mL/min)

is usually constant


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Clearance

Eliminating

Organ

CL = QE

Q Blood Flow

E Extraction Ratio


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Clearance

Parameters: Blood Flow, intrinsic clearance, protein binding

Good prediction of changes in clearance

Steady state

Q

Ci CoEliminating

Organ

int

int

CLfQ

CLfQCL

EQCL

C

CC

E

u

u

i

oi

+

=

=

=


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High-extraction drugs

Low-extraction drugs

QCL =

intCLfCL u =

int

int

int

CLfQCLfQ

CLfQCL

u

u

u

>

+

=


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Clearance

Clearance can be calculated from

Excretion rate / Concentratione.g. (mg/h) / (mg/L) = L/h

Dose / Area under the curve (AUC)e.g. mg / (mgh/L) = L/h


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Clearance

Total body clearance is the sum ofthe individual organ clearances

CL = CLren + CLhep + CLother


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Volume of Distribution

- quantifies DISTRIBUTION

- relates drug concentration (Cp)

to amount of drug in the body (X)

- gives information on the amount of

drug distributed into the tissues

Vd = X / Cp


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Apparent Volume of Distribution

X

V

C2 = X / Vd

Vd = X / C2

X

V

C1 = X / V

V = X / C1

C1 C2

C1 > C2

V < Vd


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Volume of Distribution

Dicloxacillin 0.1 L/kgGentamicin (ECF) 0.25 L/kg

Antipyrine (TBW) 0.60 L/kgCiprofloxacin 1.8 L/kgTigecycline 8 L/kg

Azithromycin 31 L/kg


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Half-Life

Half-life is the time it takes for the concentration

to fall to half of its previous value

Half-life is a secondary pharmacokinetic parameter

and depends on clearance and volume of distribution

CL

Vdt = 693.02/1


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Half-Life

CL k Vd =

k elimination rate constantCL clearanceVd volume of distribution

kkt

693.02ln2/1 ==


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Bioavailability

f is the fraction of the administered dose

that reaches the systemic circulation

- quantifies ABSORPTION

iv

po

AUC

AUCF =


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BioavailabilityRate and Extent of Absorption

Cmax

0

10

20

30

40

50

60

70

Concentration

(ng/ml) Cmax

0 2 4 6 8 10 12

Time (hours)tmaxtmax


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Protein Binding

reversibe vs. irreversible linearvs. nonlinear

rapid equilibrium

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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vascular space extravascular space

plasmaproteinbinding

blood cellbinding,

diffusion intoblood cells,

binding tointracellularbiologicalmaterial

tissue cellbinding,

diffusion intotissue cells,

binding tointracellularbiologicalmaterial

binding to

extracellularbiologicalmaterial


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Interstitium

CapillaryCell

Perfusate

Dialysate

Microdialysis


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Microdialysis


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Pharmacokinetic profile of cefpodoxime(400 mg oral dose, n = 6)

01

2

3

4

5

6

0 2 4 6 8 10

Time (h)

Co

ncentration

(mg/L)

plasma muscle free plasma


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Pharmacokinetic profile of cefixime

(400 mg oral dose, n = 6)

0

1

2

3

4

5

6

0 2 4 6 8 10

Time (h)

Concentrato

in(mg/L)

plasma muscle free plasma

Mean SD


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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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Two-compartment model

Xp

E

D

k12

DoseXc Drug in the central compartment

Xp Drug in the peripheral compartment

Drug eliminated

Xck 10

k21


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Two-compartment model

0 1 2 3 4 5 6 7 8

Time (hours)

10-1

100

101

102

103


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Short-term infusion

t [h]

0 2 4 6 8

Cp[g/ml]

0.1

1

10

Cp*max

Cp*min

Cpmin

Cpmax


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Three-compartment model

Xp

E

D

k12

D Dose

E Drug eliminated

Xck

10

k21

k31

k13

Xps

d

Xc Drug in the central compartment

Xps Drug in the shallow peripheral compartment

Xpd Drug in the deep peripheral compartment


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Three-compartment model

C a e b e c et t t

= + +

-phase: distribution phase

-phase: rapid elimination phase

-phase: slow elimination phase


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XC

XPs

XPd

t [h]

0 48 96 144 192 240 288 336

X[mg]

0

100

200

300

400

500

600


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Drug Delivery

Pharmacokinetics

Pharmacodynamics

Biopharmaceutics

PK-PD-Modeling

?

?

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