Introduction to

Pharmacokinetics

By

Dr. Shobha Rani R.H

Professor and Head
Dept. Of Pharmacy Practice
Al-Ameen College of Pharmacy
Bangalore
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Points of Discussion
Definition and types
Applications
What is a model ?
Types of Models
Advantages of models

Classification of compartment models

Salient Features
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What is Pharmacokinetics ?
Is the study of the rate processes of
Absorption
Distribution
Metabolism
Excretion
In general, ADME describes the drug movement
into, within and out of the body.
Metabolism and excretion --- Elimination
Distribution , Metabolism & Excretion --disposition
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Each of these processes has a:

Kinetic Component Rate of process

Extent Component Amount of drug
/fraction of dose that is absorbed,distributed
, metabolized or excreted

Linear Pharmacokinetics
Rate of change of concentration of drug over time:
dC/dt = -K.C
Linear refers to the fact that rate is directly proportional
to the concentration.
If rate is plotted vs time , a straight line relationship
would result.

Non Linear Pharmacokinetics

Rate is no longer linearly related to concentration.
Applies to drug for which metabolic pathways or plasma
protein binding becomes saturated at the concentrations
usually within the therapeutic range
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Applications of Pharmacokinetics
1. In drug discovery

To select the drug molecules based on their

pharmacokinetic data.
Any new drug developed should ideally
be well absorbed.
be less metabolized.
have a t1/2 between 6 10 hrs.
have a wide therapeutic window, i.e., have
high LD50 and low ED50 values.
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2. In preclinical studies
To extrapolate human kinetics from animal
data.
3. In clinical studies
To fix a dosage regimen

What is a Model?
Representation of a data.
It is defined as a simplified mathematical
description of a system or process.

Why model the data ?

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 the single dose
data , to predict the absorption profile of the drug
from the IV data.
3. Explanatory to explain unclear observations
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In modeling the mathematical expressions includes

-constants
-parameters
-variables
The simplest model for IV administration to characterize
the drug kinetics is

C= Co.e-Kt

C= D/Vd e-Kt [for IV, Co = D/Vd ]

Dose -- constant
Vd and K - parameters to be estimated by fitting
the model to the data
C and t variables ( C- dependent variable
t - independent variable )
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Types of PK models
Non compartmental Model
Compartmental Model
Physiological Model

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Non-compartmental model
This describes the pharmacokinetics of drug
disposition using concentration and time parameters.
Here there is no concept of compartmentalization.

Non-compartmental methods for calculating

absorption, distribution and elimination parameters
are based on statistical moments theory.
As the method is model independent, the same
mathematical treatment can be applied to any drug or
metabolite as long as I order kinetics is operative.

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Non compartmental model ----The basic calculations are based on the area under the
plasma concentration vs time curve (zero moment) and
the first moment curve (AUMC).
AUMC is obtained from the plot of the product of
plasma drug concentration and time (ct) vs time (t) from
zero to infinity.
AUMC is also calculated by the trapezoidal rule.
From AUC and AUMC, the mean residence time (MRT)
can be calculated, as follows:
MRT = (AUMC)/(AUC) [for IV administration]
MRT is the average time the drug molecules reside in
the body.
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Assumptions:
drug is input to the body
Some drugs irreversibly leave the body

Some drugs go to the tissues from where it

irreversibly leaves the body
Drug is distributed through Stochastic (random)
process
Convection (through the blood)
Diffusion (through the various membranes and tissues).

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As per NC model, the following two things

are valid:
1. Superposition
If one input is given which gives a
certain response (IV dose) and another
response ( oral dose ), the total
response becomes the sum of individual
responses.
2. Time Invariance
If a certain response is obtained
,if that dose is given it any other time,
the same response should be observed

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Data collected:- concentration and time

The basic calculations are based on the blood level

curve obtained by plotting plasma concentration vs time

Blood Level Curves

B

B
Conc

Conc

Log C

Time

Intravenous

C
A

Time

C
A

Extravascular

Time

AB Absorption phase
BC Elimination phase
From the graphs the various parameters (Ka, Ke,AUC,AUMC)
can be calculated.
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Compartmental model
It involves the representation of the subjects
body as a collection of compartments.
The assumptions are
Barriers exist between compartments

Transfer occurs in a certain direction

Transfer occurs at a certain order(e.g.,zero or
first order)

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The simplest compartmental model is the onecompartment model with IV bolus

administration and first order elimination of
the drug.
This approach can be expanded to include

other routes of administration such as IV

infusion and extravascular administrations

such as oral, intramuscular, subcutaneous or

topical.
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Compartment characteristics
It is a group of tissues ( with similar blood flow
or affinity characteristics)
The drug is homogeneously distributed ( log c Vs
t has the same slope for each tissue i.e. the rate
of elimination from each tissue is the same.
Drug distribution is instantaneous , thus the
compartment is well stirred.
Elimination is from central compartment
There is no irreversible tissue binding

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Physiological model
For these models, compartments are chosen to
represent physiological compartments of the body.
All physiological compartments of the body such as
gastrointestinal tract, lungs, central nervous system,
muscles, bone, etc, are included in the model.
Many of the same assumptions for the compartments
of the traditional models apply here as well.
In addition, blood flow must be known or estimated
through each compartment.

The amount of drug entering and leaving the

compartment should be determined.
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 Each

organ system forms a separate compartment

Drug is homogeneously and instantaneously distributed

Compartment is well stirred and the concentration

of the drug leaving an organ is in equilibrium with the
concentration of the drug in the organ.
An equilibrium constant or partition coefficient can be
determined from the concentration of the drug in the
tissue compared to the concentration in the blood

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Representation of physiological modeling

Heart

Input

Kidney

output

Liver

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Barriers between the compartments

Transfer is dependent on the rate of blood flow

through the physiological compartment

Each compartment has a characteristic clearance

rate
Therefore,it is necessary to know or determine the
rate of blood flow in each organ or tissue system in
the model.
Elimination is only from certain compartments such
as liver and kidneys
There is no irreversible binding of the drug to the
tissues
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There are four main objectives for analysis of

pharmacokinetic data.
1) To summarize the kinetics of the drug
(descriptive Pk)
2) To quantify one or more kinetic process of the
drug.
3) To explain the pharmacokinetics, or
4) To make pharmacokinetic predictions .
The objective of the study will determine which of
the modeling approaches to use.
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Non-Compartment Modeling :
It is useful if the study objective is to
Summarize kinetics
Quantify a PK process
To make PK predictions

This is not useful to explain the

pharmacokinetics
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Compartment models:
Limitations
1)There is little physiological or anatomical relevance
of the compartments.
2)There are many assumptions which are very difficult
to verify.
Applications
1)To develop descriptive pharmacokinetics

for a drug.
2) To quantify a Pk process or to explain the

Pharmacokinetics
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Physiological Models :Applications

1) Model is more realistic & meaningful as

blood flow, distribution and elimination from

individual organs & tissue groups are included.
2) The model parameters that are determined

such as blood flow, elimination rate &partition

co-efficient have a physiological or anatomical
meaning .

3) Its main application is in drug discovery

process to identify the kinetics and action
of a new compound.
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4) It is very useful to explain the

pharmacokinetics of a compound.

Limitations
.1)The Model is complex & sufficient data is
difficult to be collected.
2) Apart from urine /blood data , tissue
concentrations and organ blood flow rates
need to be known.

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Classification of Compartment Models:

Compartment :- Not a physiological or anatomical
region but consists of a group of tissue
With similar blood flow and/or affinity
characteristics.
Two types

Multi Compartment
One Compartment

Two Compartment

Three
Compartment

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Classification of compartment models

One compartment model
Assumptions
The body is treated as one homogeneous unit which
has no barriers to drug movement.
Mixing is instantaneous.
Drug elimination follows first order kinetics.

1
k10
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Blood analysis
Mono exponential decline
Plasma
conc

time

dAB / dt = - K AB
Vd = Dose / C0
C= C0. e Kt
Log C = log C0 - K t / 2.303
Parameters that can be estimated from this model : K , Vd
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Analysis of urine data

dU / dt ----- Rate of elimination

Log (du/dt)

Slope= -k/2.303

time

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Dose

Cumulative
Amount
Excreted

Time

Cumulative amount of drug excreted Vs time ( No

metabolism )

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Dose

U = dose

Time

Cumulative amount excreted Vs time ( with

metabolism )

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Slope=-K/2.303
Log ARE

Time

Plot of Amount remaining to be excreted Vs

time

du/dt

Slope=CL

Plasma
concentration

Rate of elimination Vs plasma conc curve

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One compartment model with IV infusion

K0
1
K10

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Css

Plasma
conc

Post infusion
Time in hr
(semilog plot)

Blood level curve for an infusion

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Slope = -K /2.303
Log(Css-C)/Css

K=Cl / Vd

Time

Estimation of K for an infusion

One Compartment Extravascular administration
K 01

1
K 10

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Multi compartment models

Input
Central

Peripheral compartments

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Multi compartment model

Takes care of distribution of drugs.
Distribution and elimination are occurring
throughout the conc.-time profile.
Slower distribution of drugs requires the use
of multi-compartment models.

Highly perfused tissues ------ central compartment

Blood, heart,liver,kidneys,lungs

Poorly perfused tissues----- peripheral compartment

(tissue compartment)

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Distribution phase

Log C

Terminal phase

Time

Two compartment model

K12

Vc

K10

Vt

K21

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C = A e

- t

+ B e

-t

Slope =- / 2.303

Log C
Slope =- / 2.303

residual plot

Time
K = C

A + B
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K12 =

+ - K21 K10

K21 = A + B

A + B
K10 =

K21

Vc = Dose
A + B
AUC = A + B

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Log C

Time

Two compartment model : extravascular

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Three compartment model

K 21

Vt
K

Vc

12

C = A e

- t

+ B e

-t

+ C e

13

3
Vdt

31

10

- t

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Summary
Pharmacokinetic models are important in both preclinical and clinical studies.
The biological system is very complex and the kinetics
of the drug is very complicated.
We can describe the drug kinetic processes or
interpret the data using simple mathematical models.
The ultimate objective of any pharmacokinetic model is
to obtain the pharmacokinetic parameters of a drug.
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