bioequivalence studies anoop agarwal. basic assumptions drug effect depends upon drug concentration...
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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)