rannan November 13, 2014 19:1

SCHOOL OF BASIC SCIENCES

DEPARTMENT OF MATHEMATICS AND
STATISTICS

Projects 201
Project 2. A Blood-Brain Pharmacokinetic Model
2 A Blood–Brain Pharmacokinetic Model
Pharmacokinetics is the study of the time variation of drug and metabolite levels in the
various fluids and tissues of the body. The discipline frequently makes use of compartment
models to interpret data. In this problem, we consider a simple blood–brain compartment
model (Figure 3.P.3),

Compartment 1 ≡ Blood,
Compartment 2 ≡ Brain,

that could be used to help estimate dosage strengths of an orally administered antidepressant
drug. The rate at which the drug moves from compartment i to compartment j is denoted
by the rate constant kji , while the rate at which the drug is removed from the blood is
represented by the rate constant K.
A pharmaceutical company must weigh many factors in determining drug dosage pa-
rameters; of particular importance are dosage strengths that will provide flexibility to a
physician in determining individual dosage regimens to conveniently maintain concentra-
tion levels at effective therapeutic values while minimizing local irritation and other adverse
side effects.

Tp

R Tb
k21
Blood Brain
Input d(t) x1, V1, c1 k12 x2, V2, c2

FIGURE 3.P.3 A two-compartment model for periodic drug dosages.

Assuming that the drug is rapidly absorbed into the bloodstream following its intro-
duction into the stomach, a mathematical idealization for the dosage regimen is that of a
periodic square wave

, 0
 FIGURE 3.P.3 A two-compartment model for periodic drug dosages.

Assuming thatF I Gthe

U R drug
E 3 . Pis
. 3 rapidly absorbed into
A two-compartment the for
model bloodstream
periodic drugfollowing
dosages. its intro-
duction into the stomach, a mathematical idealization for the dosage regimen is that of a
periodic square wave
Assuming that the drug is rapidly absorbed into the bloodstream following its intro-
duction into the stomach, a ⎧
mathematical idealization for the dosage regimen is that of a
periodic square wave ⎪ R, 0 ≤ t ≤ Tb
d(t) = ⎨
⎪ 0, Tb ≤ t <, T0p ,
⎩
0,
where R is the rate of uptake (milligrams/hour) into the bloodstream, Tb is the time period
during which the drug is absorbed into the bloodstream following oral administration, and
where is the rate of uptake (milligrams/hour) into the bloodstream, is the time period
Tp is the lengthduring
of time between
which doses.
the drug is absorbed into the bloodstream following oral administration, and
is the length of time between doses.
PROBLEMS
Project 2 PROBLEMS
resents the amount of drug (milligrams) in com- to show that and satisfy the system
1, 2, useJWBT1404-Brannan
404-c03
1. If x j Figure 3.P.3 and the mass balance
(t) represents the amount of drug (milligrams) in com- to show that x1 and x2 satisfy the system
November 13, 20
partment j, j = 1, 2, use Figure 3.P.3 and the mass balance dx
= − dx1 21 12
dx law dt = −(K + k21 )x1 + k12 x2 + d(t)
dxj input rate dt (ii)
compartment dx
dt = compartment j input rate dx 2
(ii)
21
dt dt = 12k21 x1 − k12 x2 .
compartment output rate, (i)
− compartment j output rate, (i) dt
202 Chapter 3 Systems of Two First Order Equations

2. If ci (t) denotes the concentration of the drug and V i de- ▶ It is desirable to keep the target concentration levels in
notes the apparent volume of distribution in compartment i, the brain as close as possible to constant levels between 10
use the relation ci = xi ∕V i to show that the system (ii) is trans- mg/L and 30 mg/L, depending on the individual patient. The
formed into therapeutic range must be above the minimum effective con-
dc1 k V centration and below the minimum toxic concentration. For
1
= −(K + k21 )c1 + 12 2 c2 + d(t) the purpose of this project, we will specify that concentra-
dt V1 V1
tion fluctuations should not exceed 25% of the average of the
dc2 Vk (iii) steady-state response.
= 1 21 c1 − k12 c2 .
dt V2 ▶ As a matter of convenience, a lower frequency of admin-
istration is better than a higher frequency of administration;
3. Assuming that x1 (0) = 0 and x2 (0) = 0, use the parameter once every 24 hours or once every 12 hours is best. Once ev-
values listed in the table below to perform numerical simula- ery 9.5 hours is unacceptable and more than 4 times per day
tions of the system (iii) with the goal of recommending two is unacceptable. Multiple doses are acceptable, that is, “take
different encapsulated dosage strengths A = RTb for distribu- two capsules every 12 hours.”
tion. 4. If a dosage is missed, explain through the simulations why
it is best to skip the dose rather than to try to “catch up” by
doubling the next dose, given that it is dangerous and possi-
k21 k12 K V1 V2 Tb
bly fatal to overdose on the drug. Or, does it not really matter
0.29/h 0.31/h 0.16/h 6L 0.25 L 1h in the case of the given parameter values?
5. Suppose the drug can be packaged in a timed-release form
Use the following guidelines to arrive at your recommen- so that T b = 8 h and R is adjusted accordingly. Does this
dations: change your recommendations?