The General Concepts of Pharmacokinetics and
Pharmacodynamics
Hartmut Derendorf, PhDUniversity of Florida
PHARMACOKINETICS
what the body does to the drug
PHARMACODYNAMICS
what the drug does to the body
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
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
Clearance
Volume of distribution
Half-life
Protein Binding
Bioavailability
Pharmacokinetic Parameters
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
Parameters: Blood Flow, intrinsic clearance, protein bindingGood prediction of changes in clearance
Steady state
Q
Ci CoEliminating
Organ
int
int
CLfQ
CLfQCL
EQCL
C
CCE
u
u
i
oi
High-extraction drugs
Low-extraction drugs
QCL
intCLfCL u
int
int
int
CLfQ
CLfQ
CLfQCL
u
u
u
int
int
int
CLfQ
CLfQ
CLfQCL
u
u
u
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 / (mg·h/L) = L/h
Clearance
Total body clearance is the sum of the individual organ clearances
CL = CLren + CLhep + CLother
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
Apparent Volume of DistributionX
V
C2 = X / Vd
Vd = X / C2
X
V
C1 = X / V
V = X / C1
C1 C2
C1 > C2
V < Vd
Volume of Distribution
Dicloxacillin 0.1 L/kgGentamicin (ECF) 0.25 L/kgAntipyrine (TBW) 0.60 L/kgCiprofloxacin 1.8 L/kgAzithromycin 31 L/kg
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
Half-Life
k elimination rate constantCL clearanceVd volume of distribution
kkt
693.02ln2/1
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 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
Interstitium
CapillaryCell
PerfusateDialysate
Microdialysis
Microdialysis
Bioavailability
f is the fraction of the administered dose that reaches the systemic circulation
- quantifies ABSORPTION
iv
po
AUC
AUCF
BioavailabilityRate and Extent of
Absorption
Cmax
0
10
20
30
40
50
60
70C
on
ce
ntr
atio
n (
ng
/ml)
Cmax
0 2 4 6 8 10 12
Time (hours) tmaxtmax
Compartment Models
Parameters: Rate constants, interceptsLinear and nonlinear regression
Complete concentration-time-profilesSteady-state and non-steady-state
Intravenous bolus
X E
D
k
D Dose
X Drug in the body
E Drug eliminated
One compartment model
Intravenous bolusPlasma concentration (single dose)
tkeCC 0
Vd
DC 0
D DoseC0 Initial ConcentrationVd Volume of Distribution
Normal Plot Semilogarithmic Plot
Intravenous bolus
Intravenous bolusPlasma concentration (multiple dose, steady state)
CC e
e
k t
k
0
1
CC
e kmax
0
1 CC e
e
k
kmin
0
1
Peak Trough
Intravenous bolusMultiple Dose
First-order absorption
A E
D
k
Dose
Drug at absorption site
Drug in the body
Drug eliminated
Xka
f
One compartment model
Oral administrationPlasma concentration (single dose)
CF D k
k k Vde ea
a
k t k ta
Oral administration
t [h]
0 2 4 6 8 10 12
Cp
[ng/
mL]
0
100
200
300
400
Oral administration
Average concentration (multiple dose, steady state)
CF D
CL
Oral administrationMultiple Dose
One compartment model
A E
D
k
Dose
Drug at absorption site
Drug in the body
Drug eliminated
XR0
f
Zero-order absorption
Constant rate infusionPlasma concentration (during infusion)
CR
CLe k t 0 1
Constant rate infusion
Constant rate infusionPlasma concentration (steady state)
CR
CL 0
Two-compartment model
Xp
E
D
k12
Dose
Xc Drug in the central compartment
Xp Drug in the peripheral compartment
Drug eliminated
Xc
k10
k21
Two-compartment modelPlasma concentration (single i.v. bolus dose)
C a e b et t
-phase: distribution phase
-phase: elimination phase
t [h]
0 1 2 3 4 5 6 7 8
Cp
[g/
mL]
0.1
1
10
100
Two-compartment model
Two-compartment model
Xp
Xc
Xp
Xc
Xp
Xc
initially steady state elimination phase
VD
Cc 0
Vdk
kVss c
1 12
21
VdCL
area
Volume of distribution
Two-compartment model
0 1 2 3 4 5 6 7 8
Time (hours)
10-1
100
101
102
103
C (n
g/m
l)
Short-term infusion
T
Cmax
C
18 19 20 21 22 23 24
t (h)
100
101
102
103
Cp (µ
g/m
l)
C* Cmin
*max
min
k
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
XC
XPs
XPd
t [h]
0 48 96 144 192 240 288 336
X [m
g]
0
100
200
300
400
500
600
Significance of Pharmacokinetic Parameters for Dosing
CLCDF
CLCR
desired
desired
0
VdCLD desired
)min(
)max(
desired
desired
C
CPTR
693.0
)ln( 2/1tPTR
Maintenance Dose
Loading Dose
Fluctuation
Dosing Interval
Drug Delivery
Pharmacokinetics
Pharmacodynamics
Biopharmaceutics
PK-PD-Modeling
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