Lectures 11 Bioavailability

Bio availability Its clinical significance &

Factors affecting bioavailability

Dr. Ghulam SaqulainM.B.B.S., D.L.O., F.C.P.SHead of Department of ENTCapital Hospital, Islamabad

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”.

2

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.

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.

Bioavailability differs with different routes

I/V 100% Sublingual 100% Oral/Inhalation 5 - <100% I/M, S/C 75- <100% Transdermal 80- <100% RectaL 30- < 100%

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.

6

The dose available to patient for therapeutic Effect

Bioavailable dose

Objectives of bioavailability studiesIt 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.

8

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).

9

Considerations in bioavailability studies

Bioavailability – absolute / relative

Single dose / multiple dose

Human volunteer – healthy subject / patients

10

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.

11

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

Plas

ma

conc

entr

atio

n

Time (hours)

i.v. route

oral route

12

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

13

Concentration due to repeated doses

Time to reach steady state

Concentration due to a single dose

14

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.

15

Single dose vs. multiple dose

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.

16

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.

17

3. Drug absorption pattern in disease state can be evaluated.

4. Avoids the ethical quandary of administering drug to healthy subjects.

18

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.

19

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.

20

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.

21

Measurement of bioavailability

Pharmacokinetic methods ( indirect ) 1. Blood analysis 2. Urinary excretion data

Pharmacodynamic methods ( direct ) 1. Acute pharmacological response 2. Therapeutic response

22

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.

23

Blood Analysis:

24

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.

25

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.

26

“Bioequivalence” used to compare generic drugs to

patented

Bioequivalence

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

28

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.

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.

30

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

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

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

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

Physicochemical Properties of the Drug

Water & lipid solubility

Molecular size

Stability in GI environment (pH)

Specificity for carrier proteins and enzymes

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