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BIOAVAILABILITY

PRESENTED BYSUBODH S SATHEESH

MPHARM PHARMACEUTICS

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Introduction

Essential to ensure uniformity in standards of quality, efficacy & safety of Pharmaceutical products

Reasonable assurance is to be provided that various products containing same active ingredient, marketed by different licensees are clinically equivalent & interchangeable

Release of an active substance should be known & reproducible

Both Bioavailability & Bioequivalence focus on release of substance from its dosage form & subsequent absorption in circulation

Similar approaches to measure Bioavailability should be followed in demonstrating Bioequivalence

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Bioavailability

Measurement of the relative amount & rate at which,

the drug from administered dosage form,reaches the systemic circulation & becomes available at the site of action

Bioavailable fraction (F), refers to the fraction of administered dose that enters the systemic circulation

F = Bioavailable dose

Administered dose

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Absolute Bioavailability

Compares the bioavailability of the active drug in systemic circulation following non-intravenous administration with

the same drug following intravenous administration

For drugs administered intravenously, bioavailability is 100%

Determination of the best administration route

Fab = (AUC)drug

(AUC)IV

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Absolute Bioavailability of Nimodipine for different routes:Oral : 1.17 % Nasal : 67.4 %Intravenous: 100%

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Relative Bioavailability

Compares the bioavailability of a formulation (A) of a certain drug when compared with another formulation (B) of the same drug, usually an established standard

F rel = ( AUC) drug

(AUC) standard

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Plasma concentration versus time curve

Formulation A

Formulation B

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Factors affecting bioavailability

Liquids > Solids Important for sparingly soluble drugs ↓ the size, ↑ the absorption Ionization:Unionized form penetrates the GI mucosal lining quickly pH of the fluid:Weakly acidic drugs: Aspirin, Barbiturates→ Stomach, duodenum Weakly basic drugs: Pethidine, Ephedrine→ Small intestine Strongly acidic / basic drugs: highly ionized & poorly absorbed Prolonged gastric emptying: Delays absorption due to stasis Disease states: Malabsorption, Achlorhydria, Cirrhosis, Biliary

obstruction can hamper absorption Interactions with other drugs foods etc Whether the formulation is administered in fasted or fed state Presence of other agents

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Single dose and multiple dose studies

Easier method but many disadvantages Tedious method Cannot effectively describe the steady state character

of drugs Most of the disadvantages can be overcome by

multiple dose methods

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Multiple dose studies

Clinical uses of drugs are accurately reflected Requires collection of few blood sample Better evaluation of performance of C-R

formulations Nonlinearity of p.kinetics can be easily detected Easy to predict peak and valley characters of drug

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Limitations

More difficult and costly to conduct Requires more time to complete Poor complaince by patients

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Measurement of bioavailability

Pharmacokinetic methods Plasma level time studies Urinary excretion data Pharmacodynamic methods Acute pharmacologic response Therapeutic response

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Plasma level time studies

Collection of blood samples Construction of plot Sample points to be assessed Cmax Tmax AUC

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Extent of bioavailability

F= (AUC)oral Div/(AUC)iv Doral

Fr = (AUC)test Dstd / (AUC)std Dtest

Fr = (AUC)test Dstd τtest/ (AUC)std Dtestτtest

Fr = (Cssmax) Dstd τtest/(Cssmax)std Dtest τstd

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Urinary excretion data

Method Direct measurement of bioavailability, both absolute

and relative. When coupled with plasma level-time data, it can

also be used to estimate renal clearance of unchanged drug

If Vd is known, total systemic clearance and nonrenal clearance can also be calculated.

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Disadvantages

One cannot however compute Vd and Clt from urine data alone.

One must also remember that urinary excretion data is not an accurate substitute for the plasma level data

the data can be employed as a rough estimate of the pharmacokinetic parameters.

if the drug has very long biological half-life, the resulting low urinary drug concentration may be too dilute to be assessed with accuracy

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Criteria for obtaining valid UE data

A significant amount of drug must be excreted unchanged in the urine (at least 10%).

Before administration of drug, the bladder must be emptied completely. Volunteers must be instructed to completely empty their bladder while

collecting urine samples. Frequent sampling should be done in order in order to obtain a good

curve. During sampling, the exact time and volume of urine excreted should

be noted. Urine samples must be collected for at least 7 biological half-lives in

order to ensure collection of more than 99% of excreted drug. Changes in urine pH and urine volume may alter the urinary excretion

rate

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Parameters obtained

(dXu/dt)max (tu)max Xu∞

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Extent of bioavailability

Absolute bioavailability  F = [ Xu]∞ oral x [Dose] iv/[Xu ]∞ i.v x [Dose] oral Relative bioavailability: Fr = [ Xu]∞ test x [Dose] std [Xu]∞ std x [Dose]

test With multiple dose study to steady state, the eq for

computing bioavailability is: Fr = [ Xu,ss]∞ test x [Dose] std [Xu,ss]∞ std x

[Dose] test

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Pharmacodynamic methods

Acute pharmacologic response Therapeutic response

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BIOAVAILABILITY STUDY

PROTOCOL

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Steps involved

Study objective Experimental design Washout period Drug product Route of administration Dosage regimen Frequency and duration of sampling Analysis of biological fluids

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Experimental designs

Parallel group design Latin square design Cross over design Balance incomplete block design

Parallel-Group Design

Even number of subjects in two groups

Each receive a different formulation

No washout necessary

For drugs with long half life

Treatment A Treatment B1 2

3 4

5 6

7 8

9 10

11 12

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2 formulations, even number of subjects, randomly divided into 2 equal groups

First period , each member of one group receive a single dose of the test formulation; each member of the other group receive the standard formulation

After a wash period (5 half lives), in second period , each member of the respective groups will receive an alternative formulation & experiment will be repeated.

Subjects

Period 1

Period 2

1-8 T S

9-16 S T

Parallel group design

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Latin Square Design

More than two formulations

A group of volunteers will receive formulations in the sequence shown

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Balance Incomplete Block Design (BIBD)

More than 3 formulations, Latin square design will not be ethically advisable

Because each volunteer may require drawing of too many blood samples

If each volunteer expected to receive at least two formulation, then such a study can be carried out using BIBD

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Washout period

Time interval between treatments Removal of administered dose Ensures more than 99% of washout Depends on the experimental design

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Other steps

Drug product Reference standard Route of administration Administration of drug products

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sampling

For at least three elimination half-lives (cover >80% of AUC)

• Absorption phase : 3-4 points

• Around Tmax : 3-4 points

• During elimination : 4 points

Intervals not longer than the half-life of the drug

If urine tested, collect it for at least 7 half-lives

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Selection of subjects

Healthy adult volunteers

Age: 18-45 yrs

Age/Sex representation corresponding to therapeutic & safety profile

Weight within normal limits→ BMI

Women: Pregnancy test prior to 1st & last dose of study; OC pills C/I

Drug use intended in Elders (Age >60yrs)

Teratogenic Drugs→ Male volunteers

Highly toxic drugs: Patients with concerned disease (stable) eg. Cancer

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Study conditions

Maintenance of uniform diet Washout Bioavailability trails has to be done

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Analysis of biological samples

Collection by Sampling procedure Selective methods It should be specific and highly sensitive Non specific analytical methods should be

avoided

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REFERENCES

Bioavailability and bioequivalence by S Kunal page 1-43

Biopharmaceutics and pharmacokinetics a treatise by DM Brahmankar 315-333

Biopharmaceutics and pharmacokinetics my Leon Shargel

Bioavailability and bioequivalence by Dr Mothilal

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