An introduction to population kinetics

Didier Concordet
NATIONAL
VETERINARY
SCHOOL
Toulouse
Preliminaries
Definitions :
Random variable
Fixed variable
Distribution
Random or fixed ?
Definitions :
A random variable is a variable whose value changes
when the experiment is begun again. The value it takes
is drawn from a distribution.
A fixed variable is a variable whose value does not change
when the experiment is begun again. The value it takes
is chosen (directly or indirectly) by experimenter.
Example in kinetics
A kinetics experiment is performed on two groups of 10 dogs.
The first group of 10 dogs receives the formulation A of an active principle,
the other group receives the formulation B.
The two formulations are given by IV route at time t=0.
The dose is the same for the two formulations D = 10mg/kg.
For both formulations, the sampling times are t
1
= 2 mn, t
2
= 10mn, t
3
= 30 mn,
t
4
= 1h, t
5
=2 h, t
6
= 4 h.
|
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\
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= t
V
Cl
V
D
C
t
exp
Random or fixed ?

The formulation
Dose
The sampling times
The concentrations
The dogs
Fixed
Fixed
Fixed
Random
Fixed
Random
Analytical error
Departure to kinetic model
Population kinetics
Classical kinetics
Distribution ?
The distribution of a random variable is defined by the
probability of occurrence of the all the values it takes.
Clearance
0 0.1 0.2 0.3 0.4
8.0 7.8 8.2 8.4
Concentrations at t=2 mn
An example
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0 5 10 15 20 25 30 35 40 45
0
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0 5 10 15 20 25 30 35 40 45
30 horses
Time
C
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c
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t
r
a
t
i
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n

Step 1 : Write a PK (PK/PD) model
A statistical model
Mean model :
functional relationship
Variance model :
Assumptions on the residuals
Step 1 : Write a deterministic (mean)
model to describe the individual kinetics
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0 10 20 30 40 50 60 70
0
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40
60
80
100
120
140
0 10 20 30 40 50 60 70
Step 1 : Write a deterministic (mean)
model to describe the individual kinetics
|
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\
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= t
V
Cl
V
D
C
t
exp
0
20
40
60
80
100
120
140
0 10 20 30 40 50 60 70
Step 1 : Write a deterministic (mean)
model to describe the individual kinetics
residual
Step 1 : Write a model (variance) to
describe the magnitude of departure to the
kinetics
-25
-20
-15
-10
-5
0
5
10
15
20
25
0 10 20 30 40 50 60 70
Time
R
e
s
i
d
u
a
l

Step 1 : Write a model (variance) to
describe the magnitude of departure to the
kinetics
-25
-20
-15
-10
-5
0
5
10
15
20
25
0 10 20 30 40 50 60 70
Time
R
e
s
i
d
u
a
l

0 10 20 30 40 50 60 70
Step 1 : Describe the shape of departure to
the kinetics
Time
Residual
Step 1 :Write an "individual" model
j i j i
i
i
i
j i
i
i
i
j i
t
V
Cl
V
D
t
V
Cl
V
D
Y
, , , ,
exp exp c o
|
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|

\
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+
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\
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=
j i
Y
,
j i
t
,
j
th
concentration measured on the i
th
animal
j
th
sample time of the i
th
animal
residual
CV
Gaussian residual with unit variance
Step 2 : Describe variation between
individual parameters
Distribution of clearances
Population of horses
Clearance
0 0.1 0.2 0.3 0.4
Step 2 : Our view through a sample of
animals
Sample of horses Sample of clearances
Step 2 : Two main approaches
Sample of clearances
Semi-parametric approach
Step 2 : Two main approaches
Sample of clearances
Semi-parametric approach
(e.g. kernel estimate)
Step 2 : Semi-parametric approach
Does require a large sample size to provide results
Difficult to implement
Is implemented on confidential pop PK softwares
Does not lead to bias
Step 2 : Two main approaches
Sample of clearances
0 0.1 0.2 0.3 0.4
Parametric approach
Step 2 : Parametric approach
Easier to understand
Does not require a large sample size to provide (good or
poor) results
Easy to implement
Is implemented on the most popular pop PK softwares
(NONMEM, S+, SAS,)
Can lead to severe bias when the pop PK is
used as a simulation tool
Step 2 : Parametric approach
j i j i
i
i
i
j i
i
i
i
j i
t
V
Cl
V
D
t
V
Cl
V
D
Y
, , , ,
exp exp c o
|
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\
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+
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\
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=

+ =
+ =
V
V i
Cl
Cl i
i
i
V
Cl
q
q
ln
ln
Cl ln
V ln
A simple model :
Cl

ln Cl
ln V
Cl
o
V
o
( ) V Cl,
Step 2 : Population parameters
Cl

|
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\
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= O
2
2
V V Cl
V Cl Cl
o o o
o o o
Step 2 : Population parameters
Mean parameters
Variance parameters : measure inter-individual variability
Step 2 : Parametric approach
j i j i
i
i
i
j i
i
i
i
j i
t
V
Cl
V
D
t
V
Cl
V
D
Y
, , , ,
exp exp c o
|
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\
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+
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\
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=

+ =
+ + + =
V
V i
Cl
i i Cl i
i
i
V
age BW Cl
q
q u u
ln
ln
2 1
A model including covariables
Cl
i i Cl i
i
age BW Cl q u u + + + =
2 1
ln
Cl ln
BW
Age
Age
i

BW
i

age BW
Cl 2 1
u u + +
Cl
i
q
Step 2 : A model including covariables
Step 3 :Estimate the parameters of
the current model
Several methods with different properties
Naive pooled data
Two-stages
Likelihood approximations
Laplacian expansion based methods
Gaussian quadratures
Simulations methods
Naive pooled data : a single animal
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0 5 10 15 20 25 30 35 40 45
j j j j
t
V
Cl
V
D
t
V
Cl
V
D
Y c o
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\
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+
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\
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= exp exp
Does not allow to estimate
inter-individual variation.
Time
C
o
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c
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t
r
a
t
i
o
n

Two stages method: stage 1
C
o
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c
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n
t
r
a
t
i
o
n

j i j i
i
i
i
j i
i
i
i
j i
t
V
Cl
V
D
t
V
Cl
V
D
Y
, , , ,
exp exp c o
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+
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\
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=
0
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40
60
80
100
120
140
160
180
0 5 10 15 20 25 30 35 40 45
0
20
40
60
80
100
120
140
160
180
0 5 10 15 20 25 30 35 40 45
0
20
40
60
80
100
120
140
160
180
0 5 10 15 20 25 30 35 40 45
0
20
40
60
80
100
120
140
160
180
0 5 10 15 20 25 30 35 40 45
Time
( )
1 1

,

V l C
( )
2 2

,

V l C
( )
3 3

,

V l C

( )
n n
V l C

,

Two stages method : stage 2

Does not require a specific software
Does not use information about the distribution
Leads to an overestimation of O
which tends to zero when the number
of observations per animal increases
Cannot be used with sparse data

+ =
+ =
V
V i
Cl
Cl i
i
i
V
l C
q
q

ln

ln
The Maximum Likelihood Estimator
( ) ( ) ( )
i
N
i
i i i
d y h y l q u q u

}
=
=
1
, , exp ln ,
( )
V Cl
i i i
q q q , =
Let
( )
2 2 2
, , , , , o o o u
V Cl V Cl
=
( ) ( )
i
N
i
i i i
d y h Arg q u q u
u
}
=
=
1
, , exp ln inf

The Maximum Likelihood Estimator

u

is the best estimator that can be obtained among

the consistent estimators
It is efficient (it has the smallest variance)
Unfortunately, l(y,u) cannot be computed exactly
Several approximations of l(y,u)
Laplacian expansion based methods
First Order (FO) (Beal, Sheiner 1982) NONMEM
Linearisation about 0
( )
( )
( )
( ) ( ) ( )
( )
( )
( )
j i j i
V
Cl
V
Cl
i
V
i
V
i
Cl
i j i
V
Cl
V
j i j i
i
i
i
j i
i
i
i
j i
t
D
Z Z Z t
D
t
V
Cl
V
D
t
V
Cl
V
D
Y
, ,
3 2 1 ,
, , , ,
exp
exp
exp
exp
exp
exp
exp
exp
exp exp
c

o
q q u q u q u

c o
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+
+ + +
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~
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\
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+
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=
Laplacian expansion based methods
First Order Conditional Estimation (FOCE) (Beal, Sheiner) NONMEM
Non Linear Mixed Effects models (NLME) (Pinheiro, Bates)S+, SAS (Wolfinger)
( )( ) ( )( )
( )( )( )
j i j i
i
i
i
V
i
V
i
Cl
i
Cl
i i
V
i
V
i i
Cl
i
Cl
i i j i
i
i
i
j i j i
i
i
i
j i
i
i
i
j i
t
V
l C
V
D
Z
Z Z t
V
l C
V
D
t
V
Cl
V
D
t
V
Cl
V
D
Y
, , 3
2 1 ,
, , , ,

exp

,
, ,

exp

exp exp
c o q q q q q u
q q q u q q q u
c o
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+ +
+ +
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~
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|

\
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+
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=
Linearisation about the current prediction of the individual parameter
Laplacian expansion based methods
First Order Conditional Estimation (FOCE) (Beal, Sheiner) NONMEM
Non Linear Mixed Effects models (NLME) (Pinheiro, Bates)S+, SAS (Wolfinger)
( )( ) ( )( )
( )( )( )
j i j i
i
i
i
V
i
V
i
Cl
i
Cl
i i
V
i
V
i i
Cl
i
Cl
i i j i
i
i
i
j i j i
i
i
i
j i
i
i
i
j i
t
V
l C
V
D
Z
Z Z t
V
l C
V
D
t
V
Cl
V
D
t
V
Cl
V
D
Y
, , 3
2 1 ,
, , , ,

exp

,
, ,

exp

exp exp
c o q q q q q u
q q q u q q q u
c o
|
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\
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+ +
+ +
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~
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+
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=
Linearisation about the current prediction of the individual parameter
Gaussian quadratures
( ) ( ) ( )
( ) ( )

}
= =
=
~
=
N
i
P
k
i
k
i i
i
N
i
i i i
y h
d y h y l
1 1
1
, , exp ln
, , exp ln ,
u q
q u q u
Approximation of the integrals by discrete sums
Simulations methods
Simulated Pseudo Maximum Likelihood (SPML)
( )
( )
( ) o o o
o
o o
, , ln ,
1 2
, ,
2
1
D V D y
i
i
D V
i i
i
+

( )
( )
( )
( )

=
|
|
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|

\
|
+
+

+
=
K
k
j i
V
V
Cl
Cl
Cl
V
j i
t
D
K
K i
K i
K i
1
, ,
,
,
,
exp
exp
exp
exp
1
q
q
q
u
( ) u
i
V
simulated variance
Minimize
Properties
Naive pooled data Never Easy to use Does not provide
consistent estimate

Two stages Rich data/ Does not require Overestimation of
initial estimates a specific software variance components

FO Initial estimate quick computation Gives quickly a result
Does not provide
consistent estimate

FOCE/NLME Rich data/ small Give quickly a result. Biased estimates when
intra individual available on specific sparse data and/or
variance softwares large intra

Gaussian Always consistent and The computation is long
quadrature efficient estimates when P is large
provided P is large

SMPL Always consistent estimates The computation is long
when K is large
Criterion When Advantages Drawbacks
Step 4 : Graphical analysis

+ =
+ =
V
V i
Cl
Cl i
i
i
V
Cl
q
q
ln
ln

+ =
+ + + =
V
V i
Cl
i i Cl i
i
i
V
age BW Cl
q
q u u
ln
ln
2 1
0
20
40
60
80
100
120
140
160
180
0 20 40 60 80 100 120 140
0
20
40
60
80
100
120
140
160
0 20 40 60 80 100 120 140
Observed concentrations
P
r
e
d
i
c
t
e
d

c
o
n
c
e
n
t
r
a
t
i
o
n
s

Variance reduction
Step 4 : Graphical analysis
Time
j i,

c
-4
-3
-2
-1
0
1
2
3
0 10 20 30 40 50
-3
-2
-1
0
1
2
3
0 5 10 15 20 25 30 35 40 45
The PK model seems good The PK model is inappropriate
Step 4 : Graphical analysis
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2
2.5
Cl
i
q
BW
Age
BW
Age
Variance model seems good
Variance model not appropriate
Step 4 : Graphical analysis
Normality acceptable
Cl
i
q
V
i
q
under gaussian assumption
Cl
i
q
V
i
q
Normality should be questioned
add other covariables
or try semi-parametric model
To Summarise
Write a first model for individual
parameters without any covariable
Write the PK model
Are there variations between
individuals parameters ? (inspection of O)
N
o

S
i
m
p
l
i
f
y

t
h
e

m
o
d
e
l

Y
e
s

Check (at least) graphically the model
Is the model correct ?
No
Yes
Add covariables
Interpret results
What you should no longer believe
Messy data can provide good results
Population PK/PD is made to analyze sparse data
Population PK/PD is too difficult for me
No stringent assumption about the data is required