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Bioavailability and
Bioequivalence

01/05/2024
Session Objectives
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⚫ @ the end of this session you will be able to:

 Define terms related with therapeutic and

pharmaceutical substitution.
Describe and compute relative and absolute
bioavailabilities
Identify methods for the assessment of bioavailability

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 Definition
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s
⚫ Bioavailability: is the rate and extent to which the active
ingredient is absorbed from a drug product and becomes
available at the site of action.

⚫ Bioequivalent drug products: pharmaceutical equivalent or

pharmaceutical alternative products that display comparable
bioavailability when studied under similar experimental
conditions.

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 Definitions…
⚫ Brand name:The trade name of the drug, is privately owned by the
manufacturer or distributor and is used to distinguish the specific drug
product from competitor's products (eg, Tylenol, McNeil Laboratories).
), Advil (manufactured by Pfizer), and Lipitor (manufactured by P

⚫ Chemical name: The name used by organic chemists to indicate the

chemical structure of the drug (eg, N-acetyl-p-aminophenol).

⚫ Generic name:The established, nonproprietary, or common name of

the active drug in a drug product (eg,acetaminophen).

⚫ Equivalence: Relationship in terms of BA, therapeutic response, or a set

of established standards of one drug product to another.
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 Generic substitution: The process of dispensing a different brand or
an unbranded drug product in place of the prescribed drug product.
 The substituted drug product contains the same active ingredient or
therapeutic moiety as the same salt or ester in the same dosage form
but is made by a different manufacturer.
E.g., a prescription for Motrin brand of ibuprofen might be
dispensed by the pharmacist as Advil brand or as a non branded
generic ibuprofen
 Pharmaceutical alternatives: Drug products that contain the same
therapeutic moiety but as different salts, esters, or complexes.

 E.g., tetracycline phosphate or tetracycline HCl

equivalent to 250 mg tetracycline base are considered
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 Different dosage forms and strengths within a product
line by a single manufacturer are pharmaceutical
alternatives.
 E.g., an extended-release dosage form and a standard
immediate-release dosage form of the same active ingredient.

 The FDA currently considers a tablet and capsule containing the

same active ingredient in the same dosage strength as pharmaceutical
alternatives.

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Pharmaceutical equivalents: Drug products in identical dosage
forms that contain the same:
 Active ingredient(s)
 Salt or ester
 Dosage form
 Route of administration
 Strength
 But they may differ in:
Characteristics such as shape, release mechanisms,
packaging
 Excipients (including colors, flavors, preservatives)
 Expiration time
 Labeling (to some extent)
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⚫ Pharmaceutical substitution: The process of dispensing a
pharmaceutical alternative for the prescribed drug product.
 Ampicillin suspension  ampicillin capsules
 Tetracycline hydrochloride  tetracycline phosphate
 Requires the physician's approval.

Therapeutic alternatives: Drug products containing different

active ingredients that are indicated for the same therapeutic or
clinical objectives.

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Active ingredients in therapeutic alternatives are from the same
pharmacologic class and are expected to have the same therapeutic
effect when administered to patients for such condition of use.

 Ibuprofen  aspirin;
 Cimetidine  ranitidine.
⚫ Therapeutic equivalents: Drug products are considered to be
therapeutic equivalents only if they are the same clinical effect and
safety profile.

Therapeutic substitution: The process of dispensing a

therapeutic alternative in place of the prescribed drug
product.

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 Amoxicillin  ampicillin 01/05/2024
 Relative and Absolute
bioavailability
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⚫ Relative bioavailability
Relative (apparent) bioavailability is the availability of the drug from a
drug product as compared to a recognized standard.

The relative bioavailability of two drug products given at the same

dosage level and by the same route of administration can be obtained
using the following equation:

Where drug product B is the recognized reference

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standard.
⚫ When different doses are administered, a correction for the size of
the dose is made, as in the following equation:

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⚫ Urinary drug excretion data may also be used to
measure relative bioavailability, as long as the total amount
of intact drug excreted in the urine is collected.

Where [Du]∞ is the total amount of drug excreted in the

urine
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⚫ Absolute bioavailability
The absolute bioavailability of drug is the systemic bioavailability of a
drug after extravascular administration (eg, oral, rectal, transdermal,
subcutaneous) compared to IV dosing.

Absolute availability after oral drug administration using plasma

data can be determined as follows

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⚫ Absolute availability using urinary drug excretion data can
be determined by the following:

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Example:
⚫ The bioavailability of a new investigational drug was studied in 12
volunteers.
 Each volunteer received either a single oral tablet containing 200

mg of the drug,
 5 mL of a pure aqueous solution containing 200 mg of the drug, or

a single IV bolus injection containing 50 mg of the drug.

 Plasma samples were obtained periodically up to 48 hours after

the dose and assayed for drug concentration.

 The average AUC values (0–48 hours) are given in the table
below. 01/05/2024
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Drug Product Dose (mg) AUC (mg hr/mL) Standard Deviation

Oral tablet 200 89.5 19.7

Oral solution 200 86.1 18.1
IV bolus 50 37.8 5.7
injection

From these data, calculate

1.The relative bioavailability of the drug from the oral solution
compared to the tablet and

2. The absolute bioavailability of the drug from the tablet.

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⚫ Relative availability = [AUC]A/[AUC]B
= 86.1/89.5
= 0.962
= 96.2%
⚫ Absolute availability
=
(AUC] Tab / DoseTab)/ ([AUC]IV/DoseIV
)
= (89.5/200)/(37/ 50)
= 0.4475/0.756
 Because F, the fraction of dose absorbed from the tablet, is less than 1,
= 0.592
the drug is not completely absorbed systemically, as a result of either
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poor 59.2% or metabolism by first-pass effect.01/05/2024
 Objectives of Bioavailability
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studies
 BA studies are important in the:-

 Primary stages of development of a suitable DF for a new drug

entity
 Determination of influence of excipients, patient related factors

and possible interaction with other drugs on the efficiency of

absorption
 Development of new formulations of the existing drugs

 Control of quality of a drug product during the early stages of

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 Methods of Assessing
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Bioavailability
 Different methods are used to assess drug bioavailability
 Plasma drug concentration data

 Time for peak plasma concentration (tmax)

 Peak plasma drug concentration (Cmax)

 Area under plasma drug concentration–time curve (AUC)

 Urinary drug excretion data

 Cumulative amount of drug excreted in urine(Du∞)

 Rate of drug excretion in urine (dDu/ dt)

 Time for maximum urinary excretion (t ∞)

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Plasma concentration-time curves
 When a single dose of a drug is administered orally to a patient, serial
blood samples are withdrawn and the plasma assayed for drug
concentration at specific periods of time after administration, a plasma
concentration-time curve can be constructed.

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 ⚫ Absorption Phase

At zero time  the concentration of drug in the plasma will be

zero

As the tablet passes into the stomach and/or intestine

it disintegrates, the drug dissolves and absorption
occurs.

Initially the concentration of drug in the plasma rises, as the rate

of absorption exceeds the rate at which the drug is
being removed by distribution and elimination
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  Peak Concentration

This represents the highest conc. of the drug achieved in

the plasma.

 Itis reached when the rate of appearance of drug in the

plasma is equal to its rate of removal by distribution
and elimination.
 Elimination phase:

 Eventually drug absorption ceases when the bioavailable dose has been
absorbed, and the concentration of drug in the plasma is now controlled
only by its rate of elimination by metabolism and/or excretion.
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 Minimum effective (or therapeutic) plasma
concentration: The concentration of drug in the plasma below
which no therapeutic effects of the drug occur

 Maximum safe concentration:The concentration of drug in

the plasma above which side-effects or toxic effects occur

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  Therapeutic range or window: A range of plasma drug
concentrations in which the desired response is obtained yet
toxic effects are avoided

 Onset: The time required to achieve the minimum effective

plasma concentration following administration of the dosage
form.

 Duration: is the period during which the concentration of

drug in the plasma exceeds the minimum effective plasma
concentration.
 Time of peak concentration: This is the period of time
required to achieve the peak plasma concentration of drug
after the administration of a single dose.
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 The Use of Plasma Concentration-Time Curves in
Bioavailability Studies
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 Let us see the administration of single equal doses of three

different formulations, A, B and C, of the same drug to the same
healthy individual by the same route of administration on three
separate occasions can be considered

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  The differences between the three curves are attributed solely to
differences in the rate and/or extent of absorption of the drug
from each formulation.
 The AUCs for formulation A and B are similar
The drug is absorbed to a similar extent from these two
formulations.
 Formulation A shows a fast onset of therapeutic action, but as its
peak plasma concentration exceeds the maximum safe
concentration
toxic side-effects.

 Formulation B, which gives a slower rate of absorption than A, shows a

slower therapeutic onset than A, but its peak plasma concentration lies
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within the therapeutic range
 Formulation C gives a much smaller area under the plasma
concentration-time curve, indicating that a lower proportion of the
dose has been absorbed.

 Results in the peak plasma concentration not reaching

the minimum effective concentration
Does not produce a therapeutic effect and consequently
is clinically ineffective as a single dose.

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Cumulative Urinary Drug Excretion
Curves
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 Measurements involving metabolite levels in the urine are

only valid when the drug in question is not subject to
metabolism prior to reaching the systemic circulation.

 The assessment of BA by urinary excretion is based on the

assumption that the appearance of the drug and/or its metabolites
in the urine is a function of the rate and extent of absorption.

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  The important parameters in urinary excretion studies are the
cumulative amount of intact drug and/or metabolites excreted,
and the rate at which this excretion takes place.

 A cumulative urinary excretion curve is obtained by collecting urine

samples (resulting from total emptying of the bladder) at known
intervals after a single dose of the drug has been administered.

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  The initial segments (X-Y) of the curves reflect the 'absorption phase'
(i.e. where absorption is the dominant process)

 The total amount of intact drug (and/or its metabolite) excreted

in the urine at point Z corresponds to the time at which the
plasma concentration of intact drug is zero and essentially all the
drug has been eliminated from the body.

 The total amount of drug excreted at point Z may be quite

different from the total amount of drug administered (i.e. the dose),
either because of:
 Incomplete absorption or
 The drug being eliminated by processes other than urinary
excretion.
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 The Use of Urinary Drug Excretion Curves in Bioavailability
Studies
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⚫ Following the administration of single equal doses of three different

formulations, A, B and C, of the same drug to the same healthy
individual by the same extravascular route on three different occasions

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⚫ The rate of appearance of drug in the urine from formulation A is
faster than from B, the total amount of drug eventually excreted from
these two formulations is the same.
 The cumulative urinary excretion curves for formulations A and B
eventually meet and merge

⚫ The cumulative urinary excretion curve suggests that both the rate and
extent of drug absorption are reduced in the case of formulation C

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34 THE BIOPHARMACEUTICAL
CLASSIFICATION SCHEME
 A biopharmaceutical classification scheme classifies drugs into four
classes according to:

 Solubility across the GI pH range and

 Permeability across the GI mucosa

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  According to the BCS, drug substances are classified into
 Class I – High Permeability, High Solubility
 Class II - High Permeability, Low Solubility
 Class III – Low Permeability, High Solubility
 Class IV – Low Permeability, Low Solubility

I II

III IV
Lo
w

High Lo
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Solubility 01/05/2024
  A drug is considered to be highly soluble where the highest dose
strength is soluble in 250 mL or less of aqueous media over the pH
range 1-8.

 The volume is derived from the minimum volume anticipated in the

stomach when a dosage form is taken in the fasted state with a glass of
 water.
If the volume of aqueous media taken to dissolve the drug in pH
conditions ranging from 1 to 8 is greater than 250 mL then the drug is
considered to have low solubility.

 A drug is considered to be highly permeable when the extent of

absorption in humans is expected to be greater than 90% of the
administered dose.
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37
Class I drugs
 These drugs will dissolve rapidly when presented in immediate-
release dosage forms, and are also rapidly transported across the
gut wall.

 unless they form insoluble complexes, are unstable in gastric fluids or

undergo presystemic clearance

 Examples: the b-blockers propranolol and metoprolol.

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Class II drugs
 For drugs in class II the dissolution rate is liable to be the
rate- limiting step in oral absorption.

 This class of drug should be amenable to formulation

approaches to improve the dissolution rate and hence oral
bioavailability.

 Examples: ketoprofen and carbamazepine.

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Class III drugs
 These drugs are those that dissolve rapidly but which are
poorly permeable;
 Examples: ranitidine and atenolol.

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 Class IV drugs
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 Are poorly soluble and poorly permeable.

 These drugs are liable to have poor oral bioavailability, or the oral

absorption may be so low that they cannot be given by the oral

route.

 Examples: hydrochlorothiazide and frusemide

 To improve systemic absorption: Forming prodrugs finding

an alternative route of delivery

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