Transcript No Slide Title

The General Concepts of
Pharmacokinetics and
Pharmacodynamics
Hartmut Derendorf, PhD
University of Florida
PHARMACOKINETICS
what the body does to the drug
PHARMACODYNAMICS
what the drug does to the body
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
Pharmacokinetics
the time course of drug and metabolite
concentrations in the body
Pharmacokinetics helps
to optimize drug therapy:
dose
dosage regimen
dosage form
What happens to a drug after its administration ?
("Fate of drug")
Liberation
Absorption
Distribution
Metabolism
Excretion
Pharmacokinetic Parameters
Clearance
Volume of distribution
Half-life
Bioavailability
Protein Binding
Clearance
 quantifies ELIMINATION
 is the volume of body fluid cleared per time
unit (L/h, mL/min)
 is usually constant
Clearance
Eliminating
Organ
CL = Q·E
Q Blood Flow
E
Extraction Ratio
Clearance
Q
Ci
Eliminating
Organ
Co
Ci  Co
E
Ci
CL  Q  E
Q  f u  CLint
CL 
Q  f u  CLint
Parameters: Blood Flow, intrinsic clearance, protein binding
Good prediction of changes in clearance
Steady state
High-extraction drugs
Q  fu  CLint
CL 
Q  fu  CLint
CL  Q
Q  fu  CLint
Low-extraction drugs
Q  fu  CLint
CL 
Q  fu  CLint
Q  fu  CLint
CL  fu  CLint
Clearance
Clearance can be calculated from
 Excretion rate / Concentration
e.g. (mg/h) / (mg/L) = L/h
 Dose / Area under the curve (AUC)
e.g. mg / (mg·h/L) = L/h
Clearance
Total body clearance is the sum of
the individual organ clearances
CL = CLren + CLhep + CLother
Volume of Distribution
Vd = X / Cp
- 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
Apparent Volume of Distribution
X
X
V
V
C1
C2
C1 > C2
C1 = X / V
V = X / C1
V < Vd
C2 = X / Vd
Vd = X / C2
Volume of Distribution
Dicloxacillin
Gentamicin (ECF)
Antipyrine (TBW)
Ciprofloxacin
Azithromycin
0.1 L/kg
0.25 L/kg
0.60 L/kg
1.8 L/kg
31 L/kg
Half-Life
t1/ 2
0.693  Vd

CL
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
Half-Life
t1/ 2
ln 2 0.693


k
k
CL  k  Vd
k
CL
Vd
elimination rate constant
clearance
volume of distribution
Bioavailability
F
AUCpo
AUCiv
- quantifies ABSORPTION
f is the fraction of the administered dose
that reaches the systemic circulation
Bioavailability
Rate and Extent of Absorption
70
Cmax
Concentration (ng/ml)
60
Cmax
50
40
30
20
10
0
0
2
tmax tmax
4
6
Time (hours)
8
10
12
Protein Binding
• reversibe vs. irreversible
• linear vs. 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
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
Microdialysis
Perfusate
Dialysate
Interstitium
Capillary
Cell
Microdialysis
Pharmacokinetic profile of cefpodoxime
(400 mg oral dose, n = 6)
plasm a
Concentration (mg/L)
6
m uscle
free plasm a
5
4
3
2
1
0
0
2
4
6
Time (h)
8
10
Pharmacokinetic profile of cefixime
(400 mg oral dose, n = 6)
Concentratoin (mg/L)
6
plasma
muscle
free plasma
Mean ± SD
5
4
3
2
1
0
0
2
4
6
Time (h)
8
10
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)
Two-compartment model
D
k 10
Xc
k 12
E
k 21
Xp
Dose
Xc Drug in the central compartment
Xp Drug in the peripheral compartment
Drug eliminated
Two-compartment model
103
C (ng/ml)
102
101
100
10-1
0
1
2
3
4
Time (hours)
5
6
7
8
Short-term infusion
103
Cp (µg/ml)
Cmax
C*max
102
k
C*
min
101
Cmin
100
18
19
T
20
21
t (h)
22
23
24

Three-compartment model
d
Xp
k 31
k 13
D
Xc
k 12
k 10
E
k 21
s
Xp
D Dose
E Drug eliminated
Xc Drug in the central compartment
Xps Drug in the shallow peripheral compartment
Xpd Drug in the deep peripheral compartment
600
XPd
500
X [mg]
400
XPs
300
200
XC
100
0
0
48
96
144
192
t [h]
240
288
336
Drug Delivery
?
Biopharmaceutics
Pharmacokinetics
?
PK-PD-Modeling
Pharmacodynamics