Lectures 11 Bioavailability

Workshop on Pharmacology of hearing and speech sciences

1. Bio availability
Its clinical significance &
Factors affecting bioavailability
Dr. Ghulam Saqulain
M.B.B.S., D.L.O., F.C.P.S
Head of Department of ENT
Capital Hospital, Islamabad

2. Bio availability
“Bioavailability is a measurement
of the extent of a therapeutically active medicine that reaches
the systemic circulation and is therefore available at the site
of action”.
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3. The therapeutic effectiveness of a drug depends
upon the ability of the dosage form to deliver the
medication to its site of action at a rate & amount
sufficient to elicit the desired Pharmacological
response.
This attribute of the dosage form is referred to as
physiologic availability or bioavailability.

4. Bioavailability example:-
A hypothetical drug given orally has a
bioavailability of 50%
(or 0.5), this is due to:
1.incomplete absorption in the GI tract so that
only 70% of the initial dose is absorbed.
2. subsequent metabolism of a further 20% before
it reaches the systemic circulation (e.g. first pass
through the liver).
Therefore only 50% of the original oral dose
reaches the systemic circulation.

5. Bioavailability differs
with different routes
I/V 100%
Sublingual 100%
Oral/Inhalation5 - <100%
I/M, S/C 75- <100%
Transdermal 80-<100%
RectaL 30- < 100%

6. The influence of route of administration on drug’s
bioavailability is generally in the following order:

parenteral > oral > rectal > topical
Most drugs are administered orally, for reason of stability and
convenience.
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7. The dose available to patient
for therapeutic Effect
Bioavailable dose

8. Objectives of bioavailability studies
It is important in:
1.Primary stages of development of a suitable
dosage form
2.Determination of influence of excipients, patient
related factors and interaction with other drugs on
the efficiency of absorption.
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9. 3.Development of new formulations of the existing
drugs.
4.Control of quality of a drug product during early
stages of marketing (to determine the influence of
processing factors, storage & stability of
absorption).
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10. Considerations in bioavailability studies
Bioavailability – absolute / relative
Single dose / multiple dose
Human volunteer – healthy subject / patients
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11. Absolute vs. Relative
Absolute bioavailability : when the systemic
availability of the drug administered orally is
determined in comparison to its i.v. administration.
Relative bioavailability : when the systemic
availability of the drug administered orally is
compared with that of an oral standard of the same
drug.
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12. Plasma concentration vs. time profile of a drug ingested
orally & intravenously.
0
10
20
30
40
50
60
70
0 2 4 6 8 10
P
l
a
s
m
a

c
o
n
c
e
n
t
r
a
t
i
o
n
Time (hours)
i.v. route
oral route
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13. Single dose vs. multiple dose
Single dose
Very common & easy
Less exposure to drug &
less tedious
Difficult to predict
steady state
Multiple dose
Difficult to control
More exposure to drug
& tedious
Time consuming
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14. Concentration due to
repeated doses
Time to reach steady state
Concentration due to a single
dose
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15. Multiple dose study has several advantages like:
1.More accurately reflects the manner in which the drug
should be used.
2.Drugs levels are higher due to cumulative effect which
makes its determination possible even by less sensitive
analytical methods.
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Single dose vs. multiple dose

16. 3.Better evaluation of the performance of controlled
release formulation is possible.
4.Small intersubject variability is observed which
allows use of fewer subjects.
5.Nonlinearity in pharmacokinetics, if present, can be
easily detected.
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17. Human volunteer – healthy subject vs. patients
Ideally, the bioavailability study should be carried
out in patients for whom the drug is intended to be
used.
Advantages :
1.Patient is benefited from the study.
2.Reflects better therapeutic efficacy of drug.
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18. 3.Drug absorption pattern in disease state can be
evaluated.
4.Avoids the ethical quandary of administering drug
to healthy subjects.
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19. There are some drawbacks of using patients as
volunteers.
Stringent conditions such as fasting state required is
difficult to be followed by the patients.
Studies are therefore performed in young (20-40
yrs.), healthy males adult volunteers.
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20. Female volunteers are used only when drugs such as
oral contraceptives are to be tested.
They must be informed about the importance of:
Study
conditions to be followed
Possible hazards if any.
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21. Medical examination should be performed.
Drug washout period for min. of ten biological half
lives must be allowed for between two studies in
same subject.
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22. Measurement of bioavailability
Pharmacokinetic methods ( indirect )
1. Blood analysis
2. Urinary excretion data
Pharmacodynamic methods ( direct )
1. Acute pharmacological response
2. Therapeutic response
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23. Plasma level time studies or The plasma concentration – time
curve or blood level curve.
A direct relationship exists b/w concentration of drug at the
site of action & concentration of drug in the plasma.
Serial blood samples are taken after drug administration &
analyzed for drug concentration.
A typical blood level curve obtained after oral administration of
drug.
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Blood Analysis:

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25. Acute pharmacological response
Bioavailability can be determined from the acute
pharmacologic effect – time curve
DISADVANTAGE is that pharmacological response tends to more
variable & accurate correlation between the measured response &
drug available from the formulation is difficult.

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26. Therapeutic response
This method is based on the observing the clinical response to a
drug formulation given to a patients suffering from disease for
which it is intended to be used.
Ex …for anti inflammatory drugs, the reduction in the inflammation
is determined.
The major DRAWBACK is …quantification of observed response
is too improper to allow for reasonable assessment of relative
bioavailability between two dosage forms of a same drug.
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27. “Bioequivalence” used to
compare generic drugs to
patented
Bioequivalence

28. Clinical importance of bioequivalence studies
Bioequivalence of different formulations of the same drug
substance involves equivalence with respect to the rate and
extent of systemic absorption.
Generally two formulations whose rate and extent of
absorption differ by 20% or less are considered bioequivalent
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29. When a therapeutic objectives of the drug are considered, an
equivalent clinical response should be obtained from the
comparison dosage form if the plasma drug concentration
remain above MEC for appropriate interval and don’t reach
the MTC.

30. Bioequivalence studies should be conducted for the
comparison of two medicinal products containing the same
active substance.
Two products marketed by different licensees, containing
same active ingredient(s), must be shown to be
therapeutically equivalent to one another in order to be
considered interchangeable.
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31. Clinical Significance
Change in Bioavailability may lead to under/ over
medication
Under Medication – Therapeutic failure
Hazardous specially for drugs like Antimicrobials, anticonvulsants
and oral antidiabetic agents
Over medication – Toxicity

32. Indiscriminate change of preparation from other
companies must be avoided. (change of drug brand
may lead to Non-bioequivalence)
Use of Alternate routes:
Drugs with high hepatic first pass metabolism should be
given by routes other than oral. ie., sublingual,
transdermal eg., Nitroglycerine

33. High oral doses: Some drugs have high hepatic
extraction ratio.
Less dose in hepatic Disease: In severe hepatic
cirrhosis/ portal systemic shunts, the dose of the
drugs with large extraction ration and hepatic first
pass effect should be reduced otherwise toxicity

34. Physiologic factors
1.pH Stomach ~ 1 and intestine ~ 6
2.Surface area of the of the intestine – microvilli
3.Presence of carrier proteins for absorption
4.Enzymes: endogenous and bacterial
5.GI blood flow
6.Gastric Emptying & intestinal transit

Factors Affecting Bioavailability

35. Physicochemical Properties of the Drug
Water & lipid solubility
Molecular size
Stability in GI environment (pH)
Specificity for carrier proteins and enzymes

36. Food & Drug
Food can affect both rate and extent of absorption.
Effect depends on the drug
and the nature of the meal.
Food can increase / decrease or have no effect on either rate or
extent
FOOD Affects pH, Blood flow, Gastric emptying & Interactions with
enzymes
DRUGS Affect Blood flow, Gastric emptying & Interactions with
enzymes