Pharmacokinetic Models

MODEL
“A model is a hypothesis using mathematical terms
to describe quantitative relationship.”

Itis an easy to understand representation of a

complex phenomenon.

While the term pharmacokinetic model simplifies

the drug kinetics in the body.
 Need of Using PK Models
 Using of PK model is one of the approaches to study
the drug pharmacokinetics.
 A drug is in dynamic state in the body and its
concentration keep on changing with time.
 This dynamic state of drug coupled with the complex
biological system makes it difficult to estimate the
drug in body. Therefore, simplified assumptions are
required.
 PK modeling approach is an acceptable means of
acquiring information of drug kinetics in the body.
Reliability of Pharmacokinetic Models

 A model is just an approximation of a real process.

 These models are based on hypothesis, thus rarely
equals an actual system.
 As these models are based upon hypothesis, therefore,
the reliability of the resulted predictions from a model
may be doubtful.
 However, a proposed model is made reliable by using
procedures of model fitting.
 In model fitting approach, an observed data is
matched to a mathematical equation (referred to as
model) by observing the “best fit” of data to the
model.
Reliability Of Pharmacokinetic Models

 The initial estimate is a hypothesized relationship, usually

stated in mathematical terms between an independent
variable (time) and dependent variable (concentration).

 The proposed mathematical relationship is then tested to

assess how closely it agrees with the observed data.

 Statistical parameters are used to evaluate a model best

fitting to the data.

 E.g., A model with higher regression coefficient (r 2), or with

least Akaki’s Information Criterion(AIC), or highest Model
Selection Criterion(MSC) is best estimate and is selected.
 Formulation of Pharmacokinetic Models

 Formation of a model is based on plasma level time data usually.

Based on this data, formulation of a model can be done in three
steps:

 Model postulation
Simplest model is proposed
 
 Model selection
Simplest model is selected that can best describe postulated
model.

 Model testing
Finally, fitting of model to the observed data is done with the
help of appropriate statistical tool to test the reliability of
selected model.
 Formulation of Pharmacokinetic
Models
 Model formulation is started with the simplest model
compatible with data. If not defined well, a more
complex model is tested.

 If the model is not fitted well, then next complex model

is selected and tested.

 Proper selection of a model is necessary to describe the

pharmacokinetics of a drug e.g., if a drug PK is described
by equation of 2 compartment model, then equation of
one compartment model may lead to an incorrect
conclusion about the elimination rate of the drug.
Application of Pharmacokinetic Models

Pharmacokinetic models
 Makes the complex phenomenon simple.
 Predict plasma, tissue and urine drug levels after drug
administration.
 Estimate the possible accumulation of drug and
metabolites.
 Correlate drug concentration with pharmacologic or
toxicological activity.
 Calculate the optimum dosage regimen for each
patient individually.
 Application of Pharmacokinetic
Models

 Evaluate differences in the rate or extent of

bioavailability between formulations in bioequivalence
studies.
 Explains the effect of changes in physiology or disease
on the pharmacokinetics of drugs.
 Explain drug interactions.
 Develop new drug delivery system.

All these applications lead to the improvement of

drug therapy & efficacy…….
 Types of pharmacokinetic models

Two types of PK models are:

Physiologicallybased models
Classical compartment based models
Physiologic Pharmacokinetic Model

 Physiologic Pharmacokinetic Models are

mathematical models describing drug movement
and disposition into the body based on organ blood
flow and the organ spaces penetrated by the drug.

 Simply,Physiologic Pharmacokinetic Model

considers the drug to be blood flow limited.
Physiologic Pharmacokinetic Model
 Drugs are carried to organs by arterial blood and leave organs
by venous blood.

 Insuch a model, transmembrane movement of drug is rapid,

and the membrane does not offer any resistance to drug
permeation.

Rate of drug carried Tissue drug uptake

to a tissue depend on depend on
• the rate of blood • Tissue/blood
flow to the organ partition coefficient
 Physiologically based models
 Apart from sampling tissue and monitor blood flow to the liver
in vivo, the investigator needs to understand the following
questions.
 What is the clinical implication of the liver drug concentration
value?
 Should the drug concentration in the blood within the tissue be
determined and subtracted from the drug in the liver tissue?
 What type of cell is representative of the liver if a selective
biopsy liver tissue sample can be collected without
contamination from its surroundings?
 Moreover, changes in the liver blood perfusion will alter the
tissue drug concentration.
 Therefore, Physiologically based models also have limitations.
 3. Classical compartment models

 Classical compartment model is common approach to study

drug kinetics.
 It is based on dividing the body into finite number of
compartments.
 Pharmacokinetic compartment used in classical compartment
approach is without real anatomical or physiological
meanings, rather it is mathematical concept and refers to the
volume or space within which the drug rapidly distributes.
Classical compartment models continued…..

 Compartment analysis is a mathematical treatment

of the time course of drug for description of its
pharmacokinetics.
 PK compartment may refer to those organs and
tissues with similar blood flow, drug affinity, drug
uptake and drug clearance.
 In classical compartment approach, usually the body
is considered as if it is composed of maximally 3
compartments only.
 Types of classical compartments

1. Open compartment
From an open compartment, a drug can be eliminated from
the system independently. As a model, open compartment
models are usually used in drug pharmacokinetic studies.

II. Closed compartment

From a closed compartment, a drug cannot escape.
A tissue in a model may be considered as closed when it
communicates with the environment only through the
central compartment.
Such models are usually applicable in radiotracer kinetic
study where a non-diffusible radiotracer is injected
intravenously.
III. Blood/Central Compartment(compartment 1)

 The blood or central compartment comprises of blood

and rapidly perfused tissues.
 Once the drug enters the circulating fluid, it
immediately distributes to tissues and organs that are
associated with the central compartment.
IV. Tissue/Peripheral Compartment

 This compartment is composed of fluids of distribution

and peripheral tissues.
 In this compartment, the distribution to the tissues is
not instantaneous and takes some time.
 Based on this distribution time, the peripheral
compartments are further classified as:

i. Shallow compartment (compartment 2) having

fast drug exchange with central compartment.
ii. Deep compartment (compartment 3) having slow
exchange with the central compartment.
 Assigning compartments to a model

 Inclusion or exclusion of organs/ tissues from a

model is the assigning of the compartments to a
model.
 Inclusion or exclusion of organs/ tissues in a model
is based on the distribution properties of the drugs.
 Particular compartments that may be appropriate for
a drug may not appropriate for another drug.
Compartment
Rapidly perfused tissues
(central compartment)
Poorly perfused tissues
(peripheral compartment
1)
Negligibly perfused tissues
(peripheral compartment
2)
Distribution rate Examples of the
tissues
Highest Heart, lung, kidney
Moderate Large muscle mass, skin,
adipose tissues & marrow
Very low Bone, ligament, tendons,
cartilage, teeth and hairs
 Characteristics of PK Compartment
 PK compartments are not real physiological or anatomical
regions.
 All the compartments in a model communicate drug
reversibly.
 Blood perfusion and drug affinity are the basis for tissue
grouping in a model.
 The inputs and outputs into these compartments are
defined in general forms of zero or first order kinetics.
 Within each compartment, the drug is considered to be
rapidly and uniformly distributed.
 Each drug molecule has an equal probability of leaving the
compartment ad drug moves dynamically in and out of the
compartment.
 Rate constants are used to represent the overall rate
processes of the drug entry into or exit from the
 Sampling in compartments models

 Measurement of drug concentration at biophase is not

always possible.
 Blood is easily accessible for sampling and drug
changes in blood reflect change in the drug
concentration in tissues.
 Free drug concentration gives more clear picture of the
drug concentration at biophase.
 Total amount of drug at any time will be sum of drug in
central compartment + drug in peripheral compartment.
 For some drugs, urine is the best sampling option.
Representation of compartment models

Circles or blocks are drawn to represent

compartments in a model.
Arrows reflect the rate constants of drug transfer
into and out from compartments in a model.
Two ways for representation of a compartment
model:
i. Mammilary model
ii.Caternary model
Mammilary model

 In mammilary model, the compartments are

connected like satellite.
 Eachof the compartment is able to independently
communicate with the central compartment.
 Central compartment is the sampling compartment.
 Measurement of drug concentration in blood can be
used to estimate drug concentration in tissues,
mathematically.
 Most common compartment model used in
pharmacokinetics
Caternary model
 Incaternary models, the compartments are joined to
one another in series like a train.
 A compartment depends on other for drug uptake
and excretion.
 The caternary model is rarely applied in
pharmacokinetics because not logical.
Drug transfer between compartments

Rate of drug transfer can be of zero, first

or second order.
 Pharmacological relevance of
compartment models

 The maximum drug response occurring rapidly

indicates location of biophase in central or highly
perfused tissue compartment.

 While
a delayed response of the drug is an indicator
of the availability of biophase in tissue
compartment.
 One compartment open model

Simplest PK model where drug is so distributed

in body as if it comprises only of one
compartment.
This does not mean that drug concentrations are
necessarily equal in all tissues, but implies that
the drug equilibrates rapidly in the body.
While each individual tissue may have a different
concentration of drug due to differences in the
drug affinity for that tissue but the body can be
represented by a single compartment.
 Assumptions in one compartment open model

Drug rapidly distributes between plasma

and tissues.
Changes occurring in plasma reflect
proportional changes in tissue drug levels.
Assessment of one compartment open model

 Inone compartment open model, the terminal curve of plasma level time plot
on semi log paper is a linear curve.

 The curve can be best described by a single exponential equation as:

Cp = e-kt
 
Where = y-intercept of the terminal phase,
k = elimination rate constant
t = time
• Because drug distributes immediately
to tissues and organs in the body
for one compartment model, therefore,
the entire plasma curve represents
the elimination phase.
Description of one compartment model

One compartment model can be described by

elimination rate constant, volume of distribution
and clearance.
 i. Elimination rate constant

 The fraction of drug removed per unit time”.

 The rate of elimination for most drugs from a tissue or from the body is a
first-order process, in which the rate of elimination is dependent on the
amount or concentration of drug present.
 The elimination rate constant, k, is a first-order elimination rate constant
with units of time– 1 (eg., hr– 1 or 1/hr).
 Generally, the parent or active drug is measured in the central
compartment and the total removal or elimination of the parent drug
from this compartment is effected by metabolism (biotransformation)
and excretion. The elimination rate constant represents the sum of each
of these processes:

k = km + k e
  There may be several routes of elimination of drug by
metabolism or excretion. In such a case, each of these
processes has its own first-order rate constant.
 A rate expression for

 This expression shows that the rate of elimination of

drug in the body is a first-order process, depending on
the overall elimination rate constant, k, and the
amount of drug in the body, DB, remaining at any
given time, t. Integration of above Equation gives the
following expression:
log ……1
Equation can also be expressed as

DB =
 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.
 The volume of distribution is also the apparent volume
(VD) in which the drug is dissolved.
 Because the value of the volume of distribution does not
have a true physiologic meaning in terms of an anatomic
space, the term apparent volume of distribution is used.
 The amount of drug in the body is not determined directly.
Instead, a blood sample is removed at periodic intervals
and analyzed for its concentration of drug.
 The VD relates the concentration of drug in plasma (Cp) and
the amount of drug in the body (DB), as in the following
equation:
DB = VDCP
 By substituting above Equation into Equation 1, a
similar expression based on drug concentration in
plasma is obtained for the first-order decline of drug
plasma levels:
log Cp

 where, C p = concentration of drug in plasma at time t

and C p 0 = concentration of drug in plasma at t = 0.
 Above equation can also be expressed as

Cp =
Calculation of Volume of Distribution
 Ina one-compartment model (IV administration), the
VD is calculated with the following equation:

the rate of drug elimination is

 Where, DB = VDCP
 Rearrangement of Equation

As both k and V D are constants, above

equation may be integrated as follows:
 which upon rearrangement yields the following equation:

The calculation of the apparent V D by means of Equation is

a model-independent method, because no pharmacokinetic
model is considered and the AUC is determined directly by
the trapezoidal rule.
 CLEARANCE
 The volume of fluid (containing the drug) cleared of
drug per unit of time.
 Clearance is a measure of drug elimination from the
body without identifying the mechanism or process.
 Clearance (drug clearance, systemic clearance, total
body clearance, Clt) considers the entire body as a drug-
eliminating system from which many elimination
processes may occur.
 The units for clearance are volume/time (eg., mL/min,
L/hr).
 For example, if the Cl T of penicillin is 15 mL/min in a
patient and penicillin has a V D of 12 L, then from the
clearance definition, 15 mL of the 12 L will be cleared
• the rate of drug elimination is

 Where, DB = VDCP

 Dividing this expression on both sides by Cp yields

Equation
Multicompartmental Approach
A drug may distribute in different tissue groups with
different rates.
 These different rates of distribution makes the decline
in the terminal phase on plasma level time curve
becomes nonlinear.
 The difference in rate of drug distribution is due to the
difference in blood perfusion rates and the tissue
affinity for the drugs for various tissue groups.
 A drug rapidly distributes in the blood and highly
perfuse tissues and with less rates = in less perfused
tissues and even less in the tissues with very less
perfusion.
Based o the distribution patterns the tissues
can be grouped as highly perfused, shallow
and deep tissue compartments.
One compartment model is unable to describe
such situations and a multicompartmental
approach is used to estimate the
pharmacokinetics of such drugs.
If the rate of drug distribution is same, non-
linearity of the curve is not evidenced on
plasma level time curve.
 Two Compartment Open Model
 Many drugs given in a single intravenous bolus dose
demonstrate a plasma level–time curve that does not decline as
a single exponential (first-order) process.
 The plasma level–time curve for a drug that follows a two-
compartment model shows that the plasma drug concentration
declines biexponentially as the sum of two first-order processes
—distribution and elimination.
 A drug that follows the pharmacokinetics of a two-
compartment model does not equilibrate rapidly throughout the
body, as is assumed for a one-compartment model.
 In this model, the drug distributes into two compartments, the
central compartment and the tissue or peripheral compartment.
 The central compartment represents the blood,
extracellular fluid, and highly perfused tissues. The drug
distributes rapidly and uniformly in the central
compartment.
 A second compartment, known as the tissue or
peripheral compartment, contains tissues in which the
drug equilibrates more slowly.
 Drug transfer between the two compartments is assumed
to take place by first-order processes.
The plasma level–time curve for a drug that follows a two-
compartment model may be divided into two parts, (a) a distribution
phase and (b) an elimination phase.
The two-compartment model assumes that, at t = 0, no drug is in the
tissue compartment. After an IV bolus injection, drug equilibrates
rapidly in the central compartment.
The distribution phase of the curve represents the initial, more rapid
decline of drug from the central compartment into the tissue
compartment (, line a).
Although drug elimination and distribution occur concurrently during
the distribution phase, there is a net transfer of drug from the central
compartment to the tissue compartment.
The fraction of drug in the tissue compartment during the distribution
phase increases up to a maximum in a given tissue, whose value may
be greater or less than the plasma drug concentration.
Deciding number of compartments
 Number of compartments in a model is decided
based on the plasma level time curve.
 A plasma level time curve represents the the
number of process and thereby number of
exponents.
 Phases on the terminal curve equal the number of
exponents required to describe the curve well.
 The graphical procedure used to decide the number
of compartments is known as method of residual,
curve peeling, curve subtraction and curve
feathering.
 Method of Residual
Steps involved in method of residual are:
i. Extrapolation of the terminal phase of the
plasma level time curve.
ii. Subtraction of the corresponding points
from the original curve.
iii. Replotting of the differences on the same
graph.
iv. If the replotted curve is not linear, all the
above steps are repeated.