Bioavailability Studies

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-: Presented By :--: Presented By :-Amruta S. Amruta S. SambarekarSambarekar11stst Year M.Pharm Year M.PharmDept. of Dept. of PharmaceuticsPharmaceuticsM M C P, M M C P, BELGAUMBELGAUM

BIOAVAILABILITYBIOAVAILABILITY

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CONTENTSCONTENTS

Concept of Bioavailability

Objectives of Bioavailability Studies

Considerations in Bioavailability Studies

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INTRODUCTIONINTRODUCTION

Bioavailability is defined as a measure, of the rate and amount of drug, which reaches the systemic circulation unchanged following the administration of a dosage form.

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In other words, it is the fraction of administered dose that actually reaches the systemic circulation in contrast to that stated on the label.

Bioavailability is usually determined by comparing the rate and extent of absorption of drug from the formulation under evaluation, to the data of a reference standard.

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If the reference standard is an IV dose, it is referred as Absolute Bioavailability. If the reference standard is any other dosage form than IV it is referred as Relative Bioavailability.

Reference standard can be IM injection, oral solution or a fine suspension.

Bioavailability usually ranges from 0 to 1.

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An absolute bioavailability of 1 (or 100% ) indicates complete absorption.

Relative bioavailability of 1 (or 100%) implies that bioavailability of drug from both the dosage form is the same but does not indicate the completeness of absorption.

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Bioavailability of drug from Bioavailability of drug from dosage form depends upon dosage form depends upon following,following,

- Properties of the drug - Important physiological factors - Characteristics of the dosage form

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Bioavailability StudiesBioavailability Studies

Two types are there, The first type involves an assessment of the bioavailability of a new drug formulation.

The second type study involves a comparison of a test formulation with that of a reference standard dosage form that is proved to have a therapeutic safety and efficacy.

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ObjectivesObjectives

Primary stage of development for suitable dosage form for a new drug entity.

Determination of influence of excipients, patient related factors and possible interaction with other drugs on the efficiency of absorption.

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For a approved drugs to develop a new dosage form or to improve an existing dosage form.

To find out the influence of physicochemical properties of drug and dosage form on biological performance of the drug.

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Useful in determining the safety and efficacy of the drug product.

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Considerations in Considerations in Bioavailability StudiesBioavailability Studies

Selection Of Subjects

Study Design

Washout Period

Single Vs Multiple- Dose Study Design

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Study Conditions

Pharmacological Effects of Metabolite

Assay Method

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Selection Of SubjectsSelection Of Subjects

A number of factors such as health, age, weight, enzyme status and number are concern.

It is better to have the subjects of similar kinetics to avoid major variations.

Health :Health : Subjects should be of great health that is ascertained by various biochemical and medical examination.

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Age : Age : Elderly and children have different

kinetics to adults. Subjects between 18 – 35 years are preferred.

Number :Number :Number of participants should be kept minimum required for carrying out a reliable, well designed study.

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Weight :Weight :

The apparent volume of distribution is usually proportional to weight in subjects of normal weight and height.

However, in overweight and

underweight Vd may be different. Hence, to better match the subject , normal weights are preferred. Usually 140-200lb

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Enzyme Status :Enzyme Status :

Enzyme activity can be altered by altered kinetics of the drug in case of smokers or subjects taking other drugs leading to drug-drug interaction.

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Usually, a complete cross over study design is used. With this design each subject receives all products with a washout period between each dose administration.

This is a Latin square crossover design where each subject receives each drug product only once . Here each subject act as his own control and subject to subject variation is reduced.

Study DesignStudy Design

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Washout Period :Washout Period :

The time interval between two treatments is called “washout period”.

It is required for the elimination of the administered dose of a drug so as to avoid a carryover effect

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Usually, a period of 10 half-lives should be allowed between two treatments ensuring elimination of 99.9% of the administered dose.

The number of washout period depends upon the type of crossover study design used and number of formulations to be evaluated.

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In case of Digitoxin,

Half –life : 6 to 9 days Study design :Latin square crossover

design for four formulations.Duration : 1 year

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Single- Dose Studies Recommended Single- Dose Studies Recommended ForFor

Dosage forms that are to be evaluated only for bioequivalence purpose.

Dosage forms meant for a single dose administration for a therapeutic benefit such as analgesic for relief of headache.

Single Vs. Multiple- Dose Study Single Vs. Multiple- Dose Study DesignDesign

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Multiple Dose Studies Multiple Dose Studies Recommended ForRecommended For

Dosage forms designed to achieve special release profiles. e.g. time-release products, enteric-coated preparations.

Drugs undergoing first pass metabolism.

Special dosage regimens such as Loading dose.

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Study conditionsStudy conditions

Subject should be maintained on a uniform diet and none of them should have taken any drug at least one week prior to the study.

Before the commencement of study it is necessary to define the study condition such as fasting period before the administration, time period after drug product administration, during which fasting is continued.

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In general studies are carried out on subjects fasted overnight.

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Pharmacological Effects of Pharmacological Effects of MetabolitesMetabolites

Bioavailability measurement is based on the unchanged drug.

Drugs having biologically active metabolites, their concentration in systemic circulation can influence greatly the therapeutic efficacy of the drug.

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It was found especially significant for drugs which exhibits first pass metabolism during pre-absorptive phase.

Phenacetin has more side effects than, its metabolite acteaminophen, which is also pharmacologically active form.

In case of aspirin its metabolite salicylic acid is pharmacologically inactive and exhibits serious toxicity.

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Based on above findings, it is good practice in bioavailability studies to examine the presence of major metabolites in blood and urine, to determine their concentration and, if possible, pharmacological activity of each.

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Assay Assay methodmethod

The analytical method used to quantitate the levels of drug and/or its metabolites must be selective e.g., for the unchanged drug in presence of its metabolites.

It must be sensitive enough to measure the expected low drug levels in the samples collected last.

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““Text Book Of Biopharmaceutics & Text Book Of Biopharmaceutics & PharmacokineticsPharmacokinetics”,”, Dr. Shobha Rani R. Hiremath. Pg no. 31-35.

““Biopharmaceutics & Pharmacokinetics”Biopharmaceutics & Pharmacokinetics” Venkatesh Pg no. 331, 336-338.

““Biopharmaceutics & pharmacokinetics”,Biopharmaceutics & pharmacokinetics”, D.M.Brahmankar, S.B.Jaiswal, Pg.no. 283.

REFERENCEREFERENCE

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