Mathematical Expressions of the Pharmacokinetic and

Pharmacodynamic Models implemented

in the PFIM software

Anne Dubois, Julie Bertrand and France Mentré

UMR738, INSERM, University Paris Diderot

Programmer: Anne Dubois

March 2011
 The library of pharmacokinetic (PK) and pharmacodynamic (PD) models described in this
document is implemented in the PFIM software since version 3.2.1 and in PFIM Interface
since version 3.1 ([Link]). The PK/PD libraries of PFIM are derived from the
PK/PD models implemented in the Monolix software and described by Julie Bertrand and
France Mentré in a Monolix software documentation ([Link]). PFIM is a free
library of functions. The University Paris Diderot and INSERM are the co-owners of this
library of functions (version 3.2, copyright 2010).
Contents

1 Pharmacokinetic models 5
1.1 Compartmental models and parameters . . . . . . . . . . . . . . . . . . . . . . . 6
1.1.1 One-compartment models . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.1.2 Two-compartment models . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.1.3 Three-compartment models . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.2 Models with linear elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.2.1 One-compartment models . . . . . . . . . . . . . . . . . . . . . . . . . . 9
[Link] Intravenous bolus . . . . . . . . . . . . . . . . . . . . . . . . . . 9
[Link] Infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
[Link] First order absorption . . . . . . . . . . . . . . . . . . . . . . . 10
1.2.2 Two-compartment models . . . . . . . . . . . . . . . . . . . . . . . . . . 10
[Link] Intravenous bolus . . . . . . . . . . . . . . . . . . . . . . . . . . 11
[Link] Infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
[Link] First order absorption . . . . . . . . . . . . . . . . . . . . . . . 12
1.2.3 Three-compartment models . . . . . . . . . . . . . . . . . . . . . . . . . 13
[Link] Intravenous bolus . . . . . . . . . . . . . . . . . . . . . . . . . . 14
[Link] Infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
[Link] First order absorption . . . . . . . . . . . . . . . . . . . . . . . 16
1.3 Models with Michaelis-Menten elimination . . . . . . . . . . . . . . . . . . . . . 17
1.3.1 One-compartment models . . . . . . . . . . . . . . . . . . . . . . . . . . 17
[Link] Intravenous bolus . . . . . . . . . . . . . . . . . . . . . . . . . . 17
[Link] Infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
[Link] First order absorption . . . . . . . . . . . . . . . . . . . . . . . 18
1.3.2 Two-compartment models . . . . . . . . . . . . . . . . . . . . . . . . . . 19
[Link] Intravenous bolus . . . . . . . . . . . . . . . . . . . . . . . . . . 19
[Link] Infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
[Link] First order absorption . . . . . . . . . . . . . . . . . . . . . . . 20
1.3.3 Three-compartment models . . . . . . . . . . . . . . . . . . . . . . . . . 21
[Link] Intravenous bolus . . . . . . . . . . . . . . . . . . . . . . . . . . 21
[Link] Infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
[Link] First order absorption . . . . . . . . . . . . . . . . . . . . . . . 22

2 Pharmacodynamic models 24
2.1 Immediate response models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.1.1 Drug action models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

3
 2.1.2 Baseline/disease models . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.1.3 PFIM model function examples . . . . . . . . . . . . . . . . . . . . . . . 26
2.2 Turnover response models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.2.1 Models with impact on the input (Rin ) . . . . . . . . . . . . . . . . . . . 27
2.2.2 Models with impact on the output (kout ) . . . . . . . . . . . . . . . . . . 28

Appendix 29
Appendix I: list of models in PK library . . . . . . . . . . . . . . . . . . . . . . . . . 29
Appendix I.1: PK models with linear elimination . . . . . . . . . . . . . . . . . 30
Appendix I.1: PK models with Michaelis-Menten elimination . . . . . . . . . . . 32
Appendix II: list of models in PD library . . . . . . . . . . . . . . . . . . . . . . . . . 33
Appendix II.1: Immediate response PD models for PD only . . . . . . . . . . . . 34
Appendix II.2: Immediate response PD models for PK/PD . . . . . . . . . . . . 35
Appendix II.3: Turnover PD models for PK/PD . . . . . . . . . . . . . . . . . . 36

4
Chapter 1

Pharmacokinetic models

The equations in the ensuing chapter describe the pharmacokinetic models implemented in the
PFIM software ([Link]). The presentation of the models is organised as follows:

• First level: elimination process

– Linear
– Michaelis-Menten

• Second level: number of compartments

– One compartment
– Two compartments
– Three compartments

• Third level: route of administration

– Intravenous bolus
– Infusion
– Oral (first order absorption)

• Last level: administration profile

The equations express the concentration C (t) in the central compartment at a time t after the
last drug administration.

- Single dose: at time t after dose D given at time tD (t ≥ tD )

- Multiple doses: at time t after n doses Di (i = 1, ...n) given at time tDi (t ≥ tDn )

- Steady state (only for linear elimination): at a time t after dose D given at time tD after
repeated administration of dose D given at interval τ (t ≥ tD )

5
 1.1. COMPARTMENTAL MODELS AND PARAMETERS

NB: For infusion, the duration of infusion is T inf for single dose and T infi (i = 1, ...n) for
multiple doses. D is the total administered dose for single dose; Di is the total ith administered
dose for multiple doses.
For multiple doses, the delay between successive doses is supposed to be constant and to
be greater than infusion duration (tDi+1 − tDi = constant and tDi+1 − tDi > T infi for infusion).
For steady state, the interval τ is supposed to be greater than infusion duration (τ >
T inf ).

1.1 Compartmental models and parameters

In the ensuing section, the mammillary models with one, two or three compartments are
presented with the associated parameters and the different parameterisations. Six parameters
are common to one, two or three compartment models:

- V or V1 , the volume of distribution in the central compartment

- k, the elimination rate constant

- CL, the clearance of elimination

- Vm , the maximum elimination rate for Michaelis-Menten elimination

- Km , the Michaelis-Menten constant

- ka , the absorption rate constant for oral administration

NB: Vm is in amount per time unit and Km is in concentration unit.

1.1.1 One-compartment models

The one-compartment model implemented in PFIM is described in Figure 1.1.
(a) (b)

k - CL-
V V

Figure 1.1: A mammillary model with one compartment, parameterized in micro-constant

V and k (a) or with CL and V (b).

There are two parameterisations implemented in PFIM for one-compartment models, (V and k)
or (V and CL). The equations are given for the first parameterisation (V, k). For extra-vascular
administration, V and CL are apparent volume and clearance.
CL
The equations for the second parameterisation (V, CL) are derived using k = .
V

6
 1.1. COMPARTMENTAL MODELS AND PARAMETERS

1.1.2 Two-compartment models

The two-compartment model implemented in PFIM is described in Figure 1.2. For
two-compartment model equations, C(t) = C1 (t) represent the drug concentration in the first
compartment and C2 (t) represents the drug concentration in the second compartment.
(a) (b)

k12 - Q -
V (= V1 )  (V2 ) V1  V2
k21

k CL
? ?

Figure 1.2: A mammillary model with two compartments, parameterized in micro-constants

V , k, k12 and k21 (a) or with CL, V1 , Q and V2 (b)

As well as the previously described PK parameters, the following PK parameters are used for
the two-compartment models:

- V2 , the volume of distribution of second compartment

- k12 , the distribution rate constant from compartment 1 to compartment 2

- k21 , the distribution rate constant from compartment 2 to compartment 1

- Q, the inter-compartmental clearance

There are two parameterisations implemented in PFIM for two-compartment models:

(V , k, k12 and k21 ), or (CL, V1 , Q and V2 ). For extra-vascular administration, V1 (V ), V2 , CL,
and Q are apparent volumes and clearances.

The second parameterisation terms are derived using:

- V1 = V

- CL = k × V1

- Q = k12 × V1
k12
- V2 = × V1
k21

1.1.3 Three-compartment models

The three-compartment model implemented in PFIM is described in Figure 1.3. For three-
compartment model equations, C(t) = C1 (t) represent the drug concentration in the first
compartment, C2 (t) represents the drug concentration in the second compartment, and C3 (t)
represents the drug concentration in the third compartment.

7
 1.1. COMPARTMENTAL MODELS AND PARAMETERS

(a) (b)

(V2 ) (V3 ) V2 V3

k21@I
@@k12
@
k13 
k31 Q@ I
@
2 @@

Q3
R@
@ R@
@

V (= V1 ) V1

k CL
? ?

Figure 1.3: A mammillary model with three compartments parameterized in micro-constants

V , k, k12 , k21 , k13 and k31 (a) or with CL, V1 , Q2 , V2 , Q3 and V3 (b)

As well as the previously described PK parameters, the following PK parameters are used for
the three-compartment models:
- V3 , the volume of distribution of third compartment
- k13 , the distribution rate constant from compartment 1 to compartment 3
- k31 , the distribution rate constant from compartment 3 to compartment 1
- Q2 (=Q), the inter-compartmental clearance from compartment 1 to compartment 2
- Q3 , the inter-compartmental clearance from compartment 1 to compartment 3
There are two parameterisations implemented in PFIM for three-compartment models: (V , k,
k12 , k21 , k13 and k31 ), or (CL, V1 , Q2 , V2 , Q3 and V3 ). For extra-vascular administration, V1
(V ), V2 , V3 , CL, Q2 , and Q3 are apparent volumes and clearances.

The second parameterisation terms are derived using:

- V1 = V
- CL = k × V1
- Q2 = k12 × V1
k12
- V2 = × V1
k21
- Q3 = k13 × V1
k13
- V3 = × V1
k31

8
 1.2. MODELS WITH LINEAR ELIMINATION

NB: For models with Michaelis-Menten elimination the elimination parameter is not k (or
CL) but Vm and Km for both parameterisations of one, two or three-compartment models.

1.2 Models with linear elimination

The list of PK models with linear elimination implemented in PFIM are summarised in
Appendix I.1.

1.2.1 One-compartment models

[Link] Intravenous bolus
• single dose
D −k(t−tD )
C (t) = e (1.1)
V

• multiple doses
n
Di
e−k(t−tDi )
X
C (t) = (1.2)
i=1
V

• steady state

D e−k(t−tD )
C(t) = (1.3)
V 1 − e−kτ

[Link] Infusion
• single dose

D 1 −k(t−tD )


 T inf kV 1 − e if t − tD ≤ T inf ,



C (t) = (1.4)
D 1
1 − e−kT inf e−k(t−tD −T inf )


if not.


T inf kV


• multiple doses
 n−1
X Di 1
−k(t−tD −T infi )
 −kT infi

 1 − e e i
T inf kV

i



 i=1 if t − tDn ≤ T infn ,
Dn 1

1 − e−k(t−tDn )


C (t) = + (1.5)

 T infn kV
n

 X Di 1
1 − e−kT infi e−k(t−tDi −T infi )




 if not.

i=1
T infi kV

9
 1.2. MODELS WITH LINEAR ELIMINATION

• steady state
 "
−k(t−t −T inf ) #
−kT inf
 D 1 −k(t−tD )

−kτ
1 − e e D
1 − e + e if (t − tD ) ≤ T inf ,


 T inf kV 1 − e−kτ

C (t) =
D 1 1 − e−kT inf e−k(t−tD −T inf )





 if not.
T inf kV 1 − e−kτ
(1.6)

[Link] First order absorption

• single dose
D ka
e−k(t−tD ) − e−ka (t−tD )


C (t) = (1.7)
V ka − k

• multiple doses
n
X Di ka  −k(t−tD ) −ka (t−tDi )

C (t) = e i −e (1.8)
i=1
V ka − k

• steady state

e−k(t−tD ) e−ka (t−tD )

 
D ka
C (t) = − (1.9)
V ka − k 1 − e−kτ 1 − e−ka τ

NB: Equations 1.1 to 1.9 correspond to models n◦ 1 to n◦ 6 in Appendix I.1.

1.2.2 Two-compartment models

For readability, the equations for two-compartment models with linear elimination are given
using the variables α, β, A and B defined by the following expressions:
Q CL
k21 k V V
- α= = 2 1
β β
  
1
q
2
k12 + k21 + k − (k12 + k21 + k) − 4k21 k



2


- β=
 s 
2
 1 Q Q CL Q Q CL Q CL 

 + + − + + −4
 2 V1 V2 V1 V1 V2 V1 V2 V1



The link between A and B, and the PK parameters of the first and second parameterisations
depends on the input and are given in each subsection.

10
 1.2. MODELS WITH LINEAR ELIMINATION

[Link] Intravenous bolus

For intravenous bolus, the link between A and B, and the parameters (V , k, k12 and k21 ), or
(CL, V1 , Q and V2 ) is defined as follows:
Q
α−
1 α − k21 1 V2
- A= =
V α−β V1 α − β
Q
β−
1 β − k21 1 V2
- B= =
V β−α V1 β − α

• single dose
C (t) = D Ae−α(t−tD ) + Be−β(t−tD )


(1.10)

• multiple doses
n  
Di Ae−α(t−tDi ) + Be−β (t−tDi )
X
C (t) = (1.11)
i=1

• steady state
Ae−αt Be−βt
 
C (t) = D + (1.12)
1 − e−ατ 1 − e−βτ
[Link] Infusion
For infusion, the link between A and B, and the parameters (V , k, k12 and k21 ), or (CL, V1 , Q
and V2 ) is defined as follows:
Q
α−
1 α − k21 1 V2
- A= =
V α−β V1 α − β
Q
β−
1 β − k21 1 V2
- B= =
V β−α V1 β − α

• single dose
  
A −α(t−tD )



 1−e

 D  α 
if t − tD ≤ T inf ,

  

  B
T inf
1 − e−β(t−tD )


+



 β
C (t) =   (1.13)
 A −αT inf

−α(t−tD −T inf )
1−e e


D  α

  

  if not.
T inf  B


1 − e−βT inf e−β(t−tD −T inf )


+



β

11
 1.2. MODELS WITH LINEAR ELIMINATION

• multiple doses
  
A −αT inf

−α(t−tD −T infi )
1−e i
e
 i
 n−1
Di  α

 X 

  
B

 T inf i
 −βT infi

−β (t−tDi −T infi )

−


 i=1 + 1 e e

 β
if t − tDn ≤ T inf ,


  
A


1 − e−α(t−tDn ) 




 D  α
C (t) = + 
 B
 (1.14)
T inf n −β(t−t )



 + 1 − e Dn
β





  
A


−α(t−tD −T infi )
 −αT inf

 n 1−e i
e i

X

 Di   α 
 if not.

T inf  B −βT
e ( Di
−β −T i)
 i inf

t−t inf

+ 1−e i

 i=1

β

• steady state
   
1 − e−α(t−tD )



A


−αT inf

−α(t−t −T inf )  
−ατ 1 − e

 e D
α
  

 +e 



 D 
 1 − e−ατ 
 if t − tD ≤ T inf ,
T inf −β(t−tD )
 

1−e

  
 B

  
+
 −βT inf

−β(t−t −T inf ) 
1−e e D

  

 β + e−βτ
C (t) = 1 − e−βτ (1.15)


  ! 
1 − e−αT inf e−α(t−tD −T inf )


A




1 − e−ατ
  


 D α 
if not.

  
T inf
  ! 
1 − e−βT inf e−β(t−tD −T inf ) 

  B


 + 

β 1 − e−βτ



[Link] First order absorption

For first order absorption, the link between A and B, and the parameters (ka , V , k, k12 and
k21 ), or (ka , CL, V1 , Q and V2 ) is defined as follows:
Q
−α
ka k21 − α ka V2
- A= =
V (ka − α) (β − α) V1 (ka − α) (β − α)
Q
−β
ka k21 − β ka V2
- B= =
V (ka − β) (α − β) V1 (ka − β) (α − β)

12
 1.2. MODELS WITH LINEAR ELIMINATION

• single dose

C (t) = D Ae−α(t−tD ) + Be−β(t−tD ) − (A + B)e−ka (t−tD )

(1.16)

• multiple doses
n  
Di Ae−α(t−tDi ) + Be−β (t−tDi ) − (A + B)e−ka (t−tDi )
X
C (t) = (1.17)
i=1

• steady state

Ae−α(t−tD ) Be−β(t−tD ) (A + B)e−ka (t−tD )

 
C (t) = D + − (1.18)
1 − e−ατ 1 − e−βτ 1 − e−ka τ

NB: Equations 1.10 to 1.18 correspond to models n◦ 7 to n◦ 12 in Appendix I.1.

1.2.3 Three-compartment models

For readability, the equations for three-compartment models with linear elimination are given
using the variables α, β, γ, A, B and C defined by the following expressions:
CL Q2 Q3
- a0 = kk21 k31 =
V1 V2 V3

kk31 + k21 k31 + k21 k13 + kk21 + k31 k12

- a1 = CL Q3 Q2 Q3 Q2 Q3 CL Q2 Q3 Q2

 + + + +
V1 V3 V2 V3 V2 V1 V1 V2 V3 V1

k + k12 + k13 + k21 + k31

- a2 = CL Q2 Q3 Q2 Q3

 + + + +
V1 V1 V1 V2 V3
- p = a1 − a22 /3

- q = 2a32 /27 − a1 a2 /3 + a0
p
- r1 = − (p3 /27)
1/3
- r2 = 2r1
 
q
- φ = arccos − /3
2r1
- α = − (cos (φ) r2 − a2 /3)
   
2π
- β = − cos φ + r2 − a2 /3
3

13
 1.2. MODELS WITH LINEAR ELIMINATION

   
4π
- γ = − cos φ + r2 − a2 /3
3
The link between A, B, C and the PK parameters of the first and second parameterisations
depends on the input and are given in each subsection.

[Link] Intravenous bolus

For intravenous bolus, the link between A B, and C, and the parameters (V , k, k12 , k21 , k13
and k31 ), or (CL, V1 , Q2 , V2 , Q3 and V3 ) is defined as follows:
Q2 Q3
−α −α
1 k21 − α k31 − α 1 V2 V3
- A= =
V α−β α−γ V1 α − β α − γ
Q2 Q3
−β −β
1 k21 − β k31 − β 1 V2 V3
- B= =
V β−α β−γ V1 β − α β − γ
Q2 Q3
−γ −γ
1 k21 − γ k31 − γ 1 V2 V3
- C= =
V γ−β γ−α V1 γ − β γ − α

• single dose

C (t) = D Ae−α(t−tD ) + Be−β(t−tD ) + Ce−γ(t−tD )

(1.19)

• multiple doses
n
X
Di Ae−α(t−tDi ) + Be−β(t−tDi ) + Ce−γ(t−tDi )


C (t) = (1.20)
i=1

• steady state
Ae−α(t−tD ) Be−β(t−tD ) Ce−γ(t−tD )
 
C (t) = D + + (1.21)
1 − e−ατ 1 − e−βτ 1 − e−γτ

[Link] Infusion
For infusion, the link between A B, and C, and the parameters (V , k, k12 , k21 , k13 and k31 ), or
(CL, V1 , Q2 , V2 , Q3 and V3 ) is defined as follows:
Q2 Q3
−α −α
1 k21 − α k31 − α 1 V2 V3
- A= =
V α−β α−γ V1 α − β α − γ
Q2 Q3
−β −β
1 k21 − β k31 − β 1 V2 V3
- B= =
V β−α β−γ V1 β − α β − γ

14
 1.2. MODELS WITH LINEAR ELIMINATION

Q2 Q3
−γ −γ
1 k21 − γ k31 − γ 1 V2 V3
- C= =
V γ−β γ−α V1 γ − β γ − α

• single dose
 A

−α(t−tD )
1−e


 α



 
 
 B

 D −β(t−tD ) 


1−e


 +  if t − tD ≤ T inf ,


 T inf β 
  

  C

−γ(t−tD )
1−e


 +
 γ
C (t) = (1.22)
 A −αT inf

−α(t−tD −T inf )

1−e


 e




 α 
 
 D +

  B −βT inf

−β(t−t −T inf ) 
1−e e D  if not.

 β




 T inf  

  C 
1 − e−γT inf e−γ(t−tD −T inf )


+


γ


• multiple doses
  A
−α(t−tD −T infi ) 
−αT infi

 1−e e i


  α 

 n−1
X Di  B


−β (t−tD −T infi ) 

−βT inf

 β 1−e


 + i
e i 


 i=1
T inf i 




  C −γT infi

−γ (t−tDi −T infi )

+ 1 − e e


γ



if t − tDn ≤ T inf ,


  A

 −α(t−t )



 1−e D n



  α 
 
B

 D  −β(t−tDn ) 


C (t) = +  + 1−e  (1.23)

 T inf 
n  β 


  C

−γ(t−tDn )
−


 + 1 e



 γ


  A
−α(t−tD −T infi ) 
−αT infi

1−e e

 i
 α



 

 n
X Di  B


−β (t−tD −T infi ) 

−βT inf
 β 1−e


 + i
e i  if not.
T inf

 

 i=1 i  
  C 
1 − e−γT infi e−γ (t−tDi −T infi )




 +
γ

15
 1.2. MODELS WITH LINEAR ELIMINATION

• steady state
1 − e−α(t−tD )
  
 
A


1 − e−αT inf e−α(t−tD −T inf )  



 α −ατ
+e


  −ατ






 1 − e 

1 − e−β(t−tD )

  
 


 D  B 
+ −βT −β(t−t −T  if t − tD ≤ T inf ,
 inf

inf )

−



T inf β

−βτ 1 e e D 
+ e

  
1 − e−βτ

  

  
  −γ(t−tD )


1−e

  
 
 C



−γ(t−t −T inf )  

 +  1−e −γT inf
e D 
C (t) = γ + e−γτ (1.24)

 1 − e−γτ

 ! 
1 − e−αT inf e−α(t−tD −T inf )
 




 A
1 − e−ατ

 α 

  
 

 !
−βT inf −β(t−tD −T inf ) 


−

1 e e


 D  B
+

  if not.
T inf β 1 − e−βτ

  

  
 

 −γT inf

−γ(t−t −T inf ) ! 
1−e e
 
 C D

 
+


−γτ

 γ 1−e

[Link] First order absorption

For first order absorption, the link between A B, and C, and the parameters (ka , V , k, k12 ,
k21 , k13 and k31 ), or (ka , CL, V1 , Q2 , V2 , Q3 and V3 ) is defined as follows:
Q2 Q3
−α −α
1 ka k21 − α k31 − α 1 ka V2 V3
- A= =
V ka − α α − β α − γ V1 ka − α α − β α − γ
Q2 Q3
−β −β
1 ka k21 − β k31 − β 1 ka V2 V3
- B= =
V ka − β β − α β − γ V1 ka − β β − α β − γ
Q2 Q3
−γ −γ
1 ka k21 − γ k31 − γ 1 ka V2 V3
- C= =
V ka − γ γ − β γ − α V1 ka − γ γ − β γ − α

• single dose
C (t) = D Ae−α(t−tD ) + Be−β(t−tD ) + Ce−γ(t−tD ) − (A + B + C)e−ka (t−tD )


(1.25)

• multiple doses
n  
Di Ae−α(t−tDi ) + Be−β (t−tDi ) + Ce−γ (t−tDi ) − (A + B + C)e−ka (t−tDi ) (1.26)
X
C (t) =
i=1

16
 1.3. MODELS WITH MICHAELIS-MENTEN ELIMINATION

• steady state

Ae−α(t−tD ) Be−β(t−tD ) Ce−γ(t−tD ) (A + B + C)e−ka (t−tD )

 
C (t) = D + + − (1.27)
1 − e−ατ 1 − e−βτ 1 − e−γτ 1 − e−ka τ

NB: Equations 1.19 to 1.27 correspond to models n◦ 13 to n◦ 18 in Appendix I.1.

1.3 Models with Michaelis-Menten elimination

The list of PK models with Michaelis-Menten elimination implemented in PFIM are summarised
in Appendix I.2. Presently, there is no implementation for multiple dosing with IV bolus
administration in the PFIM software. For infusion and oral administration, the implementation
in PFIM does not allow designs with different groups of doses as the dose is included in the
model.

1.3.1 One-compartment models

[Link] Intravenous bolus
• single dose

C (t) = 0 for t < tD
Initial conditions:
C (tD ) = D
V
Vm (1.28)
dC ×C
=− V
dt Km + C

[Link] Infusion
• single dose

Initial conditions: C (t) = 0 for t < tD

Vm
dC ×C
=− V + input
dt Km + C (1.29)
 D 1 if 0 ≤ t − t ≤ T inf

D
input (t) = T inf V
0 if not.


17
 1.3. MODELS WITH MICHAELIS-MENTEN ELIMINATION

• multiple doses

Initial conditions: C (t) = 0 for t < tD1

Vm
dC ×C
=− V + input
dt Km + C (1.30)
 Di 1 if 0 ≤ t − t ≤ T inf ,

Di i
input (t) = T infi V
0 if not.


[Link] First order absorption

• single dose

Initial conditions: C (t) = 0 for t < tD

Vm
dC ×C
=− V + input (1.31)
dt Km + C
D
input (t) = ka e−ka (t−tD )
V

• multiple doses

Initial conditions: C (t) = 0 for t < tD1

Vm
dC ×C
=− V + input (1.32)
dt Km + C
n
Di
ka e−ka (t−tDi )
X
input (t) =
i=1
V

NB: Equations 1.28 to 1.32 correspond to model n◦ 1 to n◦ 3 in Appendix I.2.

18
 1.3. MODELS WITH MICHAELIS-MENTEN ELIMINATION

1.3.2 Two-compartment models

[Link] Intravenous bolus
• single dose


 C1 (t) = 0 for t < tD

Initial conditions: C2 (t) = 0 for t ≤ tD
C (t ) = D


1 D
V
Vm (1.33)
dC1 × C1 k21 V2
=− V − k12 C1 + C2
dt Km + C1 V
dC2 k12 V
= C1 − k21 C2
dt V2
[Link] Infusion
• single dose
(
C1 (t) = 0 for t < tD
Initial conditions:
C2 (t) = 0 for t ≤ tD
Vm
dC1 × C1 k21 V2
=− V − k12 C1 + C2 + input
dt Km + C1 V
(1.34)
dC2 k12 V
= C1 − k21 C2
dt V2
 D 1 if 0 ≤ t − t ≤ T inf

D
input (t) = T inf V
0 if not.


• multiple doses
(
C1 (t) = 0 for t < tD1
Initial conditions:
C2 (t) = 0 for t ≤ tD1
Vm
dC1 × C1 k21 V2
=− V − k12 C1 + C2 + input
dt Km + C1 V
(1.35)
dC2 k12 V
= C1 − k21 C2
dt V2
 Di 1 if 0 ≤ t − t ≤ T inf ,

Di i
input (t) = T infi V
0 if not.


19
 1.3. MODELS WITH MICHAELIS-MENTEN ELIMINATION

[Link] First order absorption

• single dose
(
C1 (t) = 0 for t < tD
Initial conditions:
C2 (t) = 0 for t ≤ tD
Vm
dC1 × C1 k21 V2
=− V − k12 C1 + C2 + input
dt Km + C1 V (1.36)
dC2 k12 V
= C1 − k21 C2
dt V2
D
input (t) = ka e−ka (t−tD )
V

• multiple doses
(
C1 (t) = 0 for t < tD1
Initial conditions:
C2 (t) = 0 for t ≤ tD1
Vm
dC1 × C1 k21 V2
=− V − k12 C1 + C2 + input
dt Km + C1 V (1.37)
dC2 k12 V
= C1 − k21 C2
dt V2
n
Di
ka e−ka (t−tDi )
X
input (t) =
i=1
V

NB: Equations 1.33 to 1.37 correspond to models n◦ 4 to n◦ 9 in Appendix I.2.

20
 1.3. MODELS WITH MICHAELIS-MENTEN ELIMINATION

1.3.3 Three-compartment models

[Link] Intravenous bolus
• single dose


 C1 (t) = 0 for t < tD

C2 (t) =
 0 for t ≤ tD
Initial conditions: C (t) = 0 for t ≤ tD
 3
C (t ) = D



1 D
V
Vm
dC1 × C1 k21 V2 k31 V3 (1.38)
= − V − k12 C1 + C2 − k13 C1 + C3
dt Km + C1 V V
dC2 k12 V
= C1 − k21 C2
dt V2
dC3 k13 V
= C1 − k31 C3
dt V3

[Link] Infusion
• single dose

C1 (t) = 0 for t < tD

Initial conditions: C2 (t) = 0 for t ≤ tD

C3 (t) = 0 for t ≤ tD


Vm
dC1 × C1 k21 V2 k31 V3
=− V − k12 C1 + C2 − k13 C1 + C3 + input
dt Km + C1 V V
dC2 k12 V (1.39)
= C1 − k21 C2
dt V2
dC3 k13 V
= C1 − k31 C3
dt V3
 D 1 if 0 ≤ t − t ≤ T inf

D
input (t) = T inf V
0 if not.


21
 1.3. MODELS WITH MICHAELIS-MENTEN ELIMINATION

• multiple doses

C1 (t) = 0 for t < tD1

Initial conditions: C2 (t) = 0 for t ≤ tD1

C3 (t) = 0 for t ≤ tD1


Vm
dC1 × C1 k21 V2 k31 V3
=− V − k12 C1 + C2 − k13 C1 + C3 + input
dt Km + C1 V V
dC2 k12 V (1.40)
= C1 − k21 C2
dt V2
dC3 k13 V
= C1 − k31 C3
dt V3
 Di 1 if 0 ≤ t − t ≤ T inf ,

Di i
input (t) = T infi V
0 if not.


[Link] First order absorption

• single dose

C1 (t) = 0 for t < tD

Initial conditions: C2 (t) = 0 for t ≤ tD

C3 (t) = 0 for t ≤ tD


Vm
dC1 × C1 k21 V2 k31 V3
=− V − k12 C1 + C2 − k13 C1 + C3 + input
dt Km + C1 V V
(1.41)
dC2 k12 V
= C1 − k21 C2
dt V2
dC3 k13 V
= C1 − k31 C3
dt V3
D
input (t) = ka e−ka (t−tD )
V

22
 1.3. MODELS WITH MICHAELIS-MENTEN ELIMINATION

• multiple doses

C1 (t) = 0 for t < tD1

Initial conditions: C2 (t) = 0 for t ≤ tD1

C3 (t) = 0 for t ≤ tD1


Vm
dC1 × C1 k21 V2 k31 V3
=− V − k12 C1 + C2 − k13 C1 + C3 + input
dt Km + C1 V V
(1.42)
dC2 k12 V
= C1 − k21 C2
dt V2
dC3 k13 V
= C1 − k31 C3
dt V3
n
Di
ka e−ka (t−tDi )
X
input (t) =
i=1
V

NB: Equations 1.38 to 1.42 correspond to models n◦ 10 to n◦ 15 in Appendix I.2.

23
Chapter 2

Pharmacodynamic models

This chapter describes the pharmacodynamic models implemented in the PFIM software. Some
of these pharmacodynamic models can be used alone or linked to a pharmacokinetic model.
Some can only be used linked to any pharmacokinetic model. Two different types of models
are presented here:
• The immediate response models (alone or linked to a pharmacokinetic model)

• The turnover models (only linked to a pharmacokinetic model)

The list of the immediate response models implemented in PFIM is summarised in Appendix
II.1 and II.2. The list of the turnover models is summarised in Appendix II.3.

2.1 Immediate response models

For these response models, the effect E (t) is expressed as:

E (t) = A (t) + S (t) (2.1)

where A (t) represents the model of drug action and S (t) corresponds to the baseline/disease
model. A (t) is a function of the concentration C (t) in the central compartment.
The drug action models are presented in section 2.1.1 for C(t). The baseline/disease models
are presented in section 2.1.2. Any combination of those two models is available in the PFIM
library.

Parameters
• Alin : constant associated to C (t)

• Aquad : constant associated to the square of C (t)

• Alog : constant associated to the logarithm of C (t)

• Emax : maximal agonistic response

• Imax : maximal antagonistic response

24
 2.1. IMMEDIATE RESPONSE MODELS

• C50 : concentration to get half of the maximal response (i.e. drug potency)

• γ: sigmoidicity factor

• S0 : baseline value of the studied effect

• kprog : rate constant of disease progression

2.1.1 Drug action models

• linear model

A (t) = Alin C (t) (2.2)

• quadratic model

A (t) = Alin C (t) + Aquad C (t)2 (2.3)

• logarithmic model

A (t) = Alog log(C (t)) (2.4)

• Emax model
Emax C (t)
A (t) = (2.5)
C (t) + C50

• sigmoı̈d Emax model

Emax C (t)γ
A (t) = (2.6)
C (t)γ + C50
γ

• Imax model
Imax C (t)
A (t) = 1 − (2.7)
C (t) + C50

• sigmoı̈d Imax model

Imax C (t)γ
A (t) = 1 − (2.8)
C (t)γ + C50
γ

25
 2.1. IMMEDIATE RESPONSE MODELS

2.1.2 Baseline/disease models

• null baseline

S (t) = 0 (2.9)

• constant baseline with no disease progression

S (t) = S0 (2.10)

• linear disease progression

S (t) = S0 + kprog t (2.11)

• exponential disease increase

S (t) = S0 e−kprog t (2.12)

• exponential disease decrease

S (t) = S0 1 − e−kprog t


(2.13)

NB: Only, for the Imax models (equation (2.7) and (2.8)) A (t) is not added to S (t) but S0
is multiplied by A (t) in the expression of S(t).

2.1.3 PFIM model function examples

Any combination of the 9 drug action models and 5 baseline/disease models is available in
PFIM. For instance, the combination of an Emax model for the drug action (2.5) and a constant
baseline with no disease progression model (2.10) will result in the following equation:

Emax C (t)
E(t) = S0 + (2.14)
C (t) + C50

which corresponds to the model n◦ 11: immed Emax const in Appendix II.1.
As a second example, the combination of an Imax model for the drug action (2.7) with a
exponential progression as baseline/disease model (2.12) will give:
 
−kprog t Imax C (t)
E(t) = S0 e − (2.15)
C (t) + C50

which corresponds to the model n◦ 13: immed Imax exp in Appendix II.2.

26
 2.2. TURNOVER RESPONSE MODELS

2.2 Turnover response models

In these models, the drug is not acting on the effect E directly but rather on Rin or kout as
represented in Figure 2.1.

Rin- kout-
E

Figure 2.1: Turnover model of the effect E

dE
Thus the system is described with differential equations, given as a function of Rin , kout
dt
and C (t) the drug concentration at time t.
Rin
The initial condition is: while C (t) = 0, E (t) = .
kout

Parameters

• Emax : maximal agonistic response

• Imax : maximal antagonistic response

• C50 : concentration to get half of the maximal response (=drug potency)

• γ: sigmoidicity factor

• Rin : input (synthesis) rate

• kout : output (elimination) rate constant

2.2.1 Models with impact on the input (Rin )

• Emax model
 
dE Emax C
= Rin 1 + − kout E (2.16)
dt C + C50

• sigmoı̈d Emax model

Emax C γ
 
dE
= Rin 1 + γ γ − kout E (2.17)
dt C + C50

• Imax model
 
dE Imax C
= Rin 1 − − kout E (2.18)
dt C + C50

27
 2.2. TURNOVER RESPONSE MODELS

• sigmoı̈d Imax model

Imax C γ
 
dE
= Rin 1 − γ γ − kout E (2.19)
dt C + C50

• full Imax model

 
dE C
= Rin 1 − − kout E (2.20)
dt C + C50

• sigmoı̈d full Imax model

Cγ
 
dE
= Rin 1 − γ γ − kout E (2.21)
dt C + C50

NB: Equation 2.16 to 2.21 correspond to models n◦ 1 to n◦ 6 in Appendix II.3

2.2.2 Models with impact on the output (kout )

• Emax model
 
dE Emax C
= Rin − kout 1 + E (2.22)
dt C + C50

• sigmoı̈d Emax model

Emax C γ
 
dE
= Rin − kout 1 + γ γ E (2.23)
dt C + C50

• Imax model
 
dE Imax C
= Rin − kout 1 − E (2.24)
dt C + C50

• sigmoı̈d Imax model

Imax C γ
 
dE
= Rin − kout 1 − γ γ E (2.25)
dt C + C50

• full Imax model

 
dE C
= Rin − kout 1 − E (2.26)
dt C + C50

• sigmoı̈d full Imax model

Cγ
 
dE
= Rin − kout 1 − γ γ E (2.27)
dt C + C50

NB: Equation 2.22 to 2.27 correspond to models n◦ 7 to n◦ 12 in Appendix II.3

28
Appendix

List and names of the PK and PD models available in PFIM (PFIM since version
3.2.1 and PFIM Interface since version 3.1)

Appendix I: list of models in PK library

For the use in the PFIM software, some variables are required (or not) for each PK model.
They are specified in the column named Needed variables: N: the number of doses, tau: the
interval between two doses, TInf: the duration of the infusion, doseMM: dose for models with
Michaelis-Menten elimination (for models with linear elimination, dose is specified in the file
stdin.r).

29
 2.2. TURNOVER RESPONSE MODELS

Appendix I.1: PK models with linear elimination

30
 2.2. TURNOVER RESPONSE MODELS

31
 2.2. TURNOVER RESPONSE MODELS

Appendix I.2: PK models with Michaelis-Menten elimination

32
 2.2. TURNOVER RESPONSE MODELS

Appendix II: list of models in PD library

The implementation of the PD models in the PFIM software differs if the PD model is used
alone or linked to a pharmacokinetic model. The immediate response models used alone are
described in Appendix II.1. The list of the immediate response PD models for PK/PD is thus
given in Appendix II.1 plus those of Appendix II.2. Lastly, the list of turnover PD models for
PK/PD is given in Appendix II.3.
For the case where a PK model with linear elimination is associated to a turnover PD response
model, the PK model is written with a differential equations system. Consequently, only some
PK models from Appendix I.1 are implemented:

- for IV bolus, only single dose models

- for infusion and oral absorption, single dose and multiple doses

33
 2.2. TURNOVER RESPONSE MODELS

Appendix II.1: Immediate response PD models for PD only

34
 2.2. TURNOVER RESPONSE MODELS

Appendix II.2: Immediate response PD models for PK/PD

35
 2.2. TURNOVER RESPONSE MODELS

Appendix II.3: Turnover PD models for PK/PD

36