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Pharmacokinetic Drug Model

Objective

The objective of this paper is to derive and create a pharmacokinetic model that can be used to

see how the amount and concentration of a drug changes in the body after a single oral dose.

Introduction

Pharmacokinetic drug models look at how the amount and concentration of a drug changes once

it is inside the body related to the drug's absorption, distribution and excretion. A drug's effect is

related to the concentration at its site of action. Measuring this directly however is very difficult

and therefore, we measure and model the drug concentration in plasma instead. This works

because the two concentrations are directly related.

Significance of the model

Monitoring the amount and concentration of a drug in the body is important because drugs have

a therapeutic concentration range within which the drug is safe and effective. Below this range

the desired effects of the drug will not be visible and above it, toxic effects may occur. So

understanding the way the drug concentration changes helps us to determine the right dosages

and develop safe and effective drug regimens.

Developing the Model

To look at the changes in drug concentration, a compartment model is selected. The simplest

type of compartment model is a one-compartment model. In this model, all the body tissues and

fluids are represented as one compartment and only the elimination of the drug from the body
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can be taken into account. However this is a gross simplification and a much better

representation would be the two-compartment model.

In the two-compartment model, we divide the body into the "central compartment" and the

"peripheral compartment". The central represents the blood and organs heavily supplied with

blood like liver or kidney while the peripheral describes certain tissues and parts of the body not

heavily supplied with blood. Once the drug is in the central compartment, it is distributed

between the central and peripheral compartments and eliminated from the body via the central.

Central Peripheral
Drug introduced Compartment Compartment
to central
compartment

Elimination

Figure 1: A schematic drawing of a two-compartment model

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We are concerned with a drug taken orally and in such a case, the drug does not enter the central

compartment directly as shown before. Instead it first enters the gut and is continuously absorbed

from there into the central compartment as shown below:

𝑘12
Central Peripheral
Oral Dose Gut 𝑘𝑎𝑏𝑠 Compartment Compartment

𝑥𝐺 (𝑚𝑔)
𝑥𝐶 (𝑚𝑔) 𝑥𝑃 (𝑚𝑔)
𝑘21

Elimination
𝑘𝑒𝑙

Figure 2: A schematic drawing of a two-compartment model adapted for an oral dose

The rates of the movement of the drug are proportional to its amount present in the compartment

from which it is leaving. The rate constants for these movements as shown in Figure 2 are:

k abs − absorption rate constant

k el − elimination rate constant

k12 − rate constant for movement from central to peripheral

k 21 − rate constant for movement from peripheral to central

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The amounts of drug at any given time are given by:

xG − amount of drug in gut (mg)

xC − amount of drug in central compartment (mg)

xP − amount of drug in peripheral compartment (mg)

It is now possible to derive a set of equations that describes the rate of change of drug amount in

the central and peripheral compartment as well as the gut:

dxG
= −k abs ∗ xG
dt

dxC
= +k abs ∗ xG − k el ∗ xC − k12 ∗ xC + k 21 ∗ xP
dt

dxP
= − k 21 ∗ xP + k12 ∗ xC
dt

Since at t=0 all the drug is in the gut, the initial conditions will be:

xG (0) = dose given ; x C (0 ) = 0 ; x P (0) = 0

One problem with the equations above however is that after the drug enters the gut, it does not

immediately start absorbing into the bloodstream. There is a short time delay during which the

drug is dissolving and travelling to the absorbing surface of the gut. To account for this time

delay called the "time lag", k abs is made a function of time and described using the step function

where:

0 (t < 𝑡𝑎𝑔)
k abs (t) = {
constant value (t ≥ tlag)
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Results

The three equations derived earlier were solved in Matlab as a system of differential equations

using dsolve. The Heaviside function in Matlab was used to model the absorption rate constant as

a step function. A complex solution was obtained which was easier to interpret once the solution

was plotted.

A GUI program (shown below) was created which would allow the user to change the different

parameters involved in the model and observe the corresponding solution as a real time

simulation. The parameters of a few drugs were estimated from literature and pre-entered into

the system. In addition to plotting the amounts of drug in the two compartments and the gut, the

concentration of the drug in the central compartment was also plotted. The ability to administer

additional doses was also incorporated into the GUI.

Figure 3: The GUI Model

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Case 1: A single oral dose:

A single 250 mg dose of the drug Clarithromycin was modeled and the results are shown below:

Figure 4: Results obtained by modeling a single oral dose

The two horizontal lines labeled "Lethal" and "Ineffective" represent the amounts of drug above

which the drug is toxic and below which it is ineffective respectively.

As expected, the amount of drug in the central compartment increases and then decreases

exponentially with time. A short delay was observed before drug appeared in the central

compartment which meant that the time lag was successfully taken into account.
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Case 2: A successful multiple dose regimen:

As before, a single 250 mg dose of the drug Clarithromycin is given but each time the drug in the

central compartment falls below the ineffective level, an additional oral dose is given and the

results are shown below:

Figure 5: Results obtained by modeling multiple doses at regular time intervals

As seen in the results obtained, when a patient takes additional doses at regular fixed time

intervals, the amount of drug in the body always remains above the ineffective level and so for

the duration of treatment, the desired effects of the drug are always observed.
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Case 2: An overdose situation

Like in a multiple dose regimen, a single 250 mg dose of the drug Clarithromycin is given but

multiple doses of the drug are taken almost immediately after each other.

Figure 6: Results obtained by modeling an overdose situation

The results clearly show the consequences of taking a much higher dosage than prescribed. The

amount of drug increases with each dose until it is well above the lethal level at which point the

drug is harmful and potentially life-threatening.

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Effect of changing the absorption rate constant

The absorption constant (when t> tlag) was increased from 0.15 to 0.74 while keeping all other

parameters constant and its effect on the drug concentration in the central compartment was

observed:

Concentration of Drug in Central Compartment (mg/L) Concentration of Drug in Central Compartment (mg/L)
0.45 0.45
Lethal Lethal

0.4 0.4

0.35 k abs = 0.15 0.35 k abs = 0.74

0.3 0.3
Concentration (mg/L)

Concentration (mg/L)
0.25 0.25

0.2 0.2

0.15 0.15

0.1 0.1

Ineffective Ineffective
0.05 0.05

0 0
0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20
Time (hours) Time (hours)

Figure 7: Results obtained by changing the absorption constant

As shown in Figure 7, increasing the absorption constant increases the peak plasma

concentration, decreases the time taken to reach this peak concentration and decreases the

duration of effect.
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Effect of changing the elimination rate constant

The elimination constant was increased from 0.242 to 1.5 while keeping all other parameters

constant and its effect on the drug concentration in the central compartment was observed:

Concentration of Drug in Central Compartment (mg/L) Concentration of Drug in Central Compartment (mg/L)
0.45 0.45
Lethal Lethal

0.4 0.4

0.35 0.35

0.3 k el = 0.242 0.3

k el = 1.5
Concentration (mg/L)

Concentration (mg/L)
0.25 0.25

0.2 0.2

0.15 0.15

0.1 0.1

Ineffective Ineffective
0.05 0.05

0 0
0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20
Time (hours) Time (hours)

Figure 8: Results obtained by changing the elimination constant

As shown in Figure 8, increasing the elimination constant decreases the peak plasma

concentration, and also decreases the duration of the drug's effect.

Limitations of the model

Several simplifications were made when deriving this pharmacokinetic model. The clinical

parameters depend not only on the drug but to a certain extent on the patient as well. The biggest

limitation of the model was that patient variables are neglected. In reality, the patient’s age,

gender, health, height, weight, and medical history all factor into how the amount of drug

changes with time.

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Another limitation of the model can be seen in the overdose scenario. As the amount of drug in

the body increases, the elimination rate reaches a maximum because the body cannot eliminate

any faster. The model however neglects this and assumes that no matter how high the amount of

drug reaches, the elimination rate is still proportional to this amount.

Conclusion

Despite the assumptions made, the model is a good representation of what happens to a drug

when it enters the body. The patterns obtained in the results were as expected and using Matlab

made it possible to observe different scenarios and the effects of changing different parameters.

The solutions also demonstrate the usefulness of such a model when deciding the amount and

frequency of drug doses. This model is the basis for more complex models used by professionals

all over the world.

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