Compartmental Model:

One Compartment Open Model

Dr. Nahid Sharmin

Associate Professor
Department of Pharmaceutical Technology
University of Dhaka
 Chapter Outline
One compartment open model:
➢ Determination of plasma concentration from one compartment open model
➢ Elimination rate constant
➢ Apparent volume of distribution

References:
1. Applied Biopharmaceutics and Pharmacokinetics- Leon Shargel
2. Biopharmaceutics & Clinical Pharmacokinetics - M. Gibaldi.
3. Biopharmaceutics & Clinical Pharmacokinetics - Notari.
4. Basic Pharmacokinetics, (2nd ed., 2012) by Sunil S Jambhekar and Philip J Breen
5. Clinical Pharmacokinetics -John E. Murphy
6. Applied Clinical Pharmacokinetics - Larry Bauer
Pharmacokinetic models
Means of expressing mathematically or quantitatively, the time course of drug through
out the body and compute meaningful pharmacokinetic parameters.

Useful in :
• Characterizing the behavior of drug in patient.
• Predicting conc. of drug in various body fluids with dosage regimen.
• Calculating optimum dosage regimen for individual patient.
• Evaluating bioequivalence between different formulation.
• Explaining drug interaction.
Types of PK Models

1. Physiologic (Perfusion) Models

2. Compartmental Models

3. Mammillary Models
Physiologic PK models
➢ Models are based on known physiologic and anatomic data.

➢ Blood flow is responsible for distributing drug to various parts of the body.

➢ Each tissue volume must be obtained and its drug conc. described.

➢ Predict realistic tissue drug conc

➢ Applied only to animal species and human data can be extrapolated.

➢ Can study how physiologic factors may change drug distribution from one animal species to another

➢ No data fitting is required

➢ Drug conc. in the various tissues are predicted by organ tissue size, blood flow, and experimentally
determined drug tissue-blood ratios.

➢ Pathophysiologic conditions can affect distribution.

Physiological Model Simulation

➢Perfusion Model Simulation of Lidocaine IV Infusion in Man

Metabolism
Blood
Percent of Dose

RET

Muscle

Lung
Adipose

Time
Compartmental models

➢ The body is represented by a series of compartments that

communicate reversibly with each other.

k12
1 k21 2

1 2 3
Compartmental models

➢ A compartment is not a real physiologic or anatomic region, but it is a tissue or group

of tissues having similar blood flow and drug affinity.

➢ Within each compartment the drug is considered to be uniformly distributed.

➢ Drug move in and out of compartments

➢ Compartmental models are based on linear differential equations.

➢ Rate constants are used to describe drug entry into and out from the compartment.
Compartmental models

➢ The model is an open system since drug is eliminated from the system.

➢ The amount of drug in the body is the sum of drug present in the
compartments.

➢ Extrapolation from animal data is not possible because the volume is not a true
volume but is a mathematical concept.

➢ Parameters are kinetically determined from the data.

Objective

• To understand the assumptions associated with the one compartment model

• To understand the properties of first order kinetics and linear models
• To write the differential equations for a simple pharmacokinetic model
• To derive and use the integrated equations for a one compartment linear model
• To define, use, and calculate the parameters, Kel (elimination rate constant), t1/2
(half-life), Cl (clearance), V (apparent volume of distribution), and AUC (area under
the concentration versus time curve) as they apply to a one compartment linear model
“OPEN” and “CLOSED” models:

• The term “open” itself mean that, the administered drug dose is removed from body
by an excretory mechanism ( for most drugs, organs of excretion of drug is kidney).

• If the drug is not removed from the body then model refers as “closed” model.

Compartmental models

➢The compartment models are divided into two categories

✓Mammillary model

✓Catenary model
Mammillary models
It consists of one or more peripheral compartments connected to the central
compartment.

The central compartment comprises of plasma and highly perfused tissues such as lungs,
liver, kidneys, etc. which rapidly equilibrate with the drug.

The drug is directly absorbed into this compartment (i.e. blood). Elimination too occurs
from this compartment since the chief organs involved in drug elimination are liver and
kidneys, the highly perfused tissues and therefore presumed to be rapidly accessible to
drug in the systemic circulation.

The peripheral compartments or tissue compartments (denoted by numbers 2, 3, etc.)

are those with low vascularity and poor perfusion.
Mammillary models
Is the most common compartmental model used in PK. The model consists of one or more
compartments connected to a central compartment
Mammillary models
Catenary models

In this model, the compartments are joined to one another in a series like compartments
of a train. This is however not observable physiologically/anatomically as the various
organs are directly linked to the blood compartment. Hence this model is rarely used.
One-compartment open model
Instantaneous distribution model

The term open indicates that the input (availability) and output (elimination) are
unidirectional and that the drug can be eliminated from the body.

Depending upon the rate of input, several one-compartment open models can be
defined:

1. One-compartment open model, i.v. bolus administration.

2. One-compartment open model, continuous i.v. infusion.
3. One-compartment open model, e.v. administration, zero-order absorption.
4. One-compartment open model, e.v. administration, first-order absorption.
One-compartment open model

D
C= e − K t
Vd

C= concentration
D= dose
Vd: Volume of distribution
K: elimination rate constant
t: time
Intravenous Bolus Administration
When a drug that distributes rapidly in the body is given in the form of a rapid intravenous injection
(i.e. i.v. bolus or slug), it takes about one to three minutes for complete circulation and therefore the
rate of absorption is neglected in calculations.

• Since rate in or absorption is absent in IV bolus, the equation becomes:

dX
= − Rate out
dt
If the rate out or elimination follows first-order kinetics, then:
dX
= − K ΕX
dt

where, KE = first-order elimination rate constant, and X = amount of drug in the body at any time t
remaining to be eliminated. Negative sign indicates that the drug is being lost from the body.
One compartment
One compartment
How to distinguish one comp?

Plotting log(C) vs. time yields a

straight line

log (C)

Time
Fundamental parameters in one compartment

• Apparent Volume of Distribution (Vd)

• Elimination rate constant (K)
• Elimination half life (t1/2)
• Clearance (Cl)
Apparent Volume of Distribution

100 mg

dose X0
Vd = =
initial conc. C0

C= 10 mg/L C= 1 mg/L
Vd= 10 L Vd= 100 L
Apparent Volume of Distribution
• In general, drug equilibrates rapidly in the body. When plasma or any other biologic
compartment is sampled and analyzed for drug content, the results are usually
reported in units of concentration instead of amount

• Each individual tissue in the body may contain a different concentration of drug due to
differences in drug affinity for that tissue. Therefore, the amount of drug in a given
location can be related to its concentration by a proportionality constant that reflects
the volume of fluid the drug is dissolved in

• The volume of distribution represents a volume that must be considered in estimating

the amount of drug in the body from the concentration of drug found in the sampling
compartment
Apparent Volume of Distribution

• Drugs which binds selectively to plasma proteins, e.g. Warfarin have apparent
volume of distribution smaller than their real volume of distribution

• Drugs which binds selectively to extravascular tissues, e.g. Chloroquines have

apparent volume of distribution larger than their real volume of distribution.
The Vd of such drugs is always greater than 42 L (Total body water).
Apparent Volume of Distribution

• Lipid solubility of drug

• Degree of plasma protein binding

• Affinity for different tissue proteins

• Fat : lean body mass

• Disease like Congestive Heart Failure (CHF), uremia,

cirrhosis
Apparent volume of distribution estimation

6.8

Log (Conc)
1. Plot log(C) vs. time 6.6

6.4

6.2

2. Plot the best-fit line 5.8

0 1 2 3 4 5 6

Time

3. Extrapolate to the Y-axis intercept (to estimate initial

concentration, C0)
dose X0
4. Estimate Vd: Vd = =
initial conc. C0
Significance of Apparent volume of distribution

✓ Drugs can have Vd equal, smaller or greater than the body mass
✓ Drugs with small Vd are usually confined to the central
compartment or highly bound to plasma proteins
✓ Drugs with large Vd are usually confined in the tissue
✓ Vd can also be expressed as % of body mass and compared to
true anatomic volume
✓ Vd is constant but can change due to pathological conditions or
with age
Apparent Volume of Distribution

The Extent of Distribution and Vd in a 70 kg Normal Man

% Body
Vd, L Extent of Distribution
Weight

5 7 Only in plasma

5-20 7-28 In extracellular fluids

20-40 28-56 In total body fluids.

In deep tissues; bound to

>40 >56
peripheral tissues
Elimination rate constant (K)

• Elimination rate constant represents the fraction of drug removed per unit
of time.

• K has a unit of reciprocal of time (e.g. minute-1, hour-1, and day-1).

• With first-order elimination, the rate of elimination is directly proportional to

the serum drug concentration.
Elimination rate constant estimation

1. Plot log(C) vs. time

2. Plot the best-fit line

3. Calculate the slope using two points on the best-fit line

4. Estimate K:

Slope= - K/2.303

K= - Slope× 2.303
Elimination rate constant estimation

Plot log(C) vs. time

6.8

6.7
Log (Conc)

6.6

6.5

6.4

6.3

6.2

6.1

6
0 1 2 3 4 5 6

Time
Elimination rate constant estimation

Plot the best-fit line

6.8

6.7
Log (Conc)

6.6

6.5

6.4

6.3

6.2

6.1

6
0 1 2 3 4 5 6

Time
Elimination rate constant estimation

Calculate the slope using two points on the best-fit lin

6.8

6.7

log( C1 ) − log( C 2 )
6.6

Slope =
Log (Conc)

6.5

6.4
t1 − t 2
6.3

6.2
(Log(C1), t1)
6.1

(Log(C2), t2)
6
0 1 2 3 4 5 6

Time
Elimination rate constant estimation

Estimate K

6.8

6.7
Slope= - K/2.303
Log (Conc)

6.6

6.5

6.4

6.3

6.2

6.1

6
0 1 2 3 4 5 6

Time
Elimination half life (t1/2)

• The elimination half life is sometimes called ‘‘biological half-life’’ of a drug

• The elimination half life is defined as the time (h, min, day, etc.) at which the
mass (or amount) of unchanged drug becomes half (or 50%) of the initial mass of
drug
Elimination half life (t1/2) estimation

• Two methods:
• From the value of K:
0 .693
t1 / 2 =
K
Directly from Conc vs. time plot
• Select a concentration on the best fit line (C1)
• Look for the time that is needed to get to 50% of C1 ➔ half-life
Clearance (Cl)

• Clearance is a measure of the removal of drug from the body

• Plasma drug concentrations are affected by the rate at which drug is

administered, the volume in which it distributes, and its clearance

• A drug’s clearance and the volume of distribution determine its half life
Clearance (Cl)

• Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given
unit of time (drug loss from the body)

• Clearance does not indicate the amount of drug being removed. It indicates the volume of plasma (or
blood) from which the drug is completely removed, or cleared, in a given time period.

• Figures in the following two slides represent two ways of thinking about drug clearance:

• In the first Figure, the amount of drug (the number of dots) decreases but fills the same volume,
resulting in a lower concentration

• Another way of viewing the same decrease would be to calculate the volume that would be drug-free
if the concentration were held constant as resented in the second Figure
Clearance (Cl)

the amount of drug (the number of dots) decreases but fills the
same volume, resulting in a lower concentration
Clearance (Cl)
Clearance (Cl)

• The most general definition of clearance is that it is ‘‘a proportionality constant

describing the relationship between a substance’s rate of elimination (amount per unit
time) at a given time and its corresponding concentration in an appropriate fluid at that
time.’’

• Clearance can also be defined as ‘‘the hypothetical volume of blood (plasma or serum)
or other biological fluids from which the drug is totally and irreversibly removed per
unit time.’’
Clearance (Cl) estimation

• For ALL LINEAR pharmacokinetics (including one compartment) , clearance is calculated

using:
dose
Cl =
AUC
where AUC is the area under the concentration curve (it will be discussed later)

• For One compartment pharmacokinetics , clearance is calculated using:

Cl = K  Vd
Clearance (Cl)

• Drugs can be cleared from the body by different pathways, or organs, including hepatic
biotransformation and renal and biliary excretion. Total body clearance of a drug is the
sum of all the clearances by various mechanisms.

Cl t = Cl r + Cl h + Cl other
(Cl t , Cl r and Cl h  total, renal, and hepatic Cl)
Derive the equations: Reference Leon Shargel

DB= DBo e-kt

Log DB = -Kt/2.303+ log DBo

Cp=C0e-kt
Log Cp= -Kt/2.303+ log C0
Vd= D0/ k[AUC]∞0

ClT= -KVd

ClT =D0/[AUC]∞0
Practice Problems

1. A 70-kg volunteer is given an intravenous dose of an antibiotic, and serum drug

concentrations were determined at 2 hours and 5 hours after administration. The drug
concentrations were 1.2 and 0.3 ug/mL, respectively. What is the biologic half-life for
this drug, assuming first-order elimination kinetics?
Practice Problems
Practice Problems

2. A new drug was given in a single intravenous dose of 200mg to an 80 kg adult male
patient. After 6 hours the plasma drug concentration of the drug was 1.5mg/100mL
of plasma. Assuming that the apparent VD is 10% of body weight, compute the total
amount of drug in the body fluids after 6 hours. What is the half-life of this drug?
VD= (80×0.1)= 8L
VD = DB/Cp
DB = Cp VD
= (1.5/100) ×8000
=120mg

log DB = -kt/2.3+ log DB0

K= (log DB - log DB0) ×2.3/t

= 0.085 hr-1

t1/2= 0.693/ K = 8.15 hr

Area Under the Conc. Time Curve (AUC)
Area under the curve or AUC, represents the total integrated area under the plasma level time profile, and
express the total amount of active drug, which reaches the systemic circulation.
AUC = Dose/Clearance
Expressed as mcg/ml.hr
AUC is directly proportional to dose.
Importance of AUC:
• In toxicology, AUC can be used as a measure of drug exposure. It measures how much and how long the drug
stays in the body.
• The efficacy of some antibiotics is related to AUC or MIC, thus maintaining a concentration above the MIC is
more important than peak conc.
• In Biopharmaceutics, it is the most important parameter in evaluating the bioavailability of a drug from
different dosage forms, as it represents the extent of absorption. Also important to compare the
bioavailabilities of drug products.
• In Pharmacokinetics drug AUC values can be used to determine other pharmacokinetic parameters such as
clearance or bioavailability.
Calculation of AUC:

There are various methods to calculate the AUC such as planimeter method, cut and
weigh method, trapezoidal rule (mathematical method), counting square method.

Mainly two methods:

Model dependent: can be used only for one compartment IV bolus
Model independent: Can be used for any drug with any route of administration
AUC calculation: Model dependent

• With one compartment model, first-order elimination, and intravenous

drug administration, the AUC can be calculated using:

Dose C0
AUC = =
K  Vd K
AUC calculation: Model independent
AUC calculation: Model independent

1- Divide the area into different parts

based on the observed concentration
0-
1 points (parts 1-5)

1
2
3
4 5
Trapezoidal rule
1. First Segment - Extrapolate concentration back to y-axis to estimate 1 = 𝐂𝟏 +𝑪𝟎
Cp0 (conc. Of drug at time t=0). This is best done on semi-log graph AUC 0 = ⋅ 𝒕𝟏
𝟐
paper. Calculate the first AUC (AUC 10) segment using the trapezoidal
rule.
2- Calculate the area for each part of the parts 1,2,3 and 4 2 𝐂𝟐 +𝑪𝟏
AUC 1 = ⋅ (𝒕𝟐 − 𝒕𝟏 )
(until the last observed concentration) using trapezoidal rule 𝟐
𝐂𝟑 +𝑪𝟐
AUC 32 = ⋅ (𝒕𝟑 − 𝒕𝟐 )
C1 𝟐

and so on…….

C2
where C = concentration
t = time

t1 t2
AUC calculation: Model independent

3- For part 5 (area between the last

observed concentration and infinity),
the AUC is calculated using the
C* following equation:

AUC ∞last = 𝐶𝑙𝑎𝑠𝑡 /𝐾

Where K is the elimination rate constant
AUC calculation: Model independent

1200
4- The total AUC (from zero to infinity) is the
sum of the areas of parts: 1,2,3,4, and 5
1000

𝐂𝟏 +𝑪𝟎
[AUC]∞ 0= ⋅ 𝒕𝟏 + 𝐂𝟐+𝑪𝟏
⋅ (𝒕𝟐 − 𝒕𝟏 ) +…..
800
𝟐 𝟐

+ 𝐶𝑙𝑎𝑠𝑡/𝐾
600

0-
1

400 1

200
2
3
4 5
0
0 2 4 6 8 10 12
Fraction of the dose remaining

• Fraction of dose remaining (F = DB(t)/D0 ) is given by the following equation:

Amount of drug at time t 𝐷𝐵 𝐷0 ⋅ 𝑒 −𝐾⋅𝑡

F= = = 𝑒 −𝐾⋅𝑡 We know,
dose 𝐷0 = 𝐷0 DB= DBo e-kt

since t1/2= 0.693/k, the equation can be represented as:

t
t
− 0 .693
 1  t1 / 2
F=e t1 / 2
= 
2
Time to get to certain conc.

• Time to get to certain concentration (C* or Cp) is given by:

− K t − K t C0
C* = C 0  e e = We know,
C*
Cp=C0e-kt
 C0 
K  t = ln  
 C *
 C0 
ln  
t=  C * 
K
Applications of one compartment model

• Case 1: Predicting Plasma Concentrations

• Case 2: Duration of Action

• Case 3:Value of a Dose to Give a Desired Initial Plasma Concentration

Case 1: Predicting Plasma Concentrations

A 20-mg dose of a drug was administered as an intravenous bolus injection. The drug
has the following pharmacokinetic parameters: k = 0.1 h−1 and Vd = 20 L

1. Calculate the initial concentration (C0 )

2. Calculate the plasma concentration at 3 h

Case 1: Predicting Plasma Concentrations

1. Calculate the initial concentration (C0 )

dose 20 mg
C0 = = = 1 mg/L
Vd 20 L
2. Calculate the plasma conc. at 3 h

− K t -(0.1)(3)
C = C0  e = 1 e = 0.74 mg/L
Case 2: Duration of Action

• The duration of action of a drug may be considered to be the length of time

the plasma concentration spends above the MEC. Its determination is best
illustrated by example 2.
Case 2: Duration of Action

• Continuing with the drug used in

Example 1, if the therapeutic
range is between 5 and 0.3 mg/L,
how long are the plasma
concentrations in the therapeutic
range?
Case 2: Duration of Action

• As indicated in the diagram (previous slide) C0 =1 mg/L. Thus, at time

zero the plasma concentration is in the therapeutic range. The plasma
concentration will remain therapeutic until it falls to the MEC (0.3 mg/L).
At what time does this occur?

 C0 
ln  
 C *   1 
t= = ln   / 0 .1 = 12 .0 hr
K  0 .3 
 Case 3: Value of a Dose to Give a Desired Initial Plasma
Concentration

• Continuing with the drug used in Examples 1 and 2, If the initial Cp of 1

mg/L is unsatisfactory, Calculate a dose to provide an initial plasma
concentration of 5 mg/L.

dose
C0 = dose = C 0  Vd
Vd

mg
dose = 5  20 L = 100 mg
L