Bioequivalence Studies

Anoop Agarwal

Basic AssumptionsDrug effect depends upon drug

concentration at the site of actionDrug concentration at the site is

determined by rate and extent of absorption, and rate and extent of disposition

Formulations which produce similar blood levels will have similar pharmacological effects

BioEquivalenceTwo formulations which produce similar

blood levels are said to be bioequivalentBioequivalent products can be substituted

for each otherSwitch from one to another would not

affect the therapy of the patient.

BIOAVAILABILITYThe rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action21 CFR 320.1

• ABSOLUTE BIOAVAILABILITY Comparison of the bioavailability of a

particular dosage form with that following intravenous administration (100%)

e.g. oral solution vs IV

• RELATIVE BIOAVAILABILITY Availability of a drug product as

compared to another dosage form or product of same drug given in the same dose.

Determine effect of formulation differences on drug absorption

e.g. Tablets vs oral solutions

DATA OBTAINED FROM A BIOAVAILABILITY

STUDY IS USED TO DETERMINE :

The amount of drug absorbed from a dosage form.

The rate of absorption of the drug.

The duration of the drug’s presence in the body fluids.

The relationship between blood levels and therapeutic

effectiveness or toxic effects of the drug.

A direct measurement of the concentration of the drug at the

receptor site.

BIOAVAILABILITY

PHARMACEUTICAL EQUIVALENTSPharmaceutical Equivalents mean drug products that contain identical amounts of the same active drug ingredient (the same salt or ester of the same drug), in same dosage forms, but do not necessarily contain the same excipients, and that meet the same compendial or other applicable standard of identity, strength, quality and purity, including potency and where applicable, content uniformity, disintegration time and/or dissolution rate and generally be labeled for the same indications.

BIOEQUIVALENCEThe absence of a significant difference in

the rate at and extent to which the active ingredients in the pharmaceutical equivalence become available at the site of drug action in the body when administered under similar experimental conditions in an appropriately designed study

• Differences in the excipients and/ or

• manufacturing process

can lead to faster or slower dissolution and

absorption

Equivalence

If the active ingredient has been shown to

be

• SAFE and EFFECTIVE, after it is absorbed

into the blood stream

• Achieves same concentration of active

ingredients at the same rate from two

different formulations

It will produce the similar therapeutic effect

THERAPEUTIC EQUIVALENCE

FDA considers two products to be

‘Therapeutic Equivalents’ if they

Have same and established

potential for safety and efficacy

Are pharmaceutical equivalents

Are Bioequivalent

THERAPEUTIC EQUIVALENCE

Are in compliance with compendial

standards for strength, quality, purity

and identity

Are adequately labelled

Are manufactured as per GMP

BIOEQUIVALENCE

In practice, demonstration of

bioequivalence is generally the most

appropriate method of substantiating

therapeutic equivalence between

medicinal products which are

pharmaceutical equivalents

WHY BA/ BE STUDIES ARE DONE?

Comparison of different dosage

forms

Changes in formulation

Changes in manufacturing

Generic Drug Approval (ANDA)

GENERIC DRUG PRODUCT A generic product is a product

manufactured by firms other than the

innovator

More appropriately generic product is

“interchangeable multi-source

pharmaceutical product”

WHY BA / BE?Several therapeutic misadventures in

the past related to differences in

bioavailability (digoxin, phenytoin)

Need for testing performance of the

dosage form in delivering active

substance to the site of action

Concept of known and reproducible

bioavailability

• Became effective on July 1, 1977 21 CFR (Code of Federal Regulations) Part 320

• In 1984, the FDA was authorized to approve generic drug products (ANDA) under the Drug Price Competition and Patent Term Restoration Act

GUIDELINES AND REGULATIONS

• In June, 1992, the first book on statistical design and analysis of bioavailability and bioequivalence

• October 1997, the U.S. FDA circulated a draft guidance entitled “In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Approaches” for comments

HOW TO ASSESS?Plasma Drug Concentration

The time for peak plasma concentration (tmax)The peak plasma drug concentration (Cmax)The area under the plasma drug

concentration versus time curve (AUC)

Urinary Drug ExcretionThe cumulative amount of drug excreted in

the urine (Du)The rate of drug excretion in the urine

(dDu/dt)The time for maximum urinary excretion (t)

Measuring drug concentration in urine is applicable for those drugs that are not extensively metabolized prior to urine elimination.

As a rule of thumb only such drugs where 20% of the dose is excreted unchanged in urine after an IV dose

BIOEQUIVALENCEFor most oral tablets or capsule

dosage forms, BE is demonstrated

in vivo by comparing the rate and

extent of absorption of generic

product with those of the innovator

product

WAIVERUnder certain circumstances, the BA/BE

requirement is waived as in case of

• Injectables

• Ophthalmic solutions

• Antacids

• Topical applications

as in such cases dissolution concerns are not

relevant

BE A MUST!!!! Drugs with Narrow Therapeutic

Index NTI.ppt

Drugs with critical dose critical dose drug.ppt

Poorly Soluble Drugs

Slowly Soluble Drugs

Drugs Administered as high dose

Poorly absorbed Drugs

Drugs Unstable in GIT

EXAMPLES

Levothyroxine, InsulinInherent Levels

Fexofenadine, MomentasonePharmakodyamic

Celiprolol.HClNon linear kinetics

Salbutamol, ParacetamolRapid absorption

Bisoprolol, AmlodipineLong half life

Warfarin, TheophyllineNarrow range

EXAMPLESCATEGORY

BE A MUST!!!!Small changes in BE may lead to significant

changes in efficacy or safety of the product

GENERAL DESIGNTwo phases

CLINICAL PHASE ANALYTICAL PHASE

• Screening for selection

• Drug Administration

• Blood/urine sample collection

• Centrifugation

• Method Validation

• Sample Analysis

• Statistical Analysis

STUDY CONDUCTSTUDY DESIGN

INVESTIGATOR SELECTION

REGULATORY/EC APPROVAL

STUDY CONDUCTMETHOD VALIDATION

CLINICAL PHASE

ANALYTICAL PHASE

OBTAINING REF DRUG

STATISTICAL PHASE

GENERAL DESIGNSingle Dose multiple dose study.ppt

Crossover CROSSOVER DESIGN.ppt

Normal and healthy volunteersMinimum 12 (ideally 24)Fasting state at least 10 hours before

administration and 2 – 4 hours after administration

GENERAL DESIGNNo medicine one week prior to or no

medicine except the study drug during the study

Blood sample/ or urine sample collection at different timepoints over a period of time

Measurement of the concentration of drug present in the samples

CLINICAL PHASE

Volunteer Admission

Physical Examination

Icard (bed number) and assignment of randomization code

Gowning Area/wash room

Entry to CPU 0 hr sampling

Drug Administration

Hand and mouth check

Food (at specified time)

Sampling at specified intervals

monitoring of vital signs, ADR, activities

Last sampling

Discharge

Follow-up

Screening

BIOLOGICAL SAMPLE SAMPLING AREA

CENTRIFUGATION

STORAGE AREA

TRANSPORTATION

ANALYTICAL AREA

ANALYSIS (BENCH TOP)