Bioequivalent studies for conventional and controlled drug delivery sy

Bioequivalent studies for conventional and controlled drug delivery system : 

Bioequivalent studies for conventional and controlled drug delivery system Jitendra T Lalwani M.Pharm Pharmaceutics

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WHAT IS IT??? HOW IS IT??? WHY IS IT???

Definitions : 

Definitions Bioavailability The extent and rate at which its active moiety is delivered from pharmaceutical form and becomes available in the systemic circulation Bioequivalence (BE) Two formulations of a drug are said to be bioequivalent if the rate and extent to which the drug reaches the systemic action after administration of their respective formulations are statistically comparable. two products may be said to be bioequivalent if 90% confidence interval for C max , T max , mean  AUC (0-t) is within ± 20% of that of the reference product.

Definitions : 

Definitions The margin may be reduced to ± 10% for drugs with a very low therapeutic index, such as anti-arrhythmic, antiepileptic and anticoagulant drugs.

Definitions : 

Definitions Pharmaceutical  equivalents Pharmaceutical equivalents" mean drug products that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same drug, in identical dosage forms, but do not necessarily contain the same ingredients, and that meet the identical compendial or other applicable standard of identity, strength, quality and purity, including potency and where applicable, content uniformity, disintegration time and/or dissolution rates.

Definitions : 

Definitions Pharmaceutical alternatives Pharmaceutical alternatives mean drug products that contain identical therapeutic moiety, its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality and purity, including potency and where applicable, content uniformity, disintegration times and/or dissolution rates.

Definitions : 

Definitions Therapeutic equivalents A medicinal product is therapeutically equivalent with another product if it contains the same active substance or therapeutic moiety and, when administered to the same individual, shows the same efficacy and toxicity as that product, whose efficacy and safety has been established.

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Why do we need Bioequivalence studies? No clinical studies have been performed in patients with the Generic Product to support its Efficacy and Safety. With data to support similar in vivo performance (= Bioequivalence) Efficacy and Safety data can be extrapolated from the Innovator Product to the Generic Product.

Approaches to Determining BE : 

Approaches to Determining BE In vivo measurement of active moiety in biologic fluid In vivo pharmacodynamic comparison (Topical Corticosteroid) In vivo clinical comparison (Nasal suspensions) In vitro comparison (Nasal Solution, Topical solution, Oral solution)

Goals of BE: 

Goals of BE Ultimate: Bioequivalence studies impact of changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the efficacy is based Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product. Important for linking the commercial drug product to clinical trial material at time of NDA Important for post-approval changes in the marketed drug formulation

Bioequivalence study protocol : 

Bioequivalence study protocol Persons responsible Objective of the study Ethical considerations Drug information Product information Study design For conventional dosage form Single – dose, randomize, two period, two treatment, complete crossover Latin square design to be used for comparing three formulations Balanced incomplete block (BIB) design in case of more three than formulations

Bioequivalence study protocol : 

Bioequivalence study protocol Study design For controlled release dosage form: Fasting study: here bioequivalent studies are evaluated by a single dose , two period, two treatment ,two sequence ,open label randomized cross over design comparing equal dose of the test and reference product in fasted adult, healthy subjects. It required for all immediate release and modified release dosage forms . Food intervention study: This study is single dose, randomized , three treatment, three period, six sequence, crossover, limited food effect study, comparing equal dose of test product given under fasting condition with those of the test and reference products given immediately after a standard, high fat content break fast.

Bioequivalence study protocol : 

Bioequivalence study protocol Multiple dose (steady state) study: A multiple dose steady state randomized two treatment two way cross over study comparing equal dose of test and reference product in adult, healthy subject in required for oral controlled released drug products in additional to single dose fating study & food intervention study.

Bioequivalent study protocol : 

Bioequivalent study protocol Healthy volunteers Number of volunteers Inclusion criteria Exclusion criteria Conduct of the study Blood sampling Analytical method Evaluation parameters C max , T max , AUC , T 1/2 Statistical analysis

Latin square cross over design : 

Latin square cross over design Each formulation is administered just once to each subject and once in a each study period Unlike the parallel design, all subjects do not receives the same formulation at the same time; in a given study period , they are administered different formulations. Advantages: It minimize the inter subject variability in a plasma drug level Minimize the carry over effects Minimize the variegation due to time effects and thus, Make it possible to focus on more on the formulation variables which is the key to success for any bioequivalence study.

Latin square cross over design : 

Latin square cross over design Subject No. Drug formulation Study period 1 Study period 2 Study period 3 1 X Y Z 2 Y Z X 3 Z X Y 4 X Z Y 5 Y Y X 6 Z X Z Table: Latin square cross over design for 6 subject tot compare three different formulations X, Y, and

Latin square cross over design : 

Latin square cross over design Drawback: study takes a long time when no of formulations to be tasted are more, the study becomes more difficult and subject dropout rats are also high.

Statistical analysis : 

Statistical analysis Analysis of variance (ANOVA) method is applied to determined statistical difference The relative bioavailability of test formulation is in the range 80-120 % of reference standard, it is considered bioequivalent

Waiver of evidence of In vivo bioavailability : 

Waiver of evidence of In vivo bioavailability Drug product is a solution intended for only IV administration The drug product is a topical preparation. The product is an oral liquid in the form of solution e.g. elixir and which contain an active ingredient in the same concentration as approved drug product and contain no active ingredient which significantly affect the absorption of active ingredient. The product is gas for inhalation Product for local use and are intended to produce desire effect without systemic absorption

Thank you and Questions??: 

Thank you and Questions??