Objectives: learn how to define and use a PK model for multiple routes of administration..
Projects: ivOral1_project, ivOral2_project
Some drugs can display complex absorption kinetics. Common examples are mixed first-order and zero-order absorptions, either sequentially or simultaneously, and fast and slow parallel first-order absorptions. A few examples of those kinds of absorption kinetics are proposed below. Various absorption models are proposed here as examples.
Combining iv and oral administrations – Example 1
- ivOral1_project (data = ‘ivOral1_data.txt’ , model = ‘ivOral1Macro_model.txt’)
In this example, we combine oral and iv administrations of the same drug. The data file ivOral1_data.txt contains an additional column ADMINISTRATION ID which indicates the route of administration (1=iv, 2=oral)
We assume here a one compartment model with first-order absorption process from the depot compartment (oral administration) and a linear elimination process from the central compartment. We further assume that only a fraction F (bioavailability) of the drug orally administered is absorbed. This model is implemented in ivOral1Macro_model.txt using PK macros:
[LONGITUDINAL]
input = {F, ka, V, k}
PK:
compartment(cmt=1, amount=Ac)
iv(adm=1, cmt=1)
oral(adm=2, cmt=1, ka, p=F)
elimination(cmt=1, k)
Cc = Ac/V
OUTPUT:
output = Cc
A logit-normal distribution is used for bioavability F that takes it values in (0,1). The model properly fits the data as can be seen on the individual fits of the 6 first individuals
Remark: the same PK model could be implemented using ODEs instead of PK macros.
Let \(A_d\) and \(A_c\) be, respectively, the amounts in the depot compartment (gut) and the central compartment (bloodtsream). Kinetics of \(A_d\) and \(A_c\) are described by the following system of ODEs
$$\dot{A}_d(t) = – k_a A_d(t)~~\text{and}~~ \dot{A}_c(t) = k_a A_d(t) – k A_c(t)$$
The target compartment is the depot compartment (\(A_d\)) for oral administrations and the central compartment (\(A_c\)) for iv administrations. This model is implemented in ivOral1ODE_model.txt using a system of ODEs:
[LONGITUDINAL]
input = {F, ka, V, k}
PK:
depot(type=1, target=Ad, p=F)
depot(type=2, target=Ac)
EQUATION:
ddt_Ad = -ka*Ad
ddt_Ac = ka*Ad - k*Ac
Cc = Ac/V
OUTPUT:
output = Cc
Solving this ODEs system is less efficient than using the PK macros which uses the analytical solution of the linear system.
Combining iv and oral administrations – Example 2
- ivOral2_project (data = ‘ivOral2_data.txt’ , model = ‘ivOral2Macro_model.txt’)
In this example (based on simulated PK data), we combine intraveinous injection with 3 different types of oral administrations of the same drug. The datafile ivOral2_data.txt contains column ADM which indicates the route of administration (1,2,3=oral, 4=iv). We assume that one type of oral dose (adm=1) is absorbed into a latent compartment following a zero-order absorption process. The 2 oral doses (adm=2,3) are absorbed into the central compartment following first-order absorption processes with different rates. Bioavailabilities are supposed to be different for the 3 oral doses. There is linear transfer from the latent to the central compartment. A peripheral compartment is linked to the central compartment. The drug is eliminated by a linear process from the central compartment:
This model is implemented in ivOral2Macro_model.txt using PK macros:
[LONGITUDINAL]
input = {F1, F2, F3, Tk01, ka2, ka3, kl, k23, k32, V, Cl}
PK:
compartment(cmt=1, amount=Al)
compartment(cmt=2, amount=Ac)
peripheral(k23,k32)
oral(type=1, cmt=1, Tk0=Tk01, p=F1)
oral(type=2, cmt=2, ka=ka2, p=F2)
oral(type=3, cmt=2, ka=ka3, p=F3)
iv(type=4, cmt=2)
transfer(from=1, to=2, kt=kl)
elimination(cmt=2, k=Cl/V)
Cc = Ac/V
OUTPUT:
output = Cc
Here, logit-normal distributions are used for bioavabilities \(F_1\), \(F_2\) and \(F_3\). The model fits the data properly :
Remark: the number and type of doses vary from one patient to another in this example.
