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Bioavailability/Bioequivalence: Study Considerations*
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.
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:
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
(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.
New Formulations of Active Drug Ingredients or Therapeutic Moieties Approved for Marketing
(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.
Controlled Release Formulations
(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.
(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.