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BA_BE_Studies.pptx

The document discusses bioavailability and bioequivalence studies, defining bioavailability as the extent to which a drug reaches its action site and outlining types like absolute and relative bioavailability. It highlights the importance of bioequivalence studies in comparing drug products, ensuring they have identical plasma concentration profiles, and addresses in vivo and in vitro methodologies for demonstrating bioequivalence. Additionally, it covers study designs, objectives, statistical considerations, and the significance of accurate analytical methods in evaluating drug efficacy and safety.

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BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES
BIOAVAILABILITY  Bioavailability is a term used to indicate the FRACTIONAL EXTENT to which a dose of drug reaches to its site of action or a biological fluid , from which the drug has the access to its site of action. Or  It is defined as an RATE AND EXTENT of absorption of unchanged drugs from its dosage form. BIOAVAILABILITY FRACTION : BIOAVAILABLE DOSE F = ----------------------------------- ADMINISTERED DOSE
CONSIDERATIONS IN IN-VIVO BIOAVAILABILITY DESIGN :  There are 2 types of Bioavailability : 1) ABSOLUTE BIOAVAILABILITY 2) RELATIVE BIOAVAILABILITY
ABSOLUTE BIOAVAILABILITY  When the systemic availability of the drug after oral administration is compared to its IV ADMINISTRATION is called as Absolute Bioavailability.  Absolute Bioavailability after oral drug administration using plasma data can be determined as following :
 It is used to characterize a DRUG INHERENT absorption properties from the extravascular site. EXAMPLE : Absolute Bioavailability of NIMODIPINE for different route of administration ORAL - 1.17% NASAL - 67.4% IV - 100% An Absolute Bioavailability of 1 or 100% indicates complete absorption by comparing reference standard as an IV dose.
 F may be expressed as fraction ( or ) as percentage multiplying F*100 absolute availability using urinary excretion data can be determined. Du : Total amount of drug excreted in urine (Du)oral dose oral F = ---------------------------- (Du) iv dose iv
RELATIVE BIOAVAILABILITY  When the systemic availability of the drug after oral administration is compared with that of ORAL STANDARD OF SAME DRUG ( such as aqueous or non-aqueous solutions , suspensions ) is referred as Relative Bioavailability.  It is used to characterize absorption of drug from its formulation. ( AUC ) A Fr = --------------- ( AUC ) B
EXAMPLE :  Comparison between CAPSULE AMOXICILLIN and SUSPENSION AMOXICILLIN. When different doses are administered a correction for the size of dose is made as the following equation : ‘ (AUC) A / dose A RELATIVE AVAILABILITY = -------------------------- (AUC) B /dose B
 The total amount of drug excreted in the urine is collected as the percentage availability using urinary excretion data can be determined as follows : Relative bioavailability 1 or 100% indicates that bioavailability of drug from both dosage forms is same but does not indicates complete absorption. % RELATIVE AVAILABILITY = { (Du)A / (Du)B}
BIOEQUIVALENCE STUDIES DEFINITION : It refers to the drug substance in two or more IDENTICAL DOSAGE FORMS reaches systemic circulation at the same RATE TO THE RELATIVE EXTENT. i.e. their plasma concentration time profiles will be identical without significant statistical difference.
ADVANTAGES  Minimizes the effect of INTER SUBJECT VARIABILITY.  It minimizes the carry over effect.  Requires less number of subjects to get meaningful results. DISADVANTAGES  Requires LONG TIME to complete the studies.  Increases in study periods leads to high subject dropouts.  Completion of studies depends on number of formulations evaluated in the studies.
OBJECTIVES  If a new product is intended to be substitute for an approves medicinal product as a pharmaceutical equivalent or alternative , equivalence with this product should be shown or justified.  Bioequivalence studies are conducted if there is :  A risk of BIOEQUIVALENCE and / or  A risk of PHARMACOTHERAPEUTIC FAILURE or diminished clinical safety
Some of the important terms relevant in this context will be defined. EQUIVALENCE : It is a relative term that compares DRUG PRODUCT with respect to a specific characteristics or function to defined SET OF STANDARDS. There are several types of equivalence : 1. Chemical Equivalence 2. Pharmaceutical Equivalence 3. Bioequivalence 4. Therapeutic Equivalence TYPES OF BIOEQUIVALENCE STUDIES  Bioequivalence can be demonstrated either : 1. In vivo or 2. In vitro
IN-VIVO BIOEQUIVALENCE STUDY 1. ORAL IMMEDIATE RELEASE PRODUCTS WITH SYSTEMIC ACTION • Indicated for serious conditions requiring assured response. • Narrow therapeutic margin • Unfavourable physiological properties eg : Low Solubility , Metastable modifications 2. NON ORAL IMMEDIATE RELEASE PRODUCTS 3. MODIFIED RELEASE PRODUCTS WITH SYSTEMIC ACTION In vivo bioequivalence studies are conducted in the usual manner i.e. pharmacokinetic & pharmacodynamic methods.  PHARMACOKINETIC METHODS PHARMACODYNAMIC METHODS • Plasma level time studies • Acute pharmacological response • Urinary excretion studies • Therapeutic response
The drug product differs only in strength of active substance it contains some of the following conditions : i. Pharmacokinetics are linear. ii. The qualitative composition is the same. iii. The ratio between the active substances and the excipients is the same. iv. Both products are produced by the same manufacturer at the same production site. v. The product contains active ingredient in the same concentrations as the approved drug product. IN-VITRO BIOEQUIVALENCE STUDY
The drug product meets all the following requirements : a) The product is in the form of solution or solubilized form. b) The product contains active ingredient in the same concentration as the approved drug product.  The drug product has been slightly reformulated or the manufacturing method has been slightly modified by the original manufacture.  An acceptable IVIVC and the invitro dissolution rate of new product is equivalent with that of already approved medicinal product.
DESIGN OF BIOEQUIVALENCE STUDIES 1. Title 2. Study Objective 3. Study Design 4. Study Population 5. Clinical Procedures 6. Ethical Considerations 7. Facilities 8. Data Analysis 9. Drug Accountability 10. Appendix
ANALYTICAL METHODS : • Must be accurate. • Should be with Appropriate precision. • Measure the actual concentration of the active drug or active metabolites achieved in the body. REFERENCE STANDARDS : • Reference standard is generally a formulation currently marketed with a FULLY APPROVED NDA for which there are valid scientific safety and efficacy data. • Usually innovators or brand drug.
EXTENDED RELEASE FORMULATIONS • Product has claimed controlled release characteristics. • No occurrence of dose dumping. • Steady state is equivalent to currently marketed extended release formulation. COMBINATION OF DRUG PRODUCTS • To determine the rate and extent of absorption of each active ingredient administered concurrently as separate single ingredient preparations.
STUDY DESIGNS 1. FASTING STUDY • Done for IMMEDIATE RELEASE AND MODIFIED RELEASE oral dosage forms • Male and Female subjects may be used. • Blood sampling is done at appropriate intervals to obtain plasma drug concentration- time profile. • Subjects should be fasting condition – atleast 10 hours before drug administration and 4 hours after administration.
2. FOOD INTERVENTION STUDY • These studies are conducted after high fat and high calorie meal. • Meal is given 30 minutes before dosing. • No food is given for atleast 4 hours after administration. • Done for MODIFIED RELEASE DOSAGE FORMS 3. MULTIPLE DOSE • Done for EXTENDED RELEASE drug products. • Done in addition to the fasting and food intervention study. • Sampling done similar to fasting study
CROSS OVER DESIGNS • Each subject receives the test and reference drug product. • Eg : LATIN SQUARE DESIGN • Each subject receives only one drug product. • Adequate wash out periods is provided between drugs. ADVANTAGES : • Subject – to – Subject variation is reduced. • All patients donot receive same drug product on the same day
PERIOD : • Two period study – performed on 2 different days separated by a washout period - generally 10 elimination half lives. SEQUENCE : • No. of different orders in the treatment groups in a study. • For eg: two sequence , two period study would be designed.
• Concept of bioequivalence has been adopted by the pharmaceutical industry and national regulatory authorities throughout the world for over 20 years. • There is continuing attempt to understand and develop more sufficient and scientifically valid approaches to assess bioequivalence of various dosage forms including some of the tough complex special dosage forms. • Absolute and Relative bioavailability shows drug availability according to their standards.