Biopharmaceutics

SANA IJAZ
LECTURER
BIOPHARMACEUTICS

Pharmacokinetics and
Biopharmaceutics
 The key pharmacokinetics was first introduced by F.H.DOST in
1953.
 “Pharmacokinetics is the study of the kinetics of absorption,
distribution, metabolism and excretion (ADME) of the drugs
and their corresponding pharmacologic, therapeutic or toxic
response in animals and man.”
 Absorption: is the movement of the drug into the blood stream.
 Distribution: the reversible transfer of a drug from one location
to another within the body.
 The distribution of the drug between tissues is dependent
on vascular permeability, regional blood flow, cardiac output
and perfusion rate of the tissue and the ability of the drug to
bind tissue and plasma proteins and its lipid solubility.

 pH partition plays a major role as well.
 The drug is easily distributed in highly perfused organs such as the
liver, heart and kidney.
 It is distributed in small quantities through less perfused tissues like
muscle, fat and peripheral organs.
 Metabolism: is the metabolic breakdown of drugs by
living organisms, usually through specialized enzymatic systems.
 The rate of metabolism determines the duration and intensity of a
drug's pharmacologic action.
 Excretion/ elimination: of a drug is one of a number of processes
by which a drug is eliminated from an organism either in an
unaltered form (unbound molecules) or modified as a metabolite.
 The kidney is the main excretory organ although others exist such
as the liver, the skin, the lungs or glandular structures, such as
the salivary glands and the lacrimal glands. These organs or
structures use specific routes to expel a drug from the body, these
are termed elimination pathways.

Total body fluid(40L)
ECF (extracellular
fluid)
15L
Interstitial
fluid (12L)
Blood
plasma
(3L)
ICF(intracellular
fluid) 25L
Transcellular
fluid(5L)

Biopharmaceutics:
 It is the study of physiochemical properties of the drugs,
their proper dosage form in which administered and the
route of administration as related to the onset, duration and
intensity of drug action.
 Biopharmaceutics embraces the knowledge of factors that
influence
1. Protection of the pharmacological activity of the drug in
the drug product
2. The release of the drug from drug product
3. The rate of dissolution of drug at the site of administration
4. The system absorption of the drug (rate and extent).

Clinical pharmacokinetics
 “Study of time course of absorption, distribution,
metabolism and excretion of drugs and their
corresponding pharmacological response.”
 This science may be applied to a wide range of clinical
situations (renal, cardiac, hepatic, diabetes mellitus
etc)
 More correctly clinical pharmacokinetics is the
application of pharmacokinetic principles in
appropriate and rational drug therapy patient’s status
(host factors)and disease state influence the PK of the
drug.

Population pharmacokinetics
 This study deals with the Pk differences of drugs in
various population groups.
Toxicokinetics: Toxicokinetics evaluation is both a
regulatory and scientific requirement in the drug
development process. It includes the generation of data to
asses the systemic exposure. These data (ADME)help to
understand observed toxicity to administered dose and also
play a role in clinical setting, assisting in the setting of
plasma limits for early human exposure and in calculation
of safety margins.
 It is the study to determine the relationship between the
systemic exposure of an agent in experimental animals and
its toxicity.

Clinical toxicology:
 It may be defined as the prevention, diagnosis and
management of poisoning, usually in a hospital or
clinical environment.

Drug substance:
 It is the active pharmaceutical ingredient or component
in the drug product that produces the
pharmacodynamic activity.
Drug product
 A drug product is the finished dosage form (tablets,
syrups or injections) that contains the active ingredient
as essential component and it may (generally) or may
not (necessarily) contain inactive ingredients.

Reference listed drug(RLD)
 is the brand name drug (research product) that has a
full new drug application (NDA).
 FDA designates it a single reference listed drug as the
standard and an applicant relies on it when seeking the
approval of ANDA (abbreviated New Drug
Application).

Abbreviated new drug application
(ANDA)
 A pharmaceutical manufacturer must file an ANDA for
approval to market a generic drug product (branded
generic/ non patent brand). The generic manufacturer
is not required to perform non clinical toxicology or
clinical efficacy studies for ANDA.

Types of drug product
 There are two types of drug product
1. Single source drug product
2. Multiple source drug product
1.Single source drug product
 This is a drug product for which the patent has not
yet expired or has certain exclusivities so that only
one manufacturer can manufacture single source
drug products, are usually brand name (innovator).
These are research products of a pharmaceutical
manufacturer. After the patent and other exclusivities
of a brand name expire, other pharmaceutical firms
may manufacture a generic drug product (non patent
brand).

2. Multiple source drug product:
 It is a drug product that contains the same active drug
substance in the same dosage form and is
manufactured/ marketed by more than one
pharmaceutical firms.
 The U.S food and drug administration (FDA)publishes
annually in print and on internet, approved drug
products with therapeutic equivalence.
 The evaluation book, also known as Orange book
identifies drug products approved on the basis of safety
and effectiveness by FDA and contains therapeutic
equivalence evaluations for approved multi source
prescription drug products.

Generic substitution
 Is the process of dispensing a different brand (branded
generic) or unbranded generic drug products in place
of a prescribed drug product.
 The substituted drug product contains the same salt or
ester of the same active ingredient in the same
dosage form but is manufactured by a different
company.
 Paratol by high noon or paracetamol tablets by
ferozsons, can be given in place of panadol tablets
(GSK)
 10 examples assignment

Pharmaceutical Alternatives:
 Drug products that contain the same therapeutic
moiety (active principles) but as different salts or
esters or complexes are called pharmaceutical
alternatives.
 Tetracycline phosphate and tetracycline HCL
 Different dosage forms and strengths within a product
line manufactured by a same company are also
pharmaceutical alternatives e.g. standard immediate
release and slow release dosage forms.
 Tablets and capsules of the same active ingredient in
the same dosage strength are also pharmaceutical
alternative.

Pharmaceutical substitution:
 The process of dispensing a change in dosage form
for the prescribed drug products.
 Paracetamol suspension in place of paracetamol
tablets.

Therapeutic alternatives
 Drug products containing different active ingredients,
but belonging to the same pharmacological group and
are expected to have the same therapeutic effect when
given to patients.
 Cimitedine may be given instead of ranitidine.
 Lorazepam may be given for diazepam

Therapeutic substitution:
 The dispensing of a therapeutic alternative in place of
the prescribed drug product
 Amoxicillin in place of ampicillin.
Therapeutic equivalent:
 Drug products are considered therapeutic
equivalent if they are pharmaceutical equivalents
and they are expected to have the same clinical
efficacy and safety when given to patients under
conditions claimed in the label.

 FDA categorizes those drug products as therapeutically
bioequivalent if they fulfil the following criteria.
 Approved as safe and effective
 Pharmaceutical equivalent in following respects
1. Same amount of same active ingredient in the same
dosage form intended to be used by the same route of
administration.
2. Meet compendial or other standards of strength,
quality, purity and identity.

Bioequivalent criteria:
 Don't have any known or potential bioequivalent
problem, and meet an acceptable in-vitro standard.
 They are adequately labelled
 They are manufactured by fully following c GMP
regulations.
 FDA believes the drug products classified as
therapeutic equivalent can be substituted for prescribed
product will produce same clinical effect and safety
profile as prescribed product.

Bioequivalence requirement
 The requirement imposed by FDA for in vitro and in
vivo testing of particular drug products which must be
satisfied as a condition of marketing.
 Bioequivalent drug products:
 For systemically absorbed drugs the test drug (generic
/non patent)and reference drug (branded)shall be
considered bioequivalent
1. If the rate and extent of absorption of test drug don't
differ significantly from the rate and extent of
absorption of reference drug when given
administered at the same molar dose of therapeutic
ingredient under similar experimental conditions in
either a single dose or multiple doses.

2. The extent of absorption of test drug does not show
significant difference from the extent of absorption of
reference drug when at the same molar dose of
therapeutic ingredient under similar experimental
conditions in either a single dose or multiple doses and
the difference from the reference drug in rate of
absorption of test is intentional and mentioned on its
proposed labelling. As well, this difference in rate of
absorption does not influence therapeutic objectives
when test drug used chronically.

Drug concentration
 Drug concentration is an important element in
determining individual or population pharmacokinetics
 Drug levels are measured in biological samples like
plasma, saliva, milk and urine. Sometimes hair and
nails are also sites where drugs can accumulate.

Sampling of biological specimens:
 Two methods are used for sampling
1. Invasive method:
 Include sampling of blood, spinal fluid, synovial
fluid, tissue biopsy or any biological material that
requires parenteral or surgical intervention in the
patient.
1. Non- invasive method:
 Include sampling of urine, saliva, milk, faeces,
expired air or any other biological material that can
be obtained without parenteral or surgical
intervention.

Drug concentration in Blood, Plasma
and serum:
 Measurement of drug concentration in the blood, plasma or serum is the
most convenient and direct method to assess the PK of the drug in the body.
 Whole blood contains formed elements (WBCs, RBCs and platelets) and
protein like albumin and globulins.
 Generally serum or plasma is most commonly used for measuring drug
concentration.
 Plasma perfuses all tissues of the body and cellular elements in the blood.
 For practical purpose, it is assumed that the drug in plasma is in dynamic
equilibrium with the tissues, the changes in plasma drug concentration will
reflect corresponding changes in tissue drug concentration.
 Plasma: straw coloured clear liquid 91 to 92% water, 8 to 9% of solid
 Serum= plasma -fibrinogen

Plasma Level time curve:
 The plasma level time curve is constructed by measuring
drug concentrations in plasma.
 Samples are taken at various time intervals after the
administration of a drug product.
 The concentration in each plasma sample is plotted on
rectilinear graph paper against corresponding time at
which the sample was withdrawn.
 A typical plasma level time curve is as in the following
figure.

Minimum effective concentration
(MEC)
 MEC represents the minimum concentration of the
drug needed to produce the pharmacological effect
(for therapeutic purpose this the minimum
concentration needed to be present at the receptor to
produce desired effect)
 Minimum toxic concentration(MTC)
 MTC reflects the minimum concentration of drug
needed to need just barely produce a toxic effect.

Intensity
 Intensity of pharmacological response is proportional
to the number of drug receptors occupied, which is
reflected in the observation that higher plasma drug
concentrations produce a greater response, up to a
maximum.
Duration:
 Duration is the difference between the onset time
and the time for drug concentration to decline back
to MEC.

Onset time:
 Onset time corresponds to the time required for the
drug concentration to reach the MEC.
Peak plasma level (Cmax):
 it represents the maximum plasma drug concentration
obtained after administration of drug. (usually by oral
route)
tmax:
 time required to reach Cmax.
Lag time:
 The time between the administration of the drug and the
start of the absorption.

Drug concentration in tissues:
 Tissue biopsies are occasionally removed for
verification of malignancy.
 Drug concentration in tissue biopsy may not reflect
drug concentration in other tissues nor in all parts of
the tissue from where the sample is removed.
 The drug concentration in tissue biopsies may be used
to make sure whether the drug reach the tissue or not
and if reached, did it reach up to the proper level.?

Drug concentration in urine and faeces:
 The measurement of drug concentration in urine is
indirect method of measuring the bioavailability.
 The rate and extent of drug excretion reflects the rate
and extent of systemic drug absorption.
 Urinary blood excretion data can also be used to
calculate PK parameters.
 Measurements of drug in faeces reflects the amount of
unabsorbed drug following oral administration of a
dose or may reflect the amount of drug that is secreted in
bile ( and not reabsorbed)after systemic absorption.

Drug concentration in saliva:
 Free drug (unbound)diffuses in saliva
 Saliva drug levels nearly parallel the free drug rather
than total plasma drug concentration.
 The saliva drug concentrations, taken after equilibrium
with plasma drug concentration, generally provides
more stable indication of drug levels in the body.


Forensic drug measurement:
 Forensic toxicology (combination of analytical chemistry and
fundamental toxicology) is concerned with medico-legal aspects
of the chemicals.
 Measurement of drug concentrations in tissue samples obtained
at autopsy or in body fluids such as blood, urine and saliva may
be helpful in knowing whether
1. a suspect or victim has taken overdose of legal medication.
2. Has been poisoned
3. Is an addict and has been using drugs of abuse (heroine,
marijuana and cocaine)
 The appearance of social drugs in blood urine and saliva
indicates short term drug use.
 The drugs may be eliminated quickly and making it difficult to
prove that the subject has been using drugs of abuse.

 The analysis of hair samples by using very sensitive
ASSAY methods and techniques (GC/MS or LC/ MS)
 Provide information about previous drug exposure.

Bioavailability
 Bioavailability is the measure of rate and extent of active
ingredients or active moiety of a drug product that reaches
the systemic circulation and becomes available at the site of
action.
Relative availability:
 is the availability of the drug from a drug product (test)
compared to a recognized standard (reference).
[AUC]test
R.A=_______________
[AUC]reference

 When two products are used at different dose levels then
the following formula is used
[AUC]test/ [Dose]test
______________________________
[AUC]reference/ [Dose]reference
Percentage relative
availability=relative availability*100

Absolute availability
 The absolute availability of drug is the systemic
availability of a drug after extra vascular
administration (oral, rectal and any other route)
compared to intravenous dosing.
 It is measured by comparing respective AUC following
extravascular and intravenous administration.
 It can be determined as long as volume of distribution
(Vd) and elimination rate constant (Kelim) are
independent of route of administration.
[AUC]PO/ [Dose]PO
F= ___________________________________
[AUC]I/V [Dose]i/v

Purpose of bioavailability studies:
 Bioavailability studies are performed for both approved
active drug ingredients and therapeutic moieties not yet
approved for marketing by the FDA.
 The drug must meet all applicable standards of identity,
strength, quality and purity.
 It may b considered as one aspect of dug product quality
that links in vivo performance of the drug product used in
clinical trials to studies demonstrating evidence of safety
and efficacy.
 Bioavailability studies are used to define the effect of
changes in the physiochemical properties of the drug
substance and the effect of the drug product (dosage form)
on the PK of the drug.

 Absolute availability (F) can be expressed as a fraction
or as a percentage by multiply F*100.
 The absolute B.A is also equal to F, the fraction of
dose that is bioavailable, and it can be expressed as a
percentage i.e., F=1 or 100%
 For a drug given as IV bolus dose, F=1 as all the drug
is injected into the lumen of vein and all the drug is
bioavailable.
 For drugs given by all extravascular routes the value
F≤1.

Methods for assessing bioavailability:
 There are several direct and indirect methods of
assessing bioavailability.
 The selection of method depends on
1. Objection of the study
2. Ability of analysing the drug and metabolites in
biological fluid
3. Pharmacodynamic of the active principles
4. Route of administration
5. Nature of drug product

 The following parameters are useful in determining
bioavailability of a drug from a drug product.
 1. plasma drug data:
a) The time of peak plasma (blood ) concentration
(tmax)
b) The peak plasma concentration (C max)
c) The area under the curve (AUC)

 Periodical measurement of drug concentration in whole
blood, plasma, or serum, after drug administration is the
most convenient and direct method to assess systemic drug
bioavailability.
 The various parameters are as under:
1. tmax: corresponds to the time required to reach the C
max after drug administration. At tmax, absorption is
maximized and route of drug absorption exactly equals to
the rate of drug elimination. Drug absorption still
continuous after tmax is reached, but as a slower rate. In
comparing the drug product, tmax can be used as
approximate measurement of drug absorption rate. The
value of tmax will be smaller for the drug having more
rapid rate of absorption and vice versa. The units are hrs /
minutes.

2. Cmax: indicates the maximum drug concentration
obtained after extravascular administration of drug.
For many drugs a good relationship is found between
the pharmacodynamic effect and plasma concentration.
Cmax gives an indication that is drug is sufficiently
systemically absorbed to produce a therapeutic
response. Additionally it provides a warning of
possibly toxic levels of drug. The units are mcg/ml or
ng/ml

3. AUC: is a measurement of extent of drug bioavailability. It
reflects the total amount of active drug that reaches the
systemic circulation. The AUC is the area under plasma
level time curve from t=0 to t=α and is equal to the amount
of unchanged drug reaching the general circulation divided
by the clearance.
[AUC]=FD/ Clearance
clearance=KVd
F= fraction of dose absorbed
D= dose
K= elimination
Vd= volume of distribution.

 AUC can be determined by
1. Numerical integration procedure
2. The trapezoidal rule
3. Directly by the used of planimeter
4. Comparing the weight of the paper corresponding to the
area under experimental curve to the weight of the paper
of known area.
The units of AUC are mcg.hr/ml

2. Urinary data (urinary drug
excretion)
1. The cumulative amount of drug excreted in urine
(Du)
2. The rate of drug excreted in urine (d Du/dt)
3. The time for maximum urinary excretion (tα)

 Urinary drug excretion data can be useful (indirect
method) for estimating bioavailability.
 The drug must be excreted in significant quantities in
the un metabolized form for obtaining valid
parameters.
 Also urine samples must be collected timely and
sensitive methods be used for finding the amount of
drug in each sample.
1. Du: the cumulative amount of drug excreted in urine
is directly related to the total amount of drug
absorbed. Experimentally urine samples are collected
periodically after the administration of a drug
product. Each sample is analysed for free drug
(unchanged) using a specific assay.

 It can be seen that when the drug is completely
eliminated (point C), the plasma concentration
approaches zero and maximum amount of drug
excreted in the urine (Du) is obtained.

Acute pharmacodynamic effect:
 In some cases, quantitative measurement of a drug in
plasma or urine is not possible because of lack of assay
method with sufficient accuracy and/ or reproducibility.
 For locally acting, non systemically absorbed drug
products, such as topical corticosteroids, plasma drug
concentration may not reflect the bioavailability of the drug
at the site of action.
 An acute pharmacodynamic effects, such as effect on
forced expiratory volume, FEV (inhaled bronchodilators) or
skin blanching (topical corticosteroids) can be used as an
index of drug bioavailability.

Biotransformation:
 Biotransformation is the conversion of a drug to its
metabolites.
 These metabolites can be inactive, active having same
activity as their parent drug or having different activities.
 The metabolites are more excretable from the body
 Sites of biotransformation
 Brain; levodopa is converted into dopamine (active form)
(10 examples of brands)
 Cutaneous tissues; epidermis can carry out several
metabolic reaction including glucoronide conjugation.
vidarabir (an anti viral agent) has Cutaneous metabolism.
First pass drug metabolism in skin reduces the duration and
potency of locally applied drugs.

 Gastrointestinal tract: drugs can be conjugated by
various enzymes in intestinal epithelium and
consequently this presystemic metabolism cause an
incomplete bioavailability of drugs. Presystemic
metabolism of premarin in GIT is example.
 Lungs: lungs are perfused by entire blood supply. A
few drugs re prone to be metabolized in lungs.
 Kidneys: some drugs are converted to their
metabolites in kidney by the action of angiotensin
convertase enzyme.

First pass effect:
 The rapid metabolism of an orally administered drug
prior to reaching the systemic circulation is called the
first pass effect.
 Lack of the parent or intact drug in the systemic
circulation after oral administration is the evidence of
first pass effect.
 In such cases, AUC after oral administration will be
less than AUC after intravenous administration.
• F=[AUC]0-α oral/[AUC]0-α iv

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