CHAPTER NO.

7
CONCEPT OF
COMPARTMENT(S)MODELS:

COURSE IN-CHARGE: JAVERIA M. RAFIQ SHEIKH

COURSE NAME: BIOPHARMACEUTICS AND
PHARMACOKINETICS
COURSE CODE: 613-T
FIRST SEMESTER,4TH PROFESSIONAL 2021
 LEARNING OBJECTIVES
• One compartment open model.
• Intravenous Injection(Bolus)
• Intravenous infusion.
• Multi-compartment models.
• Two compartment open model.
• IV bolus, IV infusion and oral administration
• Non-compartmental Model.
• Statistical Moment Theory
• MRT for various compartment models
• Physiological Pharmacokinetic model
 PHRMACOK
INETICS

Pharmacokinetics is defined as the kinetics of drug absorption, distribution,

metabolism and excretion (KADME) and their relationship with the
pharmacological, therapeutic or toxicological response in man and animals.
 Use of pharmacokinetic principles in optimizing the drug dosage for
individual patient in order to achieving maximum therapeutic utility is
called as clinical pharmacokinetics.

 There are two aspects of pharmacokinetic studies –

1.Theoretical aspect – which involves development of pharmacokinetic
models to predict drug disposition after its administration. Statistical methods
are commonly applied to interpret data and assess various parameters.

2.Experimental aspect – which involves development of biological sampling

techniques, analytical methods for measurement of drug (and metabolites)
concentration in biological samples and data collection and evaluation.
 PHARMACOKINETIC MODELS
 Means of expressing mathematically or quantitatively, time course of drug
through out the body and compute meaningful pharmacokinetic parameters.
Useful in :
• Characterize 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.
Pharmacokinetic models are hypothetical structures that are used to describe the
fate of a drug in a biological system following its administration.
Model
• Mathematical representation of the data.
• It is just hypothetical
 PHARMACOKINETIC MODELS
• Models are used to describe changes in drug concentration in the body with time.
• Model is a hypothesis that employs mathematical terms to concisely describe quantitative
relationships of drug(s)(w.r.t time) throughout the body and compute meaningful
pharmacokinetic parameters.
• Applications of Pharmacokinetic Models
• Characterizing the behavior of drugs in patients.
• Predicting the concentration of drug in various body fluids with any dosage regimen.
• Calculating the optimum dosage regimen for individual patients.
• Evaluating the risk of toxicity with certain dosage regimens.
• Estimating the possibility of drug and/or metabolite(s) accumulation in the body.
• Determining the influence of altered physiology/disease state on drug ADME.
• Explaining drug interactions.
 WHY MODEL THE DATA ?

There are three main reasons due to which the data is subjected to modelling.
1. Descriptive: to describe the drug kinetics in a simple way.
2. Predictive: to predict the time course of the drug after multiple dosing
based on single dose data, to predict the absorption profile of the drug
from the iv data.
3. Explanatory: to explain unclear observations.
 PHARMACOKINETIC MODELING IS
USEFUL IN :-
• Prediction of drug concentration in plasma/ tissue/ urine at any point of
time.
• Determination of optimum dosage regimen for each patient.
• Estimation of the possible accumulation of drugs/ metabolites.
• Quantitative assessment of the effect of disease on drug’s adme.
• Correlation of drug concentration with pharmacological activity.
• Evaluation of bioequivalence.
TYPES OF PHARMACOKINETIC
MODELS
Mammillary model
Central compartment (comprises of plasma and highly perfused tissues such as lungs, liver,
kidneys) joined parallel to the peripheral compartment(comprises of less perfused organ) like
connection of satellites to a planet.

Catenary model
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.
 ADVANTAGES

• Gives visual representation of various rate processes involved in

drug disposition.
• Possible to derive equations describing drug concentration changes in
each compartment.
• One can estimate the amount of drug in any compartment of the system
after
drug is introduced into a given compartment.
DISADVANTAGES
• Drug given by IV route may behave according to single compartment
model
but the same drug given by oral route may show 2 compartment
behaviour.
• The type of compartment behaviour i.E. Type of compartment model may
change with the route of administration.
 Common units in Pharmacokinetics
S.no Pharmacokinetic parameter Abbreviation Fundamental units Units example
1. Area under the curve AUC Concentration x time µg x hr/mL
2. Total body clearance ClT Volume x time Litres/time
3. Renal clearance ClR Volume x time Litres/time
4. Hepatic clearance ClH Volume x time Litres/time
5. Apparent volume of distribution VD Volume Litres
6. Vol. of distribution at steady state VSS Volume Litres
7. Peak plasma drug concentration CMAX Concentration mg/L
8. Plasma drug concentration CP Concentration mg/L
9. Steady-state drug concentration Css Concentration mg/L
10. Time for peak drug concentration TMAX Time Hr
11. Dose DO Mass mg
12. Loading dose DL Mass mg
13. Maintenance dose DM Mass mg
14. Amount of drug in the body DB Mass Mg
15. Rate of drug infusion R Mass/time mg/hr
16. First order rate constant for drug absorption Ka 1/time 1/hr
17. Zero order rate constant for drug absorption KO Mass/time mg/hr
18. First order rate constant for drug elimination K 1/time 1/hr
19. Elimination half-life t Time hr
 ASSUMPTIONS
1. One compartment
 The drug in the blood is in rapid equilibrium with drug in the extra-vascular tissues. This is not an
exact representation however it is useful for a number of drugs to a reasonable approximation.

2. Rapid mixing
 We also need to assume that the drug is mixed instantaneously in blood or plasma.
 Within each compartment, the drug is considered to be rapidly and uniformly distributed i.e. the
compartment is well-stirred

3. Linear model
 We will assume that drug elimination follows first order kinetics.
Other Assumptions

• Compartment is not a real physiologic or anatomic region but a fictitious or virtual one and
considered as a tissue or group of tissues that have similar drug distribution characteristics
(similar blood flow and affinity).
• The body is represented as a series of compartments arranged either in series or parallel to
each
other, that communicate reversibly with each other
PLASMA DRUG CONCENTRATION – TIME
PROFILE
Effectiveness of Dosage
Regimen

Concentration of Drug in the Body

Conc. at Site of Conc. in whole Blood (Plasma,

action Serum), Saliva, Urine, CSF

PK Parameters determine drug

Conc.
 COMPARTMENTAL MODELS
• A compartment is not a real physiological or anatomic region but an imaginary or hypothetical one
consisting of tissue/ group of tissues with similar blood flow & affinity (similar drug distribution
characteristics).
• Our body is considered as composed of several compartments connected reversibly with each other.
• It is the traditional and commonly used approach to pharmacokinetic characterization of a drug. These
models simply interpolate the experimental data and allow an empirical formula to estimate the drug
concentration with time.
COMPARTMENTAL MODELS
 TYPES OF COMPARTMENT

1. Central compartment
Blood & highly perfused tissues such as heart, kidney, lungs, liver, etc.
2. Peripheral compartment
Poorly per fused tissues such as fat, bone, etc.
MODELS:
“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.
TYPES OF COMPARTMENTAL MODELS

• Compartment models are divided into two categories

• Depending upon arrangement of compartments
Mammillary model
Catenary model.
• Depending
upon number of
compartment assumed
One-compartment or one-compartment
open model
Two compartment
Multiple compartment
 One –
Compartment
Open Model
(Instantaneous
Distribution
 ONE – COMPARTMENT OPEN MODEL
(INSTANTANEOUS DISTRIBUTION MODEL)

 The one- compartment open model is the simplest model. Owing to

its simplicity, it is based on following assumption
1) The body is considered as a single, kinetically homogeneous unit
that has no barriers to the movement of drug.
2) Final distribution equilibrium between the drug in plasma and other
body fluid (i.e. mixing) is attained instantaneously & maintained at
all times. This model is followed by only those drugs that distribute
rapidly throughout the body.
3) Drugs move dynamically, in (absorption) & out (elimination) of this
compartment.
4) Elimination is a first order (monoexponential) process with first
order rate constant.
5) Rate of input (absorption) > rate of output (elimination).
 ONE – COMPARTMENT OPEN MODEL
(INSTANTANEOUS DISTRIBUTION MODEL)

Metabolism
Blood and KE
Ka
Drug other
body Output Excretion
Input (Elimination)
(Absorption) tissues

FIG: One-compartment open model showing input

and output processes
 ONE – COMPARTMENT OPEN MODEL
(INSTANTANEOUS DISTRIBUTION MODEL)

Depending on rate of input, several one

compartment open models are :
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
 TYPES ONE-
COMPARTMENT OPEN
MODEL
One-compartment open model, i.v. bolus administration.

One-compartment open model, continuous i.v. infusion.

One-compartment open model, e.v. administration, first-order

absorption

One-compartment open model, e.v. administration, zero-order

absorption
 One-
compartment
Open Model:
Intravenous
Bolus
 ONE-COMPARTMENT OPEN MODEL:
INTRAVENOUS BOLUS ADMINISTRATION

The drug is rapidly distributed in the body

when given in the form of intravenous
injection (i.v. bolus or slug). It takes about one
to three minutes for complete circulation &
therefore the rate of absorption is neglected in
calculation.

Blood and KE
other
body
tissues
ESTIMATION OF PHARMACOKINETIC
PARAMETERS
 For a drug that follows one-compartment
kinetics and administered as rapid i.v. injection,
the decline in plasma drug concentration is only
due to elimination of drug from the body (and
not due to distribution), the phase being called
as elimination phase. Elimination phase can be
characterized by 3 parameters—
 1. Elimination rate constant
 2. Elimination half-life
 3. Clearance

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(A) CARTESIAN PLOT OF A DRUG THAT FOLLOWS ONE-COMPARTMENT KINETICS AND GIVEN BY
RAPID I.V. INJECTION, AND (B) SEMI LOGARITHMIC PLOT FOR THE RATE OF ELIMINATION IN A
ONE-COMPARTMENT MODEL.
14

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 ELIMINATION HALF - LIFE

 Elimination half life : Also called as biological half life.

 The time taken for the amount of drug in the body as well as
plasma concentration to decline by one- half or 50% its
initial value.
 It is expressed in hours or minutes.
 Half life expressed by following equation:

t1/ 2  …(11)
KE
0.693
 The half – life is a secondary parameter that depends upon
the primary parameter clearance & apparent volume of
distribution.
 According to following equation:
t1/  0.693Vd …(12)
2 Cl T
 APPARENT VOLUME OF DISTRIBUTION

 The two separate & independent pharmacokinetic characteristics of

a drug distribution of a drug .since, they are closely related with
the physiological mechanism of body, they are called as primary
parameters.
 Modification of equation (7) defined apparent volume
of distribution :
amount of drug in the body X …(13)
Vd  
plasma drug concentration C

 The best and the simplest way of estimating Vd of a drug is

administering it by rapid i.v. injection, determining the resulting
plasma concentrationXimmediately by using the following
i.v.bolus …(14)
Vd  0 
equation: C0 C0
dose
 APPARENT VOLUME OF DISTRIBUTION
 A more general, a more useful non-compartmental method
that can be applied to many compartment models for
estimating the Vd is:
 For drugs given as i.v. bolus,
X0 …(15)a
Vd (area)  K
E
 For drugs administeredAUC extravascularly (e.v.),
FX 0 …(15)b
Vd (area)  K
E

X = dose administered AUC

0
F = fraction of drug absorbed into the systemic circulation.
 CLEARANCE
 Clearance : Clearance is the most important parameter in clinical
drug applications & is useful in evaluating the mechanism by which a
drug is eliminated by the whole organisms or by a particular organ.
 Clearance is a parameter that relates plasma drug concentration with the
rate of drug elimination according to following equations-
rate of eliminatio n …(16)
clearance
 plasma drug concentration

Or

d x /d t
Cl 
c
 Clearance is defined as the theoretical volume of body fluid containing
drug from which the drug is completely removed in a given period of
time. It is expressed in ml/min or lit/hr.
 TOTAL BODY CLEARANCE
 Clearance at an individual organ level is called as organ clearance.
 It can be estimated by dividing the rate of elimination by each organ
with the concentration of drug presented to it. Thus,
 Renal clearance
…(17)
Cl R  Rate of eliminatio n by
C
kidney
 Hepatic clearance
…(18)
Rate of eliminatio n by
Cl  C
liver
 Other organ clearance


Rate of eliminatio n by other …(19)

Cl  C
organs
 TOTAL BODY CLEARANCE
 The total body clearance, ClT = ClR +ClH + Clother
 Clearance by all organs other than kidney is some times known as
nonrenal clearance ClNR
 It is the difference between total clearance and renal
clearance according to earlier an definition (equation 17)
ClT  dx/dt …(20)
C
Substituting dX/dt = KEX from equ.3 in above equ.we get
…(21)
ClT K X
 CE

Since X/C = Vd ( from equation 13) the equ. (21) can be written
as …(22)
ClT  K E
vd
 TOTAL BODY CLEARANCE
 Parallel equation can be written for renal and hepatic
clearance as:
ClR = Ke Vd

ClH= Km Vd

Since, KE= 0.693/t1/2 ( from equa. 11), clearance can be related

to half life by the following equation
…
(23
ClT  0.693v d )
t1/2
ONE- COMPARTMENT
OPEN MODEL
Extravascul
ar
Administrat
 EXTRAVASCULAR
22
ADMINISTRATION
 When a drug is administered by extravascular route
(e.g. oral, i.m., rectal, etc.), absorption is a
prerequisite for its therapeutic activity.

 The rate of absorption may be described

mathematically as a zero-order or first-order
process. A large number of plasma concentration-
time profiles can be described by a one-
compartment model with first-order absorption and
elimination. However, under certain conditions, the
absorption of some drugs may be better described
by assuming zero-order (constant rate) kinetics.

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 ONE-COMPARTMENT OPEN MODEL
EXTRAVASCULAR ADMINISTRATION

 When a drug is administered by extravascular route ,the rate of

absorption may be described by mathematically as a zero or
first order process.
 A large number of plasma concentration time profile can be
described by a one compartment model with first order absorption
& elimination.
 Difference between zero- order and first- order kinetics are given
in fig.
DISTINCTION BETWEEN ZERO-ORDER AND FIRST-ORDER ABSORPTION PROCESSES.
FIGURE A IS REGULAR PLOT, AND FIGURE B A SEMI LOG PLOT OF AMOUNT OF DRUG
REMAINING TO BE ABSORBED (ARA) VERSUS TIME T.\
23

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 ONE-COMPARTMENT OPEN MODEL
EXTRAVASCULAR ADMINISTRATION
 Zero order absorption is characterized by a constant rate
of absorption .
 After e.v. administration , the rate in the change of amount
of
thedrug
bodyindx/dt is difference between the rate of input (absorption)
dxev/dt and rate of output( elimination) dxE/dt .
 dx /dt = rate of absorption – rate of elimination

dx dx e v dx E …(1)
dt  dt - dt
 ONE-COMPARTMENT OPEN MODEL
EXTRAVASCULAR ADMINISTRATION
 During the absorption phase, the rate absorption is greater than
the rate of elimination
dxev dx E …(2)
dt  dt
 At peak plasma concentration , the rate of absorption equals the
rate of elimination and the change in amount of drug in the body
is zero
dx dx …(3)
ev  E
dt  dt
 The plasma level time curve is characterized only
Elimination
by the phase. …(4)
dx e v dx E

 MULTI-
COMPARTME
NT MODELS
• Ideally a true pharmacokinetic model should be the one with a rate constant for
each tissue undergoing equilibrium.
• Therefore best approach is to pool together tissues on the basis of similarity in
their distribution characteristics.
• The drug disposition occurs by first order.
• Multi-compartment characteristics are best described by administration as i.v
bolus and observing the manner in which the plasma concentration declines with
time.
The no. Of exponentials required to describe such a plasma level-time profile
determines the no. Of kinetically homogeneous compartments into which a
drug will distribute.
The simplest and commonest is the two compartment model which classifies the
body tissues in two categories :
1. Central compartment or compartment
2. Peripheral or tissue compartment or compartment.
 TWO COMPARTMENT OPEN MODEL-IV BOLUS
ADMINISTRATION:
Elimination from central compartment
Fig:

1 2
Central peripheral

• After the iv bolus of a drug the decline in the plasma conc. Is bi-
exponential.
• Two disposition processes- distribution and elimination.
• These two processes are only evident when a semi log plot of C vs. T is
made.
• Initially, the conc. Of drug in the central compartment declines rapidly, due
to the distribution of drug from the central compartment to the peripheral
compartment. This is called distributive phase.
 TWO-COMPARTMENT OPEN MODEL
body tissues are broadly classified into 2 categories –
Central Compartment or Compartment 1
 Comprising of blood and highly perfused tissues like
liver, lungs, kidneys, etc. that equilibrate with the
drug rapidly.
 Elimination usually occurs from this compartment.

Peripheral or Tissue Compartment or a

Compartment 2 s
 Comprising of poorly perfused and slow
equilibrating tissues such
muscles, skin, adipose, etc. and considered as a
hybrid of several functional physiologic units.

Classification of a particular tissue, for example brain, into central or peripheral

compartment depends upon the physicochemical properties of the drug.

Depending upon the compartment from which the drug is eliminated, the two-compartment model
can be categorized into 3 types:
1.Two-compartment model with elimination from central compartment.
2.Two-compartment model with elimination from peripheral compartment.
3.Two-compartment model with elimination from both the compartments.
 THREE COMPARTMENT
MODEL AND
APPLICATIONS OF
PHARMACOKINETIC
PARAMETERS IN DOSAGE
DETFELOPMENT
 THREE COMPARTMENT MODEL

• Gibaldi & feldman described a three compartment open model

to explain the influence of route of administration; Intravenous
vs. Oral, on the area under the plasma concentration vs. Time
curve.
• Portman utilized a three compartment model which
included metabolism & excretion of hydroxy nalidixic acid.
 DRUG INPUT

DEEP
CENTRAL TISSUE TISSUE
COMPARTMEN COMPARTMEN COMPARTM
T T ENT

K10

THREE COMPARTMENT CATENARY MODEL

RAPID IV
DRUG INPUT

K21 K13
DEEP
TISSUE CENTRAL
TISSUE
COMPARTMEN COMPARTMEN
COMPARTMEN
T T K31 T
K12
DRUG OUTPUT
K10

THREE COMPARTMENT MAMMILLARY MODEL

 Three compartment model consist of the following compartments .
 Central compartment.
 Tissue compartment.
 Deep tissue compartment.

 In this compartment model drug distributes most rapidly in to first or

central compartment.
 Less rapidly in to second or tissue compartment .
 Very slowly to the third or deep tissue compartment. The third compartment
is poor
in tissue such as bone & fat.
• Each compartment independently connected to the central compartment.

• Notari reported the tri exponential

equation c=a e-t+ b e-βt+ c e-γt
• A,B,C are the y-intercept of extrapolated
lines.
• Α,β,γ are the rate constants
 PHARMACOKINETIC
PARAMETERS
Bioloigical half-life ::
• It is defined as the time taken for the amount of drug in the body as well as
plasma to decline by one half or 50% its initial value.
• Concentration of drug in plasma as a function of time
is c=a e - t+ b e -β t+ c e -γ t
• In this equation α>β>γ some time after the distributive phase (i.e. When
time become large) the two right hand side terms values are equal to zero.
• The eq.. Is converted in to
c=a e-αt

Taking the natural logarithm on both sides

the rate constant of this straight line is ‘α’ and biological half life
is t1/2 =0.693/α
 PHYSIOLOGICAL
MODELS
Also known as Physiological based pharmacokinetic model.
• They are drawn on the basis of known anatomic and physiological data and thus present
a more realistic picture of drug disposition in various organs and tissues.
Two types
• Perfusion rate-limited model
lipophilic drugs
• Diffusion-limited models
hydrophilic drugs
 PHYSIOLOGICALLY BASED
PHARMACOKINETIC MODELS
• Blood flow rate limited or perfusion rate
limited model.
• Drawn on the basis of anatomic and
physiologic data.(More realistic)
• Organs or tissues having no perfusion are
excluded.
• Drug movement to a particular region is
much more rapid than its rate of delivery
to that region by blood - perfusion rate
limited model.
• Thus, applicable to highly membrane
permeable drugs, i.e. Low molecular
weight, poorly ionized and highly lipophilic
drugs.
• For highly polar, ionized and charged
drugs, the model is referred to as 81
membrane permeation rate limited.
82
 DISTRIBUTED
PARAMETER MODEL
• Useful
for assessing regional differences in drug concentrations in
tumours or necrotic tissues.
• It take into account –
 Variations in blood flow to an organ, and
 Variations in drug diffusion in an organ.
 SUMMARY
• We have discuss in this chapter, how to Determine total body clearance
and volume of distribution using non-compartmental techniques.
• Outline the basic principles of Compartment modeling and
pharmacokinetics involved in it.
• Summarize the complexities involved in the general application of
pharmacokinetic principles
 PHARMACOKINETIC
MODELLING

Compartmen Non-Compartment Physiologic

t Models Models
Models

AUC, MRT, MAT, Cl,

Caternary Mamillary
VSS
Model Model

One compt Multi compt Two compt

iv
bolus i v bolus
Single oral
Dose
iv
infusion Oral
Intermittent i v infusion
drug
Multiple
 REFERENCE BOOKS
• Biopharamaceutics and Clinical pharmacokinetics by Milo Gibaldi
• Applied biopharmaceutics and pharmacokinetics Textbook by Leon Shargel
• Pharmacokinetic-pharmacodynamic modeling and simulation Book by Peter
L. Bonate
• Essentials of Biopharmaceutics and Pharmacokinetics Book by Ashutosh
Kar
• Pharmacokinetics: Principles and Applications by Mehdi Boroujerdi
• Basic Pharmacokinetics by Mohsen A. Hedaya
• Clinical Pharmacokinetics: Concepts and Applications by Malcolm
Rowland, Thomas N. Tozer
• Biopharmaceutics and Pharmacokinetics Book by A. P. Pawar and J. S.
Kulkarni