INTRODUCTION OF BIOAVAILABILITY AND BIOEQUIVALENCE

INTRODUCTION

• A multisource drug product is a drug product that contains the same active drug substance in the same dosage form and is marketed by more than one pharmaceutical manufacturer. 
• Single-source drug products are drug products for which the patent has not yet expired or has certain exclusivities so that only one manufacturer can make it. Single-source drug products are usually brand-name (innovator) drug products. After the patent and other exclusivities for the brand-name drug expires, a pharmaceutical firm may manufacture a generic drug product that can be substituted for the branded drug product.  
• Since the formulation and method of manufacture of the drug product can affect the bioavailability and stability of the drug, the generic drug manufacturer must demonstrate that the generic drug product is bioequivalent and therapeutically equivalent to the brand-name drug product.  
• Drug product selection and generic drug product substitution are major responsibilities for physicians, pharmacists, and others who prescribe, dispense, or purchase drugs. To facilitate such decisions, the U.S. Food and Drug Administration (FDA) publishes annually, in print and on the Internet, Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the Orange Book . 
• The Orange Book identifies drug products approved on the basis of safety and effectiveness by the FDA and contains therapeutic equivalence evaluations for approved multisource prescription drug products. These evaluations serve as public information and advice to state health agencies, prescribers, and pharmacists to promote public education in the area of drug product selection and to foster containment of health care costs.

BIOAVAILABILITY (BA): 

• "Bioavailability means the rate and the extent to which the active drug ingredient of therapeutic moiety is absorbed from a drug product and becomes available at the site of action."( FDA Official Statement in 1977) 
• "The rate at which, and the extent to which the drug substance and/or its active metabolites reach(es) the systemic circulation." ( International Consensus Statement in 1991) 

BIOEQUIVALENCE (BE): 

• A relative term which denotes that the drug substance in two or more dosage forms, reaches the systemic circulation at the same relative rate and to the same relative extent i.e., their plasma concentration time profiles will be identical without significant statistical difference. 

BIOEQUIVALENT DRUG PRODUCTS: 

• This term describes pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions. 
• For systemically absorbed drugs, the test (generic) and reference listed drug (brand-name) shall be considered bioequivalent if: 
• the rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses;  or
• The extent of absorption of the test drug does not show a significant difference from the extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the reference drug in the rate of absorption of the drug is intentional, is reflected in its proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug.  
• When the above methods are not applicable (eg, for drug products that are not intended to be absorbed into the bloodstream), other in-vivo or in-vitro test methods to demonstrate bioequivalence may be appropriate. 
• Bioequivalence may sometimes be demonstrated using an in-vitro bioequivalence standard, especially when such an in-vitro test has been correlated with human in-vivo bioavailability data. In other situations, bioequivalence may sometimes be demonstrated through comparative clinical trials or pharmacodynamic studies.  
• Bioequivalent drug products may contain different inactive ingredients, provided the manufacturer identifies the differences and provides information that the differences do not affect the safety or efficacy of the product.  

NEED FOR BIOAVAILABILITY –BIOEQUIVALENCE STUDIES: 

• BA:
• To evaluate the absolute systemic   availability of an oral,    topic,intramuscular, or any other dosage form 
• To determine if bioavailability parameters are linear over the proposed clinical dose range 
• To estimate the inter and intra subject variability
• To study food effects 
• To define the effect of changes in the physicochemical properties of the drug substance and the effect of the drug product (dosage form) on the pharmacokinetics of the drug. 
• BE: 
• Surrogate for therapeutic equivalence to enable-switchability
• An appropriate measure for the quality control of the product in vivo 

WHEN SHOULD “BE STUDIES” BE CONDUCTED? 

• When a generic formulation is tested against an innovator brand 
• Where a proposed dosage form is different from that used in a pivotal clinical trial 
• When significant changes are made in the manufacture of the marketed formulation 

BIOAVAILABILITY:

WHY DO WE CARE ABOUT BA? 

• The therapeutic effectiveness of a drug depends upon the ability of the dosage form to deliver the medicament to its site of action at a rate & amount sufficient to produce the desired pharmacologic response. 
• For most of the drugs, the pharmacologic response is directly related to the plasma levels. Bioavailability is an absolute term. 
• The true dose is not the drug swallowed; BUT is the drug available to exert its effect 
• Dissolution 
• Absorption
• Survive metabolism 
• May have a drug with very low bioavailability
• Dosage form or drug may not dissolve readily
• Drug may not be readily pass across biological membranes (i.e. be absorbed)
• Drug may be extensively metabolized during absorption     process (first-pass, gut wall, liver). 
• Important component of overall variability
• Variable bioavailability may produce variable exposures

There fore,

• The rate of absorption & extent of absorption both are important consideration. 
• A) Rate of absorption: - It may be fast or slow. 
• If fast, we get rapid onset of action, which are desired in treatment of acute conditions like asthma attack, pain etc.
• Slow rate of absorption is desired when prolong duration of action is needed or to avoid side effects. 
• B) Extent of absorption :- It is of significance in the treatment of chronic conditions like hypertension, epilepsy etc. 
• If the size of the dose administered is same, then the bioavailability of a drug from dosage form depends upon 3 major factors. 
• Pharmaceutical factors
• Patient related factors 
• Route of administration
• The influence of route of administration on drug‘s bioavailability generally follows this order: 
• Parenteral > oral > rectal > topical.
• Within parenteral route, i.v. injection of a drug results in 100% bioavailability as the absorption process is bypassed. 
• In case of oral route, the dose available to the patient is called Bio available dose which is often less than the administered dose.
• Therefore, the bio-available fraction F, refers to the fraction of administered dose that enters the systemic circulation. 

OBJECTIVES OF BA STUDIES: 

Bioavailability studies are important in the… 

• Primary stages of development of a suitable dosage form for a new drug entity. 
• Determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption. 
• Development of new formulations of the existing drugs. 
• Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption.

CHARACTERISTICS  OF  DRUGS  WITH GREATEST POTENTIAL FOR BIOAVAILABILITY PROBLEM: 

• The drug has a narrow therapeutic ratio. 
• The drug has low solubility in water and / or the dissolution rate of the dosage form is slow.
• The drug product contain high ratio of excipient to active ingredient. 
• The absorption of the drug is limited to a specific region of g.i. tract. 
• The metabolism of the drug is rapid. 
• The drug exhibits dose dependent pharmacokinetics. 

CONSIDERATION IN BIOAVAILABILITY STUDY DESIGN: 

1. BIOAVAILABILITY (ABSOLUTE  VS. RELATIVE)

• Absolute bioavailability
• When the systemic availability of a drug administered orally is determined in comparison to its intravenous administration, is called as absolute availability.

• Intravenous dose is selected as a standard due to its 100% bioavailability 
• If the drug is poorly water soluble, intramuscular dose can be taken as standard. 
• Its determination is used to characterize a drug‘s inherent absorption properties from extravascular site. 
• Relative bioavailability
• When the systemic availability of a drug after administration is compared with that of standard of the same drug it‘s referred to as relative bioavailability (Fr). 

• The standard is a pure drug evaluated in a crossover study. 
• Its determination is used to characterize absorption of drug from its formulation.
• Both F AND Fr ARE EXPRESSED AS PERCENTAGE.

2. SINGLE DOSE   VS.  MULTIPLE DOSE  STUDY

• Single dose bioavailability studies are very common, easy, offer less exposure and less tedious. But, it‘s difficult to predict the steady state characteristics and intersubject variability by this method. 

• Multiple dose study is difficult to control(poor subject compliance), exposes the subject to more drug , highly tedious and time consuming but has several advantages like: 
• More accurately reflect the manner in which the drug should be used. 
• The drug blood levels are higher due to cumulative effect which makes its determination possible using less sensitive analytical method. 
• Better evaluation of performance of a controlled release formulation is possible. 
• Nonlinearity in pharmacokinetics, if present, can be easily detected. 
• Easy to predict the peak & valley characteristic of the drug since the bioavailability is determined at steady – state. 
• Requires collection of fewer blood samples. 
• Can be ethically performed in patients because of the therapeutic benefit to the patient.
• In multiple dose study, one must ensure that steady state level has been reached. For this, the drug should be administered for 5-6 elimination half lives before collecting blood sample.

• The USFDA requires both single and multiple dose administration, as well as a determination of the effect of food on the absorption of the drug from the dosage form. 

3. HUMAN VOLUNTEERS-HEALTHY SUBJECTS  VS.  PATIENTS 

• Ideally, bioavailability studies should be carried out in patients for whom the drug is intended to be used because of the apparent advantages.
• The patient will be beneficial from the study. 
• Reflects better therapeutic efficacy of a drug. 
• Drug absorption pattern in disease states can be evaluated. 
• Avoids the ethical requirements of administering drugs to the healthy subjects.
• In multiple dose study, they prefer patients rather than healthy humans. 
• But, the drawbacks of using patients as volunteers are – disease, other drugs the patients may be taking, physiological changes, etc. may modify drug absorption pattern.
• Strict study conditions such fasting state required to be followed by the subject is also difficult.In short, establishing a standard set of conditions necessary for a bioavailability study is difficult with patients as volunteers. 
• That‘s why such studies should be performed in young – 20 – 40 years, healthy, male, adult volunteers, body weight within a range ± 10%, under restricted dietary and fixed activity condition. 
• The consent of volunteers must be obtained and they must be informed about the conditions to be followed during the course of studies – to abstain from any other medication for at least 2 weeks and to fast overnight  prior to and for a minimum of 2-4 hours post dosing as well as possible hazards if any.