Bioavailability/Bioequivalence: Study Considerations*


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Bioavailability/Bioequivalence: Study Considerations*


Ramana S. Uppoor†


* The opinions expressed herein are those of the author and do not necessarily reflect those of the US Food and Drug Administration.


† Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.


Introduction


Studies to measure bioavailability (BA) and/or establish bioequivalence (BE) are important elements in support of drug development and approval. BA is defined in 21 Code of Federal Regulations (CFR) 320.1 (US regulations) as 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.1 However, the Indian Guidelines define BA as the relative amount of drug from an administered dosage form which enters the systemic circulation and the rate at which the drug appears in the systemic circulation.2 BA can generally be documented by a systemic exposure profile obtained by measuring drug and/or metabolite concentration in the systemic circulation over time.1 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. BA studies focus on determining the process by which a drug is released from the oral dosage form and moves to the site of action. BA data provide an estimate of the fraction of drug absorbed, as well as its subsequent distribution and elimination.


BE is defined in 21 CFR 320. as the ‘absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study’.1 The Indian Drugs and Cosmetics Act (Schedule Y) BA/BE Guidelines define BE as ‘BE of a drug is achieved if its extent and rate of absorption are not statistically different from those of the reference product when administered at the same molar dose’.2 In BE studies, one compares the systemic exposure profile of a test product to the reference product. For BE purposes, a single dose BE study is preferred since it is considered to be more sensitive in detecting formulation and BA differences.3,4 BA and BE studies are generally required to be submitted in support of a regulatory submission that seeks approval of a drug product. BE studies are generally required when it is necessary to show that the test product is bioequivalent to a reference product (e.g. for generics) or when the to-be marketed formulation is significantly different from the clinically studied formulation.


This chapter focuses on the general BA and BE study requirements and then the BA/BE protocol considerations. In this regard, some considerations will be provided for different types of BA/BE studies.


Bioavailability Study Requirements


The general BA/BE requirements are set forth in 21 CFR 320,1 Drugs and Cosmetic Act of India (DCA)2 and EMEA (European Medical Agency) and are provided in greater detail in several FDA Guidances, including the FDA Guidance for Industry: ‘Bioavailability and BE Studies for Orally Administered Drug Products–General Considerations’3 and ‘Guidelines for Bioavailability and Bioequivalence Studies’ read in conjunction with Schedule Y to the Drugs and Cosmetics Rules of India.2 Pertinent general BA/BE study requirements are listed below.


Types of Evidence to Establish BA or BE


BA or BE may be determined by several in vivo and in vitro methods. The following in vivo and in vitro approaches, in descending order of accuracy, sensitivity and reproducibility, are considered scientifically acceptable for determining the BA or BE of a drug product.



1. (a) An in vivo test in humans in which the concentration of the active ingredient or active moiety, and, when appropriate, its active metabolite(s), in whole blood, plasma, serum, or other appropriate biological fluid is measured as a function of time. This approach is particularly applicable to dosage forms intended to deliver the active moiety to the bloodstream for systemic distribution within the body; or (b) an in vitro test that has been correlated with and is predictive of human in vivo BA data; or (c) an in vivo test in animals that has been correlated with and is predictive of human BA data.

2. An in vivo test in humans in which the urinary excretion of the active moiety, and, when appropriate, its active metabolite(s), is measured as a function of time. This method is not appropriate where urinary excretion is not a significant mechanism of elimination.

3. An in vivo test in humans in which an appropriate immediate pharmacological effect of the active moiety, and, when appropriate, its active metabolite(s), is measured as a function of time if such effect can be measured with sufficient accuracy, sensitivity and reproducibility. This approach is applicable only when appropriate methods are not available for measurement of the concentration of the moiety or its active metabolite, but a method is available for the measurement of an appropriate immediate pharmacological effect. This approach may be particularly applicable to dosage forms that are not intended to deliver the active moiety to the bloodstream for systemic distribution.

4. Well-controlled clinical trials in humans that establish the safety and effectiveness of the drug product, for purposes of establishing BA, or appropriately designed comparative clinical trials, for purposes of demonstrating BE. This approach is the least accurate, sensitive and reproducible of the general approaches for determining BA or BE.

Guidelines for the Conduct of an In Vivo BA Study1,3


In most cases, BA and BE studies are conducted in healthy adult volunteers. In some situations, however, an in vivo BA study may be preferable and most properly conducted in suitable patients, for example due to tolerability reasons.


The basic design of an in vivo BA study is determined by the following:



1. The scientific questions to be answered

2. The nature of the reference material and the dosage form to be tested

3. The availability of analytical methods

4. Benefit to risk considerations, which affects testing in humans

In vivo BA testing of a drug product shall be in comparison to an appropriate reference material unless some other approach is more suitable for valid scientific reasons.


For New Chemical/Biological Entities



1. The purpose of an in vivo BA study involving a drug product containing an active drug ingredient or therapeutic moiety that has not yet been approved for marketing is to determine

(a) the BA of the formulation proposed for marketing and


(b) the essential pharmacokinetic characteristics of the active drug ingredient or therapeutic moiety, such as the rate of absorption, the extent of absorption, the half-life of the therapeutic moiety in vivo and the rate of excretion and/or metabolism. Dose proportionality of the active drug ingredient or the therapeutic moiety needs to be established after single-dose administration and in certain instances after multiple-dose administration. This characterisation is a necessary part of the investigation of the drug to support drug labelling.



2. The reference material in such a BA study should be a solution or suspension containing the same quantity of the active drug ingredient or therapeutic moiety as the formulation proposed for marketing.

3. The reference material should be administered by the same route as the formulation proposed for marketing unless an alternative or additional route is necessary to answer the scientific question under study. For example, in the case of an active drug ingredient or therapeutic moiety that is poorly absorbed after oral administration, it may be necessary to compare the oral dosage form proposed for marketing with the active drug ingredient or therapeutic moiety administered in solution both orally and intravenously.

New Formulations of Active Drug Ingredients or Therapeutic Moieties Approved for Marketing



1. The purpose of an in vivo BA study involving a drug product that is a new formulation, a new dosage form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for marketing is to

(a) determine the BA of the new formulation, new dosage form, or new salt or ester relative to an appropriate reference material and


(b) define the pharmacokinetic parameters of the new formulation, new dosage form, or new salt or ester to establish dosage recommendation.



2. The reference material should be taken from a current batch of an approved drug product that contains the same active drug ingredient or therapeutic moiety, if the new formulation, new dosage form, or new salt or ester is intended to be comparable to or to meet any comparative labelling claims made in relation to the approved drug product.

Controlled Release Formulations



1. The purpose of an in vivo BA study involving a drug product for which a controlled release claim is made is to confirm that all of the following conditions are met:

(a) The drug product meets the controlled release claims made for it.


(b) The BA profile established for the drug product rules out the occurrence of any dose dumping.


(c) The drug product’s steady-state performance is equivalent to a currently marketed noncontrolled release or controlled release drug product that contains the same active drug ingredient or therapeutic moiety.


(d) The drug product’s formulation provides consistent pharmacokinetic performance between individual dosage units.



2. The reference material(s) for such a BA study shall be chosen to permit an appropriate scientific evaluation of the controlled release claims made for the drug product. The reference material shall be one of the following or any combination thereof:

(a) A solution or suspension of the active drug ingredient or therapeutic moiety.


(b) A currently marketed non-controlled release drug product containing the same active drug ingredient or therapeutic moiety and administered according to the dosage recommendations in the labelling of the non-controlled release drug product.


(c) A currently marketed and approved controlled release drug product containing the same active drug ingredient or therapeutic moiety and administered according to the dosage recommendations in the labelling proposed for the controlled release drug product.


Combination Drug Products



1. Generally, the purpose of an in vivo BA study involving a combination drug product is to determine if the rate and extent of absorption of each active drug ingredient or therapeutic moiety in the combination drug product is equivalent to the rate and extent of absorption of each active drug ingredient or therapeutic moiety administered concurrently in separate single-ingredient preparations.

2. The reference material in such a BA study should generally be two or more currently marketed, single-ingredient drug products each of which contains one of the active drug ingredients or therapeutic moieties in the combination drug product.

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Oct 21, 2016 | Posted by in GENERAL SURGERY | Comments Off on Bioavailability/Bioequivalence: Study Considerations*

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