Bioavailability

ILOS
❖ Understand the concept of bioavailability (BA)

and the purpose of BA study

❖ Difference between absolute and relative BA

❖ Method of assessment of bioavailability

 History
▪ The concept of bioavailability (physiological availability) was
introduced by Oser et al in1945.
▪ Bioavailability concept entered the political arena in the late 1960’s
as a result of increasing number of prescriptions being written
generically
 Definition
According to FDA

➢ The rate and extent to which the active ingredient or active moiety is
absorbed from a drug product and becomes available at the site of
action.
➢ For drug products that are not intended to be absorbed into the
blood stream, bioavailability may be assessed by measurements
intended to reflect the rate and extent to which the active ingredient
or the active moiety becomes available at the site of action.
how fast the drug enters the rate of
systemic circulation absorption

how much of the nominal extent of

strength enters the body absorption
 Drug substance
Drug substance is the active pharmaceutical ingredient (API) or component
in the drug product that furnishes the pharmacodynamic activity.

Drug product
The finished dosage form that contains the active ingredient,
generally but not necessarily, in association with inactive ingredients.
 Brand name
The trade name of the drug, which is privately owned by manufacturer or
distributor (mother company) and is used to distinguish the specific drug
product from the competitor’s products. (Branded generics are generic products sold
under a brand name also)

Generic name
The established, nonproprietary, or common name of the active drug
in the drug product (e.g. acetaminophen)

Chemical name
The name used by organic chemists to indicate the chemical structure of
the drug.
 Chemical
Name

Brand Generic
Name Name
New patented drug product
(by a brand or innovator) → is approved.
Manufacturer has provided detailed
evidences that the drug product is safe &
effective for a specific purpose.
After the period of patent exclusivity has ended →
generic drug products may be marketed on
condition that the product is supposed to be
effective for the same clinical indication as the
innovator product.
This is based on the fact that they contain the same
drug in the same dose and dosage form.
So, any manufacturer proposes to introduce a
product into the market (new generic drug product) →
must provide evidence that the drug product is
equivalent to an established innovator product
 Drug product

Single source Multisource

The patent has not yet The drug product that contains
expired or has certain the same A.P.I. in the same
exclusivities so that only dosage form and is marketed by
manufacturer can make it more than one manufacturer.

➢ Formulation & method of manufacture affect the rate & extent of drug travel from its dosage
form to its site of action (bioavailability) & also affect the stability of the drug product.
➢ The generic drug manufacturer must demonstrate that the generic drug product is bioequivalent
and therapeutically equivalent to the brand name drug product.
 Documentation
For
Approved drug products
❑ The FDA publishes annually Approved drug products with therapeutic equivalence
evaluations known as ➔ orange book.

❑ The orange book identifies DP approved on the basis of safety and effectiveness by
the FDA and contains therapeutic equivalence evaluations for approved multisource
prescription drug products.

U.S. Food and Drug Administration (.gov)

[Link] › drug-approvals-and-databases
 The approval process

➢ New Drug application NDA: After the end of clinical trials, sponsors submit their
data to the FDA to request approval of the new product in the US.
N.B….. In Egypt, NDA is submitted to Egyptian Drug Authority (EDA).

➢ Abbreviated New Drug Application ANDA: Drug manufacturers must file an ANDA
for approval of a generic drug product.

▪ Generic drug applications are termed "abbreviated" because they are generally
not required to include preclinical (animal) and clinical (human) data to establish
safety and effectiveness.
 The approval process “cont”

➢ Reference listed drug “RLD” is identified by the FDA as an approved drug product
to which new generic versions are compared to show that they are bioequivalent.

▪ A drug company seeking approval to market a generic equivalent must refer to the
Reference Listed Drug in its Abbreviated New Drug Application (ANDA).

➢ Drug product selection: The process of selecting the drug product in a

specified dosage form
 Important terms
Pharmaceutical Equivalents
DP in identical dosage forms that contain
• The same AI (the same salt or same ester)
• The same route of administration
• Identical in strength or in concentration.
These drug products may differ in characteristics such as
shape, scoring configuration, release mechanisms, packaging, excipients (flavors,
colors, preservatives), expiration time, labeling.

Pharmaceutical Alternatives
DP that contain the same therapeutic moiety but differ in dosage form, strength, salt
or ester of the active therapeutic moiety.
e.g. DP containing either tetracycline phosphate or tetracycline HCl equivalent to 250
mg of tetracycline base.
 Important terms “cont”
Bioequivalent drug products
Two or more pharmaceutical equivalent or pharmaceutical alternative products
produce similar rate and extent of absorption of the active ingredient (bioavailability)
when administered in equivalent dosage regimen

Therapeutic Equivalents
DP are considered therapeutic equivalents only if they are pharmaceutical equivalents
and if they can be expected to have similar rate and extent of absorption of the active
ingredient (bioavailability) when administered to patients.

Interchangeable Drug Products

Pharmaceutical equivalents or bioequivalents that are accepted as therapeutic
equivalents.
 Therefore

Pharmaceutical equivalence + bioequivalence

= therapeutic equivalence.

Pharmaceutical alternative + bioequivalence

≠ therapeutic equivalence.
 Fundamental Concepts

The availability of a drug or its active metabolite to the end-organ or receptor is

controlled by three principal factors namely:

a. The rate and extent of release of the drug from the drug product and its subsequent
absorption from the solution state ( tested in case of absolute & relative BA).

b. The so-called "first pass effect” ( tested in case of absolute BA).

c. The combined processes of plasma protein binding, tissue binding, drug distribution to
various body fluids, metabolism and urinary, fecal and/or lung excretion.
Relative & Absolute Bioavailability

Area Under The Curve (AUC)

why

AUC is derived from drug concentration and time so it gives a

measure how much and how long a drug stays in a body.
 AUC It is used as a measure of the total amount of unaltered
drug that reaches the systemic circulation.

𝐹𝐷𝑜 • [Link] ➔total quantity of available drug

[𝐴𝑈𝐶] =
𝐾 𝑉𝐷 • F ➔ fraction of the dose absorbed
• K ➔ elimination rate constant
Constants
• Vd ➔ apparent volume of distribution

❖After IV administration F =1 ➔ completely available.

After oral administration F

0 (no drug absorption) 1 (complete drug absorption)

 Relative Bioavailability

❖ Relative or apparent bioavailability is the availability of a drug product as

compared to a recognized standard (std)
❖ It can be obtained as follows:
Relative bioavailability = [AUC]A A= test & B is the recognized
[Link]
[AUC]B
❖ When different doses are administered a correction of the size of the dose
is made as follows:

[AUC]A /dose A
Relative bioavailability =
[AUC]B /dose B
 Relative Bioavailability

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

❖ Percent Relative availability using urinary data can be determined as follows:

[𝐷u ]∞
A
% Relative bioavailability = ∞ × 100
[𝐷u ]B
[Du]∞is the total amount of drug excreted in urine
 Absolute Bioavailability
F
❖ The absolute bioavailability of a drug in a drug product may be measured by
comparing the respective AUC’s after oral and IV administration.
❖ This measurement may be performed as long as Vd and K are constant &
independent of the route of administration.
[AUC]PO /dose PO
Absolute availability = F =
[AUC]IV /dose IV

Absolute availability F may be expressed as a

N.B • fraction
• percent by multiplying by 100
 𝐹𝐷 𝑜 𝐹𝐷 𝑜
[𝐴𝑈𝐶]∞ = [𝐴𝑈𝐶]∞
𝑜 =
𝑜
𝐶𝑙 𝑇 𝐾𝑉𝑑

This measurement may be performed as long as Vd and K are

independent of the route of administration.
 Absolute Bioavailability
F

❖ Absolute availability from urine data can be determined as follows:

∞
[𝐷u ]PO /dosePO
Absolute availability = F = ∞
[𝐷u ]IV /doseIV
 F
The fraction of the dose which is bioavailable.

For drugs given I.V., F = 1

For all extra-vascular routes F ≤ 1.

 Problem

Four different drug products containing the same antibiotic were given to 12 adult male
volunteers (av. wt = 78 Kg) in a four-way crossover design. The volunteers were fasted
for 12 hours prior to taking the drug product. Urine samples were collected up to 72
hours after the administration of the drug to obtain the maximum urinary drug
excretion, Du∞ . The data is presented in the following table.
1. What is the absolute bioavailability of the drug from the tablet?
2. What is the relative bioavailability of the capsule to the oral solution?
Drug product Dose Du∞ [𝐷u ]∞
PO /dosePO 340/4 = 0.85
Absolute availability = =
mg/Kg [𝐷u ]∞
IV /doseIV 20/0.2
IV solution 0.2 20 [𝐷u ]∞
A
% Relative bioavailability = ∞ × 100 = 0.947 𝑜𝑟 94.7%
Oral solution 4 380 [𝐷u ]B
Oral tablet 4 340
Oral capsule 4 360
 Methods Of Assessing Bioavailability

❖ There are several direct and indirect methods of assessing bioavailability in humans

❖ The selection of a method depends on

1. The purpose of the study

2. The analytical method of drug measurement

3. The nature of the drug product

 Methods Of Assessing Bioavailability “cont”

❖ The parameters that are useful in determining the bioavailability of a drug product
include 1. Plasma Data: (tmax), (Cp max), (AUC)

2. Urine data (Du∞), (dDu/dt), (t∞)

3. Acute pharmacologic effect
4. Clinical Observation
5. In-vitro study (drug dissolution)

❖ Since the free or therapeutically active drug can be accurately quantitated in

biological fluids, therefore, plasma & urine data ➔ most objective information on
bioavailability.
 Plasma data
a. Tmax ➔ time of peak plasma concentration.

ln(k a / k ) 2.3 log(ka / k )

t max = tmax =
ka − k ka − k

▪ Tmax corresponds to the time required to reach

maximum drug absorption.

▪ Tmax reflects differences in absorption rates, the

faster the drug is absorbed the lower will be t max

Typical plasma level-Time curve for a drug
given in a single oral dose ▪ The units of t max are units of time eg. hours or

minutes.
 Plasma data “cont”

b. Cmax➔ the peak plasma conc.

▪ It represents the maximum plasma drug conc. obtained

after oral administration of drug.

▪ Cmax provides an indication that the drug is sufficiently

systemically absorbed → therapeutic response.

▪ Cmax also provides warning of possibly toxic levels of

Typical plasma level-time curve for a drug drug.

given in a single oral dose
▪ Units are conc. units (eg, mg/ml or ng/ml).
 Plasma data “cont”

c. AUC ➔ The area under the plasma level time curve

𝐹𝐷 𝑜 𝐹𝐷 𝑜
[𝐴𝑈𝐶]∞
𝑜 = [𝐴𝑈𝐶]∞
𝑜 =
𝐶𝑙 𝑇 𝐾𝑉𝑑
▪ It is a measurement of the extent of drug
bioavailability.

▪ It reflects the total amount of active drug which

reaches the systemic circulation.

Typical plasma level-time curve for a drug ▪ It is determined by a numerical integration procedure
given in a single oral dose
such as the trapezoidal rule method.

▪ The units of AUC are conc. time (eg, ug hr/ml).

 Applied example I

A, B & C are diff. formulations for the same DP. They are given to volunteers & then
Construct a plasma conc.-time curve.

1. AUCA= AUCB ➔same extent of drug absorption

2. T max A< t max B ➔ A faster rate than B

3. AUC C= 0.5 AUCA ➔ C gives half the extent of A

4. T max A =t max C ➔A & C have the same rate of drug

absorption
 Applied example II

A A B A

Plasma conc.
Plasma conc.
B
Plasma conc.

Time Time Time

A faster in absorption rate A faster in absorption rate A &B same absorption rate
B less in extent A &B same in extent (AUC) B less in extent (AUC)