BIOAVAILABILITY AND BIOEQUIVALENCE INFORMATION
Bioavailability is defined as the rate and extent (amount) of absorption of unchanged drug from its dosage form. That means rate and extent at which the drug or metabolite enters into the systemic circulation. Bioavailability is the fraction of administered drug that reaches to the systemic circulation in a chemically unchanged form.
For example: 100 mg of drug is administered orally in that 60 mg of the drug is absorbed in unchanged form, the bioavailability is Sixty percent (60%) or 0.6.
The bioavailability of a drug from it’s dosage form depends on three major factors:
- Pharmaceutical factors related to physicochemical properties of the drug and dosage form characteristics
- Patient related factors.
- Route of administration
The amount of drug that reaches the systemic circulation is called as Systemic availability
Objectives of bioavailability studies:
* Primary stages of development of a suitable dosage form foe a new drug entity to obtain evidence of its therapeutic utility.
* 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 drug.
* Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors storage and stability on drug absorption.
*Compassion of availability of a drug substance from different dosage forms of form the same dosage form produced by different manufactures.
Bioavailable fraction ( F ):
Bioavailable fraction refers to the fraction of administered dose that enters in the systemic circulation. Formula for bioavailable fraction is-
F= Bioavailable dose / Administered dose
Bioavailable dose means dose available to the patient. It is less than the administered dose.
The influence of route of administration on drug’s bioavailability is generally in the following order
Parenteral route > Oral route > Rectal route > Topical route
SUBJECT SELECTION CRITERIA IN BIOAVAILABILITY STUDIES:
- Healthy adult volunteers..
- Age 18-45 years.
- Choice of gender based on usage and safety criteria.
- Studies should be conducted individuals representative of the general population, taking into account age, sex, race.
- Weight within the normal limit-> BMI
- Women pregnancy test prior to 1st and last dose of study.
- If drugs products is to be used predominantly in elders, then test should include as many subjects of 60 years of age or older as possible.
- Pregnant women or those taking contraceptive pills should not be include in the test.
- Drug hazardous for one group of users choice of subjects may be narrowed down, examle: teratogenic drugs should be conducted only on males.
- Drugs primarily intended for use in only males or only females volunteers of only respective gender should be include in the studies.
- For drugs where risk of toxicity or side effects is significant, studies may be carried out in patients, but whose disease state is stable.
- Sample size is estimated by:
> published data
*Significance level desired, usually 80% or more.
Expect deviation from the reference product as compatible with the Bioequivalence (BE)
*Minimum no. Should not be less than 12
*If no data available, reference ratio of 0.95 used.
THE VARIOUS STUDY DESIGN METHODS FOR PERFORMING BIOAVALIBILITY:
ABSOLUTE BIOAVAILABILITY: when the systemic availability of a drug administered orally is determined in comparison to its intravenous administration is called as absolute bioavailability denoted by the symbol Fab.
Fab= (AUC) drug / (AUC) i.v.
RELATIVE BIOAVAILABILITY: When the systemic availability of a formulation (A) of a certain drug is compared with another formulation (B) of the same drug is called as relative bioavailability. Usually an established standard.
Frel = (AUC) drug / (AUC) standard
SINGLE DOSE STUDY: The dose to be administered for a bioavailability study is determined from clinical experiment. It is very common study, steady state characteristics is difficult to predict with one dose.
MULTIPLE DOSE STUDY: It is easy to study the peak and vally characteristics, they are more accurate, the drug blood levels are high so very less sensitive methods can be used. Can be ethically performed in patients as it has therapeutic benefits.
*PATIENT RELATED FACTORS: Healthy human volunteers vs Patients.
Ideally the bioavailability study should be carried out in patients for whom the drug is intended to be used because patient will benefit from study.
METHODS TO DETERMINE BIOAVAILABILITY:
- Plasma level time study.
- Urinary excretion study
- Acute Pharmacologic response.
- Therapeutic response.
Bioequivalence is a relative term in which drug substances two or more identical dosage forms reaches the systemic circulation at the same relative rate & same relative extent, their plasma concentration – time profiles also identical without significant statistical differences. Bioequivalence concept in which equivalency between the drugs are established.
When do we do Bioequivalence (BE) Studies?
- For Generic formulation
- Change of formulation ( tablet to capsule )
- Establishment of Pharmacokinetic parameters
- Study of formulation & process variables
- Clinical service form to final market form
- Regulatory requirements
- Change of process or manufacturing site (some times)
VARIOUS TYPES OF BIOEQUIVALANCE:
CHEMICAL EQUIVALANCE: It indicates that two or more drug products contain the same or more drug products the same labelled chemical substance as an active ingredient in the same amount.
PHARMACEUTICALLY EQUIVALENT: This term implies that two or more drug products are identical in strength, quality, purity, content, uniformity, disintegration and dissolution characteristics they may however differ in containing different excipients.
BIOLOGICAL EQUIVALANCE: It is a relative term which denotes that the drug substance in 2 or more identical dosage form reaches the systemic circulation at the same relative rate and to the same relative extent; i.e. their plasma concentration time profile will be identical without significant difference.
THERAPEUTIC EQUIVALANCE: Two or more drugs products that contain the same therapeutically active ingredient and bring out the same pharmacological effects and can control the disease to the same extent and the drug may not be chemically equivalent.
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