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7.1 Pharmacokinetics: Introduction to compartmental

and physiological models.
Introduction to the one compartmental open model
and its assumptions.
Concept of zero order and first order rate kinetics

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 2 categories of factors that can be evaluated from plasma

concentration time profile:

 PK parameters

 PD parameters

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 Minimum effective conc (MEC)

 Maximum safe conc. (MSC)/ (MTC)
 Onset of action
 Onset time
 Duration of action
 Intensity of action
 Therapeutic range
 Therapeutic index

 Peak plasma conc. (Cmax)

 Time for peak conc. (tmax)
 Area under the curve (AUC)
 Elimination half life (t1/2)
 Clearance (Cl)
 Volume of distribution (Vd)

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Cl

KE

t1/2 tmax

Ka
V
Dose

cmax

 Model approach

 Model-independent approach (non-compartmental analysis)

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Methods for
analysis of PK
data

Model
Model approach independent
approach

Non
Compartment Physiological Distributed
compartmental
model model parameter model
analysis

Mammillary Perfusion limited

Catenary Diffusion limited

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 A model is a hypothesis that employs mathematical terms

to concisely describe quantitative relationships.
 Pharmacokinetic models provide concise means of
expressing mathematically or quantitatively, the time
course of drug(s) throughout the body and compute
meaningful pharmacokinetic parameters.
 In this approach, models are used to describe changes
in drug concentration in the body with time.

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Characterizing the behavior of drugs in patients

Predicting the conc. of drug in various body fluids with any

dosage regimen

Predicting the multiple dose conc. curves from single dose

experiments

Calculating the optimum dosage regimen for individual

patients

Evaluating the risk of toxicity with certain dosage regimen

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Correlating plasma drug conc with

pharmacological response

Evaluating the BE/ BiE between 2 different

formulations of the same drug

Estimating the possibility of drug/

metabolite accumulation in the body

Determining the influence of altered

physiology or disease states on drug ADME

Explaining drug interactions.

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As they are
Traditional hypothetical,
and most they are
commonly based on
used FIVE
assumptions:

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1
• Body is represented as compartments arranged either
in series or parallel to each other, which communicate
reversibly with each other

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• Each compartment is not real physiologic or anatomical
region but tissues having similar drug distribution
characteristics

3 • Within each compartment, drug is considered to be

rapidly and uniformly distributed

4 • The rate of movement between compartments follows

first order kinetics

5 • Rate constants are used to represent rate of entry into

and exit from the compartment.
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2 categories
depending upon
arrangement of
compartments

Mammillary
model – parallel Catenary model –
to central in series
compartment

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• Plasma and highly perfused

Central tissues like lungs, liver, kidney.
compartment Drug is eliminated from this
compartment

Peripheral/
• Tissues with low vascularity
tissue and poor perfusion.
compartments

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K10
1

One-compartment, open model, IV administration

K01 K10
1

One-compartment, open model, EV administration (oral,

rectal)

K12
1 2
K21

K10

Two-compartment, open model, IV administration

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K01 K12
1 2
K21
K10

Two-compartment, open model, EV administration (oral,

rectal)

K13 K31

K12
1 2
K21

K10
Three-compartment, open model, IV
administration 18

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K13 K31

K12
K01
1 2
K21

K10

Three-compartment, open model, EV administration (oral,

rectal)

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 Compartments are joined in series like compartments of a train

 This is not observable anatomically as all compartments are linked
to blood.
 Hence, this is rarely used

K01 K12 K13

1 2 3
K21 K31

K10

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Simple and flexible. Thus widely used

Gives a visual representation of various rate processes involved in drug disposition

Shows how many rate constants are needed to describe the process

Enable writing of differential equations for each of the rate processes

Enables monitoring of drug conc. change in each with a limited amount of data

Useful for predicting drug conc-time profile in both normal and disease states.

Important in development of dosage regimens

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Bear no relationship with physiological functions or anatomical structure of the body

Several assumptions have to be made

Extensive efforts are needed in development of exact model

Model is based on curve fitting of complicated multiexponential mathematical

equations

Model may vary within a population

The drug behavior within the body may fit different compartment models depending
on the route of administration

Differences between results from human and animal studies

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IV Dose

Qlung

Lung

Heart
QL - QG
QL
QG
Gut Liver

Venous blood
Arterial blood

KM

Kidney
Ke

QHPT
HPT

QPPT
PPT
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 Exchange of drug between capillary drug and interstitial

water is considered very rapid
 Cell membrane is considered to be very permeable to the
drug
 Capillary membrane does not offer any resistance to drug
permeation
 Constant ratio of drug concentration between organ and
venous blood is quickly established

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Diffusion (membrane
Perfusion rate limited permeation) rate
limited
• Assumption – • Assumption –
diffusion > perfusion perfusion > diffusion
• Applicable to highly • Applicable to polar,
membrane ionised charged
permeable drugs drugs.
• Eg. thiopental, • Eg. Nitroglycerine,
lidocaine epinephrine

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 Drug movement and disposition in the body based on organ

blood flow and the organ spaces penetrated by the drug.
 In its simplest form, a physiologic pharmacokinetic model
considers the drug to be blood flow limited.
 Drugs are carried to organs by arterial blood and leave
organs by venous blood.
 Differential mass balance equations are written for each
compartment to describe the inflow, outflow, accumulation,
and disappearance of drug, and are solved simultaneously
with the aid of a computer.

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Figure 1: Non eliminating tissue organ

• Uptake of drug into the tissues is rapid, and a constant ratio of

drug concentrations between the organ and the venous blood is
quickly established.
• This ratio is the tissue/blood partition coefficient:
……..1

where P is the partition coefficient

• The magnitude of the partition coefficient can vary depending

on the drug and on the type of tissue.
• for example: Adipose tissue has a high partition for lipophilic
drugs 29

 The rate of blood flow to the tissue is expressed as Qt

(mL/min), and the rate of change in the drug concentration
with respect to time within a given tissue organ is expressed
as

……..2

……..3

where Cart is the arterial blood drug concentration and Cven is

the venous blood drug concentration. Qt is blood flow and
represents the volume of blood flowing through a typical tissue
organ per unit of time
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 If drug uptake occurs in the tissue, the incoming concentration,

Cart, is higher than the outgoing venous concentration, Cven.
 In the blood flow-limited model, drug concentration in the blood
leaving the tissue and the drug concentration within the tissue are
in equilibrium, and Cven may be estimated from the tissue/blood
partition coefficient
 Using equation 1 and 3;

……..4

 Equation 4 describes drug distribution in a non eliminating organ

or tissue group. For example, drug distribution to muscle, adipose
tissue, and skin is represented in a similar manner by Equations 5,
6, and 7, respectively

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 For tissue organs in which drug is eliminated , parameters

representing drug elimination from the liver (k LIV) and
kidney (k KID) are added to account for drug removal
through metabolism or excretion.

Figure 2: A typical eliminating tissue organ

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 The rate of drug elimination may be described for each organ or

tissue

……..5

……..6

……..7

……..8

……..9

……..10

where LIV = liver, SP = spleen, GI = gastrointestinal tract, KID = kidney, LU = lung, FAT = adipose, SKIN =33
skin, and MUS = muscle

 The mass balance for the rate of change in drug concentration in

the blood pool is:

……..11

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BLOOD FLOW LIMITED MODEL DIFFUSION-LIMITED MODEL

Rapid drug equilibrium assumes that Cell membrane acts as a barrier for the
drug diffusion is extremely fast and that drug, which gradually permeates by
the cell membrane offers no barrier to diffusion
drug permeation
If no drug binding is involved, the tissue Blood flow is very rapid and drug
drug concentration is the same as that of permeation is slow, a drug concentration
the venous blood leaving the tissue gradient is established between the
tissue and the venous blood
Rate limiting step is Blood flow Rate limiting step is Permeation across
the cell membrane
Assumption greatly simplifies the Time lag in equilibration between blood
mathematics involved and tissue, the pharmacokinetic equation
for the diffusion-limited model is very
complicated.
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Mathematical treatment is straight forward

Better picture of drug distribution characteristic can be obtained

Influence of altered physiology and diseases states can be easily obtained.

Frequently used in animals because invasive methods can be used to collect

tissue samples

Correlation of data in various species is possible

Mechanism of ADME of drug can be easily explained

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Obtaining the experimental data is very exhaustive

Most physiological models assuming an average blood flow

for individual subjects and hence prediction of individualized
dosing is difficult

The no. of data points is less than the PK parameters to be

assessed

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1. It is analogous to physiological model but takes into

consideration:
1. Variation in blood flow to an organ
2. Variations in drug diffusion in an organ
2. It is specifically useful for assessing regional differences
in drug conc in tumor or necrotic tissues
3. Collection of data is much more difficult

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 Model independent method

 Base on assumption that drug and metabolite follow linear kinetics
 Based on statistical moments theory
 Involves collection of experimental data following a single dose

MRT – mean residence time

AUMC – area under the first moment
curve
AUC – area under the zero moment
curve

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 MRT – average amount of time spent by the drug in the body

before being eliminated
 It is the statistical moment analogy of half life
 It represents time for 63.5% of IV bolus dose to be eliminated
 AUC and AUMC can be calculated by trapezoidal rule

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 MRT is merely the expected value or mean of the distribution.

 MRT provides a fundamentally different approach than classical
pharmacokinetic models, which involve the concept of dose, half-
life, volume, and concentration.
 MRT is an alternative concept to describe how drug molecules
move in and out of a system.
 The concept is well established in chemical kinetics, where the
relationships between MRT and rate constants for different
systems are known.
 In the last two decades, MRT has been well characterized for
various pharmacokinetic models, although MRT application is
less developed in pharmacodynamics.

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 Widely used to estimate the important PK parameters like BA,

Cl and Vd

 The method is also useful in determining t1/2, Ka

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 Easy of derivation of PK parameters by simple algebraic

equations
 The same mathematical treatment can be applied to any drug
or metabolite that follow first order kinetics
 Detailed description of drug disposition characteristic is not
required

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 It provides limited information regarding plasma drug conc

time profile

 It does not adequately treat non-linear kinetic cases

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• PK described by grouping body

Compartment tissues which are kinetically same
model • Rate constants are used to describe
transfer of drug between body tissues

Non-
• PK described by time and
compartment concentration averaged parameters
model

Physiological • PK described by realistic physiologic

parameters like blood flow and tissue
model partition coefficient

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 Zero-order elimination kinetics : "Elimination of a constant

quantity per time unit of the drug quantity present in the
organism.“
 First order elimination kinetics : "Elimination of a constant
fraction per time unit of the drug quantity present in the
organism. The elimination is proportional to the drug
concentration.

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 The plasma concentration – time profile

during the elimination phase is linear
 For example 1.2 mg are eliminated every
hour, independently of the drug
concentration in the body.
 Order 0 elimination is rather rare, mostly
occurring when the elimination system is
saturated.
 eg is the elimination of phenytoin,
phenylbutazone, warfarin, heparin, ethanol,
acetaminophen, tolbutamide, theophylline,
salicylates, caffeine etc

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 For first order elimination, the plasma concentration – time

profile during the elimination phase shows an exponential
decrease in the plot with linear axes and is linear if plotted on
a semi-logarithmic plot (plasma concentration on logarithmic
axis and time on linear axis)
 For example, 1% of the drug quantity is eliminated per
minute. Many drugs are eliminated by first order kinetics.

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Elimination kinetics First order Zero order

Curve in the plasma

concentration vs. time plot exponential decay linear
after i.v. bolus

Curve in the log plasma

concentration vs. time plot linear non-linear
after i.v. bolus

Relation between elimination rate is elimination rate saturates

elimination rate and drug proportional to drug with higher drug
concentration concentration concentration

Term in clinical
linear kinetics non linear kinetics
pharmacology

95 % of drugs, at therapeutic the remaining 5 %, and

Concerns
concentrations ethanol

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Sr. Zero order kinetics First order kinetics

no.
1 Definition: the process that takes place at a Definition: the process that is directly
constant rate independent of drug proportional to the drug concentration
concentration involved in process involved in process
2 Constant rate process Linear kinetic process
3 Rate of process cannot be increased even Rate of process increases linearly with
if the conc is increased drug conc
4 Conc independent process Conc dependent process
5 dc/dt = -K0 C0 = -K0 dc/dt = -KC
6 Units of rate constant = mg/min min-1 or hr-1
7 General equation General equation
C = C0 – K0 t C = C0e-Kt
log C = log C0 – Kt/2.303
8 Half life: t1/2 = 0.5 C0/K0 Half life: t1/2 = 0.693/K
9 Half life depends on the initial drug conc Half life is conc independent and it is a
constant value
10 At some point a zero order process comes The process never comes to an end since
to an end it takes place at certain proportion of the
conc existing at that time
11 Eg. IV infusion, CR systems, carrier ADME (not linked with carriers)
processes after saturation 53

 It takes place at a constant rate independent of the conc.

 Eg. A patient was given 100 ml of drug by IV infusion,
assuming that the infusion rate follows zero order kinetics at a
rate of 10 mg/min

How much drug would be administered every 5 mins? • 50 mg

How much time would it take for 80 mg drug to be administered? • 8 mins

By what time would the whole drug be administered? • 10 mins

If the administered dose of the drug is 200 mg and if it is infused at the

same rate how much time would it take for complete administration? • 20 mins
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 It takes place at the constant proportion of drug conc available at

that time thus it depends on the initial conc
 Eg. A patient was given 100 mg drug orally and it was assumed to
be following first order kinetics at a rate of 10% per min of the
existing conc at that time

How much drug would be absorbed in the first min? • 10 mg

How much drug would be absorbed in the second min? • 9 mg

How much drug would be absorbed in the third min? • 8.1 mins

After sometime if 1 mg is remained to be absorbed then also 10% of

that 1 mg would be absorbed. So when would a first order process end? • Never 55

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