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Bioequivalence Studies Anoop Agarwal. Basic Assumptions Drug effect depends upon drug concentration at the site of action Drug concentration at the site.

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Presentation on theme: "Bioequivalence Studies Anoop Agarwal. Basic Assumptions Drug effect depends upon drug concentration at the site of action Drug concentration at the site."— Presentation transcript:

1 Bioequivalence Studies Anoop Agarwal

2 Basic Assumptions Drug effect depends upon drug concentration at the site of action Drug 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

3 BioEquivalence Two formulations which produce similar blood levels are said to be bioequivalent Bioequivalent products can be substituted for each other Switch from one to another would not affect the therapy of the patient.

4 BIOAVAILABILITY The 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 action 21 CFR 320.1

5 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

6 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

7 PHARMACEUTICAL EQUIVALENTS Pharmaceutical 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.

8 BIOEQUIVALENCE The 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

9 PHARMACEUTICAL EQUIVALENCE DOES NOT IMPLY BIOEQUIVALENCE Differences in the excipients and/ or manufacturing process can lead to faster or slower dissolution and absorption

10 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

11 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

12 THERAPEUTIC EQUIVALENCE Are in compliance with compendial standards for strength, quality, purity and identity Are adequately labelled Are manufactured as per GMP

13 BIOEQUIVALENCE In practice, demonstration of bioequivalence is generally the most appropriate method of substantiating therapeutic equivalence between medicinal products which are pharmaceutical equivalents

14 WHY BA/ BE STUDIES ARE DONE? Comparison of different dosage forms Changes in formulation Changes in manufacturing Generic Drug Approval (ANDA) ‏

15 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”

16 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

17 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

18 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

19 This new guidance requires the sponsors to provide evidence of individual bioequivalence for approval of generic drugs. For New Drugs, BE needs to be done when scale up of operations is undertaken for marketing.

20 HOW TO ASSESS? Plasma Drug Concentration The time for peak plasma concentration (t max ) ‏ The peak plasma drug concentration (C max ) ‏ The area under the plasma drug concentration versus time curve (AUC) ‏ Urinary Drug Excretion The cumulative amount of drug excreted in the urine (D u ) ‏ The rate of drug excretion in the urine (dD u /dt) ‏ The time for maximum urinary excretion (t) ‏

21 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

22 BIOEQUIVALENCE For 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

23 WAIVER Under 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

24 BE A MUST!!!! Drugs with Narrow Therapeutic Index NTI.ppt NTI.ppt Drugs with critical dose critical dose drug.ppt critical dose drug.ppt Poorly Soluble Drugs Slowly Soluble Drugs Drugs Administered as high dose Poorly absorbed Drugs Drugs Unstable in GIT

25 EXAMPLES Levothyroxine, Insulin Inherent Levels Fexofenadine, Momentasone Pharmakodyamic Celiprolol.HCl Non linear kinetics Salbutamol, Paracetamol Rapid absorption Bisoprolol, AmlodipineLong half life Warfarin, TheophyllineNarrow range EXAMPLESCATEGORY

26 BE A MUST!!!! Small changes in BE may lead to significant changes in efficacy or safety of the product


28 GENERAL DESIGN Two phases CLINICAL PHASEANALYTICAL PHASE Screening for selection Drug Administration Blood/urine sample collection Centrifugation Method Validation Sample Analysis Statistical Analysis



31 GENERAL DESIGN Single Dose multiple dose study.ppt multiple dose study.ppt Crossover CROSSOVER DESIGN.ppt CROSSOVER DESIGN.ppt Normal and healthy volunteers Minimum 12 (ideally 24) ‏ Fasting state at least 10 hours before administration and 2 – 4 hours after administration

32 GENERAL DESIGN No 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

33 CLINICAL PHASE Volunteer Admission Physical Examination Icard (bed number) and assignment of randomization code Gowning Area/wash room Entry to CPU0 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


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