7 Ba Be

B I O AVA I L I B I L I TA S
Ika Mustikaningtias, M.Sc., Apt.

L a b Fa rm a ko l o g i & Fa r masi Klinik
J u r u s a n Fa rm a s i FIKes
Universitas Jenderal Soedirman
BIOAVAILIBILITAS???
Bioavailability means 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.
Bioequivalent drug products may contain different inactive

ingredients, provided the manufacturer identifies the
differences and provides information that the differences do
not affect the safety or efficacy of the product
2
BIOAVAILIBILITY STUDIES
Bioavailability studies are performed for both approved active drug

ingredients and therapeutic moieties not yet approved for
marketing by the FDA.
New formulations of active drug ingredients must be approved by
the FDA before marketing.
In approving a drug product for marketing, the FDA ensures that
the drug product is safe and effective for its labeled indications for
use.
To ensure that these standards are met, the FDA requires
bioavailability/pharmacokinetic studies and, where necessary,
bioequivalence studies for all drug products (FDA Guidance for
Industry, 2003).
Bioavailability may be considered as one aspect of drug product
quality that links in-vivo performance of the drug product used in
clinical trials to studies demonstrating evidence of safety and
efficacy.
3
BIOAVAILIBILITY vs bioequivalence STUDIES
Bioavailibility Bioequivalence
to define the effect of to compare the bioavailability
changes in the of the same drug (same salt
physicochemical properties of or ester) from various drug
the drug substance and the products
effect of the drug product
(dosage form) on the
pharmacokinetics of the drug
4
Bioavailibility Parameter
AUC
To measure of the
total amount of
unaltered drug that
reaches the systemic
circulation
C0
AUC =
𝑘
5
Bioavailibility Parameter
• F is the fraction of the dose absorbed.

• After IV administration, F is equal to unity, because the
entire dose enters the systemic circulation. Therefore, the
drug is considered to be completely available after IV
administration.
• After oral administration of a drug, F may vary from a
value of 0 (no drug absorption) to 1 (complete drug
absorption)
6
RELATIVE AVAILABILITY
The relative availability of two drug products given at the same

dosage level and by the same route of administration can be
obtained using the following equation :
This fraction may be multiplied by 100 to give percent relative

availability.
7
RELATIVE AVAILABILITY
When different doses are administered, a correction for the size

of the dose is made, as in the following equation:
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. The percent relative
availability using urinary excretion data can be determined as
follows:
8
ABSOLUTE AVAILABILITY
The absolute availability of drug is the systemic availability of a

drug after extravascular administration (eg, oral, rectal,
transdermal, subcutaneous) compared to IV dosing
The absolute availability of a drug is generally measured by
comparing the respective AUCs after extravascular and IV
administration
Absolute availability after oral drug administration using plasma
data can be determined as follows:
Absolute availability after oral drug administration using urinary

drug excretion data can be determined by the following:
9
QUIZ TIME
Practice Problem
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.
From these data, calculate:

(a) the relative bioavailability of the drug from the tablet compared
to the oral solution and
(b) the absolute bioavailability of the drug from the tablet. 11
Add Image Drug product Dose (mg) AUC
Oral tablet 200 89.5
Oral solution 200 86.1
IV bolus 50 37.8
injection
12
bioequivalence
Differences in the predicted clinical response or an adverse event may
be due to differences in the pharmacokinetic and/or pharmacodynamic
behavior of the drug among individuals or to differences in the
bioavailability of the drug from the drug product.
Bioequivalent drug products that have the same systemic drug
bioavailability will have the same predictable drug response. However,
variable clinical responses among individuals that are unrelated to
bioavailability may be due to differences in the pharmacodynamics of
the drug.
Differences in pharmacodynamics, ie, the relationship between the drug
and the receptor site, may be due to differences in receptor sensitivity
to the drug. Various factors affecting pharmacodynamic drug behavior
may include age, drug tolerance, drug interactions, and unknown
pathophysiologic factors.
13
Design and Evaluation of Bioequivalence
Studies
Bioequivalence studies are performed to compare the bioavailability

of the generic drug product to the brand-name product. Statistical
techniques should be of sufficient sensitivity to detect differences in
rate and extent of absorption that are not attributable to subject
variability. Once bioequivalence is established, it is likely that both
the generic and brand-name dosage forms will produce the same
therapeutic effect.
14
Design
Fasting study
Food – intervention study
Multiple-dose study
15
Fasting study
Bioequivalence studies are usually evaluated by a single-dose, two-period,
two-treatment, two-sequence, open-label, randomized crossover design
comparing equal doses of the test and reference products in fasted, adult,
healthy subjects.
This study is required for all immediate-release and modified-release oral

dosage forms.
Both male and female subjects may be used in the study. Blood sampling is
performed just before (zero time) the dose and at appropriate intervals after
the dose to obtain an adequate description of the plasma drug concentration–
time profile. The subjects should be in the fasting state (overnight fast of at
least 10 hours) before drug administration and should continue to fast for up
to 4 hours after dosing. No other medication is normally given to the subject
for at least 1 week prior to the study.
16
Food intervention study
The study design uses a single-dose, randomized, two-
treatment, two-period, crossover study comparing equal
doses of the test and reference products.
Following an overnight fast of at least 10 hours, subjects are
given the recommended meal 30 minutes before dosing. The
meal is consumed over 30 minutes, with administration of the
drug product immediately after the meal.
The drug product is given with 240 mL (8 fluid ounces) of
water. No food is allowed for at least 4 hours postdose.
This study is required for all modified-release dosage forms
and may be required for immediate-release dosage forms if
the bioavailability of the active drug ingredient is known to be
affected by food (eg, ibuprofen, naproxen).
17
Crossover design
Drug Product
Subject Study Study Study
period 1 period 2 period 3
1 A B C
2 B C A
3 C A B
4 A B C
5 B C A
6 C A B
18
CROSSOVER DESIGN
PERIOD 1 PERIOD 2
Sequence T R
1
Sequence R T
2
19
Replicated crossover design
PERIOD PERIOD Period Period

1 2 3 4
Sequenc T R T R
e1
Sequenc R T R T
e2
20
Evaluation data
AUC 0-t
AUC 0-
T max
C max
k
T½
Multiple dose  plus % fluctuation = 100 x (Cmax –
Cmin)/Cmin
21
ANOVA
Between T and R  no significant difference for

all parameters
p ⩽ 0,05
CI 95%
22
Clinical Signifi cance of Bioequivalence
Studies
Bioequivalence of different formulations of the same drug substance involves

equivalence with respect to rate and extent of systemic drug absorption.
Clinical interpretation is important in evaluating the results of a bioequivalence
study. A small difference between drug products, even if statistically
significant, may produce very little difference in therapeutic response.
Generally,two formulations whose rate and extent of absorption
differ by 20% or less are considered bioequivalent. The considered
that differences of less than 20% in AUC and C max between drug products are
"unlikely to be clinically significant in patients." The Task Force further stated
that "clinical studies of effectiveness have difficulty detecting differences in
doses of even 50–100%." Therefore, normal variation is observed in medical
practice and plasma drug levels may vary among individuals greater than
20%.
23
Clinical Signifi cance of Bioequivalence
Studies
According to , a small, statistically significant difference in drug

bioavailability from two or more dosage forms may be detected if the
study is well controlled and the number of subjects is sufficiently large.
When the therapeutic objectives of the drug are considered, an
equivalent clinical response should be obtained from the comparison
dosage forms if the plasma drug concentrations remain above the
minimum effective concentration (MEC) for an appropriate interval and
do not reach the minimum toxic concentration (MTC).
Therefore, the investigator must consider whether any statistical
difference in bioavailability would alter clinical efficiency.
24
Notes : Bioequivalence Studies
Special populations, such as the elderly or patients on drug

therapy, are generally not used for bioequivalence studies.
Normal, healthy volunteers are preferred for bioequivalence
studies, because these subjects are less at risk and may more
easily endure the discomforts of the study, such as blood
sampling.
Furthermore, the objective of these studies is to evaluate the
bioavailability of the drug from the dosage form, and use of
healthy subjects should minimize both inter- and intrasubject
variability.
25
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B I O AVA I L I B I L I TA S

Ika Mustikaningtias, M.Sc., Apt.

Bioavailability means the rate and extent to which the

Bioequivalent drug products may contain different inactive

Bioavailability studies are performed for both approved active drug

• F is the fraction of the dose absorbed.

The relative availability of two drug products given at the same

This fraction may be multiplied by 100 to give percent relative

When different doses are administered, a correction for the size

Urinary drug excretion data may also be used to measure

The absolute availability of drug is the systemic availability of a

Absolute availability after oral drug administration using urinary

The bioavailability of a new investigational drug was studied in 12

From these data, calculate:

Bioequivalence studies are performed to compare the bioavailability

Food – intervention study

This study is required for all immediate-release and modified-release oral

PERIOD PERIOD Period Period

Between T and R  no significant difference for

Bioequivalence of different formulations of the same drug substance involves

According to , a small, statistically significant difference in drug

Special populations, such as the elderly or patients on drug

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