Pharmacokinetics is the discipline concerned with the description of the fate of drugs in the

organism, i.e. how the body handles the administered drug. The fate of the drug in the
organism can be characterized by a number of different processes that together make up the
organism's handling of the substance. These are: Absorption, distribution and elimination.
Elimination can in turn be divided into two processes, metabolism and excretion. An
important part of pharmacokinetics is a mathematical model description of the
aforementioned processes. Here, it is utilized that a number of biological processes in the
organism can be described using first-order kinetics, i.e. the change in concentration of the
drug substance is proportional to the actual concentration in the respective area of the
organism. An important tool in the pharmacokinetic model description is compartmental
models. The principle of this model description is to describe the human organism in the form
of a number of spaces or compartments, into which the drug substance is distributed. The
simplest model is a 1-compartment model, where it is assumed that the drug substance
distributes evenly, i.e. with the same concentration, in a certain volume, called the apparent
distribution volume, Vd. This volume can correspond to a larger or smaller part of the body,
depending on the properties of the drug substance. The absorption of the drug substance into
the organism depends on the mode of administration, i.e. the way the substance is
administered. Model-wise, the simplest mode of administration is intravenous administration,
where a needle is inserted into a vein and the drug is then injected directly into the
bloodstream. The drug substance will then be transported to the heart, from where it is
distributed through the circulatory system to the rest of the organism. With intravenous
administration, there are no absorption processes involved and these can therefore be
omitted from the model description. Using the principle of first-order kinetics, the
mathematical description of a 1-compartment model will be as follows:
The organism is considered a compartment, i.e. the change in concentration is proportional to
the concentration in the organism.

𝑑𝐶
Equation (1): = −𝐾 ∗ 𝐶
𝑑𝑡

Note that the change in concentration is a decrease, as elimination starts immediately after
administration, hence the negative sign. The rate constant, K, is referred to as the elimination
rate constant, as there is only an elimination process in this simple model. In the following,
the elimination rate constant will be denoted as Ke, i.e. equation (1) can be written as

𝑑𝐶
Equation (2): = −𝐾𝑒 ∗ 𝐶
𝑑𝑡

From this

𝑑𝐶
Equation (3): = −𝐾𝑒 ∗ 𝑑𝑡
𝑐
Given that the drug substance administration is assumed to occur instantaneously at t = 0, and
that the change in concentration is followed at time t, the following is obtained when C0 is the
concentration at time t = 0 and C is the concentration at time t.

𝐶 𝑑𝐶 𝑡
Equation (4): ∫𝐶0 = ∫0 −𝐾𝑒 ∗ 𝑑𝑡
𝑐

𝐶
Equation (5): ln = −𝐾𝑒 ∗ 𝑡
𝐶0

𝐶
Equation (6): = 𝑒 −𝑘𝑒 ∗ 𝑡 ↔ 𝐶 = 𝐶0 ∗ 𝑒 −𝑘𝑒 ∗ 𝑡
𝐶0

By using the rules of logarithms, equation (5) can be re-written as:

𝐶
Equation (7): ln = ln 𝐶 − ln 𝐶0 = − 𝐾𝑒 ∗ 𝑡
𝐶0

Equation (8): ln 𝐶 = −𝐾𝑒 ∗ 𝑡 + ln 𝐶0

By assuming that the administration of the drug occurs instantly at t = 0 and that the change
in concentration is followed at time t, if C0 is the concentration at time t = 0 and C is the
concentration at time t, then the equation (5) can be rewritten using logarithmic rules as:

From equation (8), it can be seen that if the concentration of the drug is set as a function of
time on a semi-logarithmic graph with a logarithmic y-axis, a straight line is obtained with a
slope of -Ke and an intersection on the y-axis at ln C0. Therefore, it is possible to
experimentally determine values for Ke by plotting the concentration measurements against
time on a semi-logarithmic graph.

Figure 1 below shows the graphical representation of equations (6) and (8). An important
parameter that describes a specific property of a drug in a one-compartment model is the
half-life. The half-life, t_(1/2), is the time it takes for the organism to reduce the concentration
to half.

By using equation (8), an expression for 𝑡1 , can be calculated by inserting t = 𝑡1 og C = 0.5 * C0

2 2

into the equation.

ln(0.5 ∗ 𝐶0 ) = −𝐾𝑒 ∗ 𝑡1 + 𝑙𝑛𝐶0

2
 ln 0.5 + 𝑙𝑛 𝐶0 = −𝐾𝑒 ∗ 𝑡1 + 𝑙𝑛𝐶0
2
ln 0.5 = −𝐾𝑒 ∗ 𝑡1
2

ln 0.5 ln 2
Equation (9): 𝑡1 = =
2 −𝐾𝑒 𝐾𝑒

Figure 1: Concentration course in a 1-compartment model after IV administration, in a graph with

linear axes (left) and in a semi-logarithmic graph (right).

As seen from equation (9), the half-life of the drug can be calculated from the elimination rate
constant Ke and vice versa. It is also noted that t 1 is independent of the administered dose and
2
the concentration in the organism. The intersection point on the y-axis, ln C0, is used to
calculate the apparent volume of distribution Vd, given the dose, D is known.

When both the apparent volume of distribution and the elimination rate constant are known,
the total clearance of the substance can be calculated. Clearance expresses the volume of
blood cleared of the drug per unit of time and is a characteristic constant for the particular
drug for the individual patient. Clearance is calculated from the expression:

Equation (10): 𝐶𝑙 = 𝐾𝑒 ∗ 𝑉𝑑

In most cases where drug treatment is used, a single dose is not sufficient, but repeated doses
must be given over a treatment period. To achieve a suitable plasma concentration, a new
dose will often be given before the first dose is fully eliminated, resulting in accumulation in
the body. The degree of accumulation can be described by the expression:
 1
𝑅𝑎𝑘𝑘 =
1 − 𝑒 −𝐾𝑒 ∗ τ
Where τ is the dosing interval, meaning the time between two identical doses.

In a dosing schedule where accumulation occurs, steady state will occur when the elimination
rate has reached the level where between two doses, a quantity of the drug substance
equivalent to the dose given is eliminated. The concentration course in a single dose interval
at steady state can be described by the expression:

𝐷 𝑒 −𝐾𝑒 ∗ t
Equation (11): 𝐶= 𝑉𝑑
∗ 1−𝑒 −𝐾𝑒 ∗ τ

Where 0 ≤ t ≤ τ

The maximum plasma concentration in a dosing interval is achieved immediately after

administering a dose, i.e., for t = 0:

𝐷 1
Equation (12): 𝐶𝑚𝑎𝑥 = ∗
𝑉𝑑 1−𝑒 −𝐾𝑒 ∗ τ

While the lowest plasma concentration in the dosing interval is achieved immediately before
the next dose, i.e. for t = τ.
𝐷 𝑒 −𝐾𝑒 ∗ τ
Equation (13): 𝐶𝑚𝑖𝑛 = 𝑉𝑑 ∗ 1−𝑒 −𝐾𝑒 ∗ τ

The plasma concentration at a given time can be found by:

Equation (14): 𝐶 = 𝐶𝑆𝑆 ∗ (1 − 𝑒−𝐾𝑒 ∗ t )