1

Pharmacodynamic models
2
Interactions
Pharmacological
Targets
ABSORPTION
PHARMACODYNAMICS
Dose response relation : PK and PD stages
ELIMINATION
DISTRIBUTION
Functional
Therapeutic
Response
PHARMACOKINETICS
Biophase
Concentrations
Bacteria
Insects
Parasites
Plasma
Concentrations
Cellular
Action
Administered
drug
3
Population Dose-Response : Variability
Mild Extreme
Many
Few


N
u
m
b
e
r

o
f

I
n
d
i
v
i
d
u
a
l
s


Response to SAME dose
Sensitive
Individuals



Maximal
Effect
Resistant
Individuals



Minimal
Effect
Majority of
Individuals

Average Effect
5
Digoxin in Human: Therapeutic and adverse effects
Variability of pharmacodynamic origin
6
Pharmacokinetics / Pharmacodynamics
Quantification of drugs effects
To link intensity of the effect with drug concentration
Objective: to determine the range of drug concentrations (drug
exposure) associated with a desired effect
Quantification of drug disposition processes
To link the quantity of administered drug with plasma and tissular
concentrations
Objective: to determine the external (administered) doses that
produce a given exposure
7
Effect Endpoints
Graded
Quantal
Continuous scale (dose effect)
Measured in a single biologic unit
Relates dose to intensity of effect
All-or-none pharmacologic effect
Population studies
Relates dose to frequency of effect
8
Relation between concentration and
the intensity of an effect
Direct effects models
Indirect effects models

Relation between concentration and
probability of occurrence of an effect
Fixed-effect model

9
Direct effect models
Models describing relations between intensity of an effect
and drug concentrations at the site of action
Can be used in in vivo PK/PD modelling when it exists a
direct and immediate link between plasma concentrations
and effect


Emax model
Simplifications of the Emax model :
Linear model
Log-linear model
A useful extension of the Emax model :
Sigmod-Emax model
10
concentration
Effect /response
11
concentration
Effect /response
12
concentration
Effect /response
Emax
Emax / 2
EC
50
POTENCY
EFFICACY
E =
E
max
. C
EC
50
+ C
13
Emax model
Relation described by two parameters
E
max
: intrinsic activity, EFFICACY
EC
50
: conc. Associated with half-maximal effect
POTENCY
Empirical justifications
The most simple mathematical description of the occurrence of a
maximum

Theoretical justifications
Ligand-receptor interaction
E =
E
max
. C
EC
50
+ C
14
Drug-Receptor Interactions
k
1

k
2

Drug
Receptor
Effect
Drug-Receptor
Complex
(K
D
= k
2
/k
1
)
Ligand-binding
domain
Effector domain
| |
| | | |
| | Drug K
Drug Receptor
Complex
D
max
+

=
15
Consequences of amplification phenomenon
Log[conc.]
Binding to the receptor
100 %

50 %

K
D EC
50
EC
50
< K
D
Effect
16
Log[conc.]
Range of therapeutic concentrations :
100 %

50 %

K
D EC
50
- No enzyme saturation
- Linear kinetics
Consequences of amplification phenomenon
Binding to enzyme Effect
17 concentrations Log [concentrations]
Graphical representations
Emax model
18
Theoretical basis
[L] + [R] [RL] Effect
relations K
D
/ EC
50

Graphical representation
conc. in arithmetic scale : hyperbola
conc. in logarithmic scale : sigmod
Comparison of drugs in term of efficacy and
potency
Emax model
19
Less potent, more efficacious
More potent, less efficacious
A
B
EC
50
,
A

EC
50
,
B

Log (concentrations)
Efficacy and potency
Effect
E
max
,
A

E
max
,
B

Emax model
20
Inhibition of an effect :
Emax-inhibition
Fractional Emax-inhibition




E = E
0
-
I
max
. C
IC
50
+ C
Emax-inhibition
E = E
0
.(1 -
C
IC
50
+ C
)
21
Simplifications of the Emax model
Linear model
Log-linear model
22
Linear model
E = S.C + E
0

Effect is linearly related to concentrations
Parameters of the model (S, E
0
) are estimated by linear
regression

23
conc
Effect /response
Emax
Emax / 2
EC
50
Linear model
24
E = S.C + E
0

Examples : in vivo plasma concentrations of
digoxin and systolic function
quinidine and duration of Q-T interval
verapamil and duration of P-R interval
pilocarpine and salivary flow
Linear model
25
Log-linear model
E = S.logC + b
Developed with in vitro pharmacology
Graphical characteristic of log transformation
Wide concentration ranges : zoom on the small
concentrations
Linearization of the portion of the curve from 20%
to 80% of maximal effect : linear regression to estimate
the slope
Problem : maximal effect is not estimated
26
Log conc
Effect /response
Emax
Emax / 2
EC
50
Log-linear model
27
E = S.logC + E
0

Examples : in vivo plasma concentrations of
propranolol and reduction of
exercise-induced tachycardia
Log-linear model
28
Extension of Emax model
Sigmod Emax model
29
Sensitivity of the concentration-effect relation
E =
E
max
. C
n

EC
50
n
+ C
n

Sigmod Emax model
Log[conc.]
Effect
E
80
E
20
30
Empirical model
when conc.-effect relation cannot be not fitted with Emax
the third parameter provides flexibility around the
hyperbola

Influence of n the shape of the relation
n = 1: classical Emax
n < 1: upper before EC
50
, lower after EC
50

n > 1: lower before EC
50
, upper after EC
50


E =
E
max
. C
n

EC
50
n
+ C
n

Sigmod Emax model
31
Empirical model
Introduced by Archibald Hill to describe the cooperative binding
of oxygen to haemoglobin : Hill coefficient
Theoretical basis : receptor occupancy

Examples : in vivo plasma concentrations
n < 1 : Conc.-effect relation very flat propranolol
n > 5 : all-or-none response tocaidine /NSAID
n = SENSITIVITY of the conc-effet. relation
Sigmod Emax model
32
Sensitivity : influence of the pharmacodynamic endpoint
Log[conc.]
Effect
COX inhibition
Quantification of lameness (force
plate)
E
80
Surrogate endpoint
versus
Clinical endpoint
Sigmod Emax model
NSAID
33
Sensitivity of the concentration-effect relation
Impact on selectivity and safety
Therapeutic index
TD
50
ED
50
TD
1
ED
99
Safety factor
34
Extension of Emax model
Sigmod Emax model
Sigmod Emax inhibition
35
0
10
20
30
40
50
60
70
80
90
100
1 10 100 1000 1000
Melatonine (ng/mL)
Observed
Predicted
Sigmoid Emax-inhibition
B
C
X
D A
D Y
|
.
|

\
|
+

+ =
1
n n
n
X EC
X E
E Y
+

=
50
max
0
36
Relation between concentration and
the intensity of an effect
Direct effects models
Indirect effects models

Relation between concentration and
probability of occurrence of an effect
Fixed-effect model

37
Response
(R)
Kin Kout
= Kin - Kout*R
dR
dt
Decrease of the response
Increase
of the response
+ -
- +
Indirect effect models
38
Relation between concentration and the
intensity of an effect
Direct effects models
Indirect effects models

Relation between concentration and
probability of occurrence of an effect
Fixed-effect model

39
Fixed-effect model
The link between a concentration and the probability
of occurrence of a defined effect
Concept of threshold concentration
The threshold concentration is different from a subject
to another one : it is a random variable, characterized
by a distribution in the population
We can association concentrations with a probability
of occurrence of the effect
Example : adverse effects of digoxin

40
Histogram
20
40
60
80
100
120
20 %
40 %
60 %
80 %
100 %
C
10%
C
50%

Fixed-effect model

Variability of pharmacodynamic origin
Determination of the therapeutic window
41
Sensitivity of the concentration-effect relation
Impact on selectivity and safety
Sensitivity of the relation
=
variability of the response in the population
42
Transformation of the probability of the response
Logit
e
P

+
=
1
1
( )
( )
| | +

= ; -
P 1
P
Ln P Logit
| | 1 ; 0 P
Fixed-effect model : the logistic regression
Assumption: the Logit is linearly linked to the explicative variable
( ) .X P Logit
2 1
+ =
Reciprocal of the Logit equation :
( ) .X
2 1
e 1
1
P
+
+
=