Introduction & Overview

Presenter
Dr. Afrasim Moin
Asst. Professor
Department of Pharmaceutics
University of Hail
Preamble
• Xenobiotics/drugs are compounds that are foreign to the
body & have the potential to cause harm rather than
healing when used in a wrong dose

• Medieval alchemist Paracelsus stated: ‘‘Only the dose

makes a thing not a poison.’’

• Duration of drug therapy ranges from a single dose

(acute condition) to drugs taken lifelong (chronic
2
conditions).
KINETICS
• The frequency of administration of a drug in a
particular dose is called as dosage regimen

• Therapeutic and the toxic effects depend on the

concentration of drug .

• Depending upon the physiological & therapeutic

objective dosage regimen is established to provide an
effective concentration of a drug in the body

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• Drugs are rarely administered as pure chemicals and
are almost always given as formulated preparations

• The objective of dosage form design is to achieve a

predictable therapeutic response to a drug(minimum
dose) included in a formulation which is capable of large
scale manufacture with reproducible product quality

• Same type of dosage form by different routes of

administration, e.g. an aqueous solution of a given drug
administered by the oral and intramuscular routes

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• Same routes of administration but different types of
dosage form, e.g. tablet & hard gelatin capsule
administered by the oral route

• Same type of dosage form by the same route of

administration but with different formulations of the
dosage form, e.g. oral aqueous suspensions

• The rate and extent of absorption, and hence the time

course of a drug in the plasma and therefore at its
site(s) of action they are variations

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• Drug to be effective, enough of it needs to reach its
site(s) of action and stay there long enough to be able
to exert its pharmacological effect when given in
desired dosage regimen

• To achieve the above the clear understanding of

principles of Biopharmaceutical & Pharmacokinetics
essential

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Biopharmaceutics
• Defined as the study of the factors influencing the
bioavailability of a drug in man and animals such as
 Method of manufacture,
 Physicochemical properties of drugs
 Chemical nature of a drug
 Excipients used

• Use of the above information to develop a dosage

form that will provide consistent bioavailability at a
desirable rate & optimize drug therapy

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Pharmacokinetics
• Defined as the kinetics of ADME and their
relationship with the pharmacological, therapeutic or
toxicological response in man and animals
 Bioavailability measurements
 Effects of physiological and pathological conditions
on ADME
 Dosage adjustment of drugs in disease states
 Correlation of pharmacological responses with
administered doses
 Individualization drug therapy

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Relationship between the administered dose and amount of
drug in the body
• Intravenous route, the amount of drug that reaches
general circulation is the dose administered

• For the extravascular route, the amount of drug that

reaches general circulation is the product of the
bioavailable fraction (F) and the dose administered.

• Above Equations suggest that we must know or

determine all the parameters (i.e., K, V d, F ) for a given
drug.
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Plasma Drug Concentration-Time Profile
• A direct relationship exists between the drug
concentrations at the site of action & the concentration of
drug in plasma.
• Pharmacokinetic & Pharmacodynamic parameters can
be evaluated

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PHARMACOKINETIC PARAMETERS
Peak plasma concentration (Cmax)
• The point of maximum concentration of drug in plasma is
called as the peak & the concentration of drug at peak is
known as peak plasma concentration or peak height
concentration

• Represents maximum drug concentration & is expressed in

µg/ml

• It depends upon administered dose, rate of absorption &

elimination. It is related to the intensity of pharmacological
response

• Absorption rate equals elimination rate of drug

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Time of Peak Concentration (tmax)
• The time for drug to reach Cmax after extravascular
administration & is expressed in hours
• Useful in estimating the rate of drug absorption
• Useful for assessing the efficacy of drugs used to treat acute
condition

Area under the curve (AUC)

• Represents the total integrated area under the plasma level-
time profile & expressed in µg/ml*hours
• Express the total amount of drug that’s comes into the systemic
circulation i.e extent of absorption
• Determined by Planimeter Method, Cut and weigh Method etc.
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Pharmacodynamic Parameters
Minimum Effective Concentration (MEC)
• Minimum concentration of drug in plasma (receptor
site) required of produce the therapeutic effect.
• Concentration of drug below MEC is said to be in the
sub-therapeutic level

Maximum safe concentration (MSC) / Minimum toxic

concentration (MTC)
• Concentration of drug in plasma above which adverse
or unwanted effect are precipitated
• Concentration above MSC is said to be in the toxic
level.

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Onset of action: Beginning of pharmacological response
is onset of action & occurs when the plasma drug
concentration just exceeds MEC.

Onset time : It corresponds to the time for the plasma

concentration to reach MEC

Duration of action : the time period for which the plasma

concentration of drug remains above the MEC level is
called as duration of drug action.

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Intensity of action : Maximum pharmacological response
produced by the peak plasma concentration of drug.

Therapeutic range : Drug concentration between MEC

and MSC represents the therapeutic range. It is also
known as therapeutic window.

Therapeutic index : The ratio of MSC to MEC. It is also

defined as the ratio of dose required to produce toxic or
lethal to therapeutic effect.

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Pharmacokinetic Models
A model is a hypothesis that provide concise means of
expressing mathematically or quantitatively, the time
course of drug(s) throughout the body & compute
meaningful PK parameters.

The process is described mathematically by equations

which incorporate exponential terms (eK. or e-K ) which
suggests that ADME processes are ‘‘first order’’

Drug transfer in the body is possibly mediated by

passive diffusion & indicting directly proportional
relationship between the observed plasma
concentration and the administered dose
.
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Compartment Models
• The body is represented as a series of compartments
arranged either in series or parallel to each other, which
communicate reversibly with each other.

• Each compartment is not a real physiological/anatomical

but a fictitious or virtual & considered as a tissue or
group of tissues that have similar drug distribution
characteristics (similar blood flow and drug affinity )

• The rate of drug movement between compartment is

described by first-order kinetics.

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Mammillary model
• One or more peripheral compartments connected to the central
compartment parallely.

• Central compartment comprises of plasma and highly perfused

tissues. The drug is directly absorbed & Eliminated from here.

• Peripheral compartment or tissue compartment (denoted by

number 2,3, etc.) are those with low vascularity and poor
perfusion.

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• Distribution of drug into compartments is given by
rate constant K. The subscript indicates the direction
of drug movement; thus k12 refer to drug movement
from compartment 1 to compartment 2

• The number of rate constants which will appear in a

particular compartment model is given by R.

• For intravenous administration R=2n-1 &

extravascular administration R=2n

Where n= number of compartments.

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Model 1
• One compartment open model, IV injection

K
1

Model 2
• One compartment open model with first order
absorption

ka K
1

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Model 3
• Two compartment open model, IV injection

Model 4
• Two compartment open model with first order
absorption

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Catenary Model
• Compartments are joined to one another in series like
compartment of a train

• Not observable physiologically as the various organs are

directly linked through the blood compartment

• Hence this model is rarely used.

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Advantages
• It gives a visual representation of various rate processes
involved in drug deposition.
• It shows how many rate constant are necessary to
describe this processes.
• It enables monitoring of drug concentration change with
time with a limited amount of data.
• Predicting drug concentration – time profile in both
normal & pathological condition.

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• Help development of dosage regimen.

• Relates plasma drug levels to therapeutic and toxic

effects in the body.

• Easy tabulation of parameters such as V d, t1/2, etc.

Disadvantages

• The compartments and parameters bear no relationship

with the physiological functions.

• Several assumptions have to be made.

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IV bolus one-compartment model

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• The plotted curve is a straight line, which clearly indicates

the presence of a single pharmacokinetic phase ( elimination

phase.)

• Since the drug is administered intravenously, there is no

absorption phase.

• The straight-line also suggests that distribution is

instantaneous; thus the drug is rapidly distributed in the

body.

• These data can be accurately and adequately described by

mono-exponential
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IV bolus two compartment model

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• Two phases in the concentration versus time data.

• The first phase (curvilinear portion) represents drug

distribution in the body; and only after a finite time

• We see a straight line which suggests that drug is being

distributed slowly and requires a two-compartment
model for accurate characterization

• The equation employed to characterize these plasma

concentration versus time data will be biexponential

• Here A and α are parameters associated with drug

distribution and B and β are parameters associated with
drug post-distribution phase

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Extravascular administration: One compartment model

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• There are two phases in the profile: absorption and
elimination

• In distribution profile contains only one phase data can

be described accurately described by one-compartment
model

• There are two phases for the plasma concentration

versus time data, a biexponential equation is required to
describe the data accurately

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Extravascular administration: Two compartment
model
• Three phases include
absorption, distribution &
post-distribution

• The plasma concentration

versus time profile, indictes
drug fits two-compartment
model

• These data can be described

accurately by the equation
that will contain three
exponential terms
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