Therapeutics I – PK – PK after IV Bolus Administration Two Compartment Model Page

Dr. Beringer
September 8th, 2009
Therapeutics 1 - Pharmacokinetics
Notes by Tony Dao

PK after IV Bolus Administration Two Compartment Model

First hour – Went over the homework; answer key is on the website.

Objectives

Today’s lecture will focus on the Two Compartment Model in IV bolus administration. We should
be able to describe the differences between the 1 and 2 compartment model by the end of this
lecture, as well as define all parameters of the 2 compartment pk model. We will go over
mathematical expressions to calculate the plasma concentration at any time following a single iv
bolus that follows the 2 compartment pk model. We will also determine the pk parameters of the
2 compartment pk model from plasma concentrations obtained after a single iv bolus. Finally, we
should be able to analyze the effect of changing one or more of the pk parameters on the plasma
concentration time profile after a single iv bolus of drugs that follow the 2 compartment pk
model.

Distributive Models

Last week we talked about the models briefly and

about what the compartment models are. In the
1 compartment model, if we gave the drug to the
patient, the drug distributes instantaneously
followed by rapid equilbrium. For many drugs,
this assumption works very well. For other drugs
that don’t work with this model, it may go
through the 2 compartment pk model. It first
distributes to the rapid diffused organs , then
later on slow distribution to other tissues of the
body.

This plot shows the difference in the

concentration time curve for these two models.
Both of these are IV bolus doses. Note the bottom one has a characteristic biexponential curve.
Why do we see rapid falling in the beginning and slower rate later on? This is because the first
part is distribution and the second part is elimination. Distribution is typically faster than
elimination so that’s why the graph looks the way it does.

Why not one compartment?

Most drugs need time to distribute to the

tissues, and some tissues are perfused more
rapidly than others. Drugs also bind to tissues
differently so the affinity of the drug to the
tissue may affect its distribution.

This tableshows some examples of highly and

slowly perfused tissues and organs. Different
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drugs will have different distributions in terms of these organs. For the most part, highly
perfused would include central organs such as the heart, brain, liver, kidney, and endocrine
glands. Skin, muscle, adipose, and marrow are also highly perfused. The slowly perfused tissues
include bone, ligaments, tendons, cartilage, teeth, and hair.

Two compartment PK Model

The only way to differentiate these two models is after an IV dose. Right after an oral dose, it’s
hard to differentiate the absorption and distribution from each other because these two even ts
occur at the same time. In that sense, you give a patient an IV dose, a washout, then an oral
dose. We will go over the details how to differentiate these processes next week. You can see it
clearly here however that after distribution, elimination will occur.

In diagram A, all the drug is in the

blood stream, and this is our Cmax
concentration. Now we move on to
B, and we see some drug
distributed to tissues, and some to
organs and elimination, but we
don’t see elimination yet. This is
where you see the concentration
falls quickly on the curve.
Typically, the peripheral
compartment is larger than the
central compartment. Then we get
to diagram C, and this point has
the equilibrium between the central and periphery compartment. This occurs at the end of
distribution and beginning of elimination on the graph. This is where the curve changes. In part
D, we see the color faded because we eliminated drug. This is the point where the graph is all
elimination. Since the two compartments are in equilibrium, we’re losing drug in both
compartments.

For drugs that we’re going to monitor levels on, if the first phase is relatively small and the Cmax
occurs at a short time, the first phase would not be conclusive of any therapeutic toxicity or
safety/efficacy issues. These are what you would see for aminoglycosides. We typically ignore
this section because the area is so small and transient that it does not relate to efficacy. That’s
why we consider the aminoglycosides as a 1 compartment drug.

The only time the first phase is important is if you schedule a drug with a late dose. If the patient
received the dose later than scheduled, and the peak levels were still being obtained on a
regular schedule, then the peak level obtained might have been obtained during the first phase.
Therefore, the peak level obtained would be inaccurate because it’s higher than it should be.
Therefore, an unexperienced pharmacist might interpret the level as toxic when it really isn’t and
change the dosing of the patient. The key thing to note is that this alters the interpretation of the
level, but it would not affect the actual efficacy or safety of the drug. When you see these high
peaks, you should investigate the dosing and time of which peaks were taken relative to dosing
before making a conclusion on toxicity.

Terms
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The previous graph was depicting our two-compartment PK model shown here. This diagram also
has some mathematical terms associated with certain aspects of it. Here are some definitions.

1 – Central compartment (blood and highly perfused tissues)

2 – Tissue or peripheral compartment (slowly perfused tissues)
K – First order elimination rate constant
K12, k21 – First order transfer rate constant between central and peripheral compartments
X1 – Drug amount in central compartment
X2 – Drug amount in peripheral compartment

Differential equations

These differential equations represent the rates of drug amounts in the compartments.

Equation 1: dX1/dt = -k*X1 – k12*X1 + k21*X2

For this equation, we are looking at the drug amount X1 in compartment 1. The elimination is
accounted for by the –k*X1 term. The distribution from compartment 1 to 2 is accounted for by
the –k12*X1 term. However, since drug is coming from compartment 2 to compartment 1, there’s
also the +k21*X2 in the equation.

Equation 2: dX2/dt = -k21*X2 + k12*X1

In this equation, we are looking at the drug amount X2 in compartment 2. There’s only going to
be a loss through the drug traveling back to compartment 1 which is accounted for by –k21*X2.
However, drug gained in compartment 2 from compartment 1 can also happen, which is
accounted for by +k12X1.

Integrated Equations

When we integrate the previous rate equation, we get what’s called a biexponential equation
for the plasma concentration as a function of time.

Equation: C1 = Ae-αt + Be-βt

The first half of the equation deals with the distribution phase. The second part of the equation
deals with the elimination phase. Α and β are hybrid first-order rate constants (macroconstants)
for the fast distribution (α) phase and the slow elimination (β) phase, respectively.

Equation: α + β = k12 + k21 + k

Equation: α*β = k21*k
These equations show the relationship between the macro and microconstants

Biexponential equation

Equation: C1 = Ae-αt + Be-βt

The A and B are analagous to your C0. These are the Y intercepts of each exponential segment.
Mathematically, they are expressed as follows:

A = D(α-k21) B = D(k21-β)
V1(α-β) V1(α-β)

Plasma Concentration Time Profile

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B has units of concentration. We can extrapolate back and get B if we have the equation. You
can get the second curve α to determine initial concentration A. What you are doing is
subtracting the points on the distribution curve with the elimination line. So we can take points
along the distribution phase and subtract the concentration of time T at what we expect it to be,
and we get the dotted line. The slope of this steep dotted line is our α constant.

Determination of Appropriate Model

Why do we care if it’s one or two

compartment? This slide shows the
consequences of the compartment
determination being incorrect. The
elimination rate constant would be
different if we chose the wrong model. We
would see a higher k1 than k2. This would
also affect half life, making our half life
look faster. We can misinterpret these
levels if we use a one compartment model
and say the drug eliminates too quickly
and increase the dose.

If levels of a patient are way off from

population estimate, then we might want
to double check our model determination.

Revised PK Parameters

This is a little more complicated. You can do this graphically through method of residuals, or you
can do computer modeling via nonlinear regression and Bayesian analysis. Today we’re going to
talk about the simple method of residuals.

Method of Residuals

We have our curve here. The first

step is to look at the elimination
phase and get a few points and
extrapolate back to the Y intercept.
Our slope here is –B/2.303. Now we
need to figure out the distribution
part.

We take the four points here. W, x, y,

and z are on the distribution curve.
We have W’, x’, y’, and z’ also on the
extrapolated line. What we do here is
take W – W’, X – X’, etc.
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We plot these new numbers to obtain a new

line. The slope of this new line is going to give
the alpha distribution constant, and the Y
intercept will give you A.

Calculation of Microconstants

Remember earlier we had the equations

that related the microconstants to the
macroconstants. Using these equations,
we can find the values of the
microconstants. These are shown in the
left slide.

Half lives, t1/2α, and t1/2β

These are important values in the 2 compartment model. We have half lives associated with
each exponential in the biexponential equation. The distribution phase half life is given by t1/2α =
0.693/α, and the elimination phase half=life is t1/2β=0.693/β. Remember half lives are
important in determining things like the time it takes to eliminate a drug from the body (that’s
3.3 half lives). The α half life is usually used when you determine when to sample.

Apparent Vd

There are several different types of volumes of distribution that can be calculated in the 2
compartment model. These calculations are based on the availability of the data. Keep in mind
it’s important to refer to the same volume parameter when comparing kinetic changes in disease
states.

VC
This is the volume of the central compartment. This is
defined by this equation shown here. The importance of this
equation lies in the fact that it is used to determine the
highest concentration after an iv bolus dose.
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Varea or Vb
This is larger than the Vc compartment. It’s the volume
of distribution during the elimination phase because of
its relationship between AUC and β, and Vc and k .
Usually, this parameter is good in dosing calculations.
This number is easily calculated from β and AUC values.

Vextrap
This is based on extrapolating the volume back from
the elimination phase; Dr. Beringer does not want us
to use this volume.

Vss

This is not based on elimination, and this

is when central and peripheral come into
equilibrium. This is a common volume
used. This is calculated usually by
computer models.

Apparent volumes of distribution

This is the relationship of the four volumes in relation with each
other. Varea is usually determined by elimination. Vc is smallest,
before distribution; useful for calculating loading dose. In one
compartment models, these V are all the same.