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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/01 04:42:48」(JST)

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A bioequivalency profile comparison of 150 mg extended-release bupropion as produced by Impax Laboratories for Teva and Biovail for GlaxoSmithKline.

Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same.

Birkett (2003) defined bioequivalence by stating that, "two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailabilities (rate and extent of availability) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards."^[1]

The United States Food and Drug Administration (FDA) has defined bioequivalence 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."^[2]

Bioequivalence

In determining bioequivalence, for example, between two products such as a commercially available Brand product and a potential to-be-marketed Generic product, pharmacokinetic studies are conducted whereby each of the preparations are administered in a cross-over study to volunteer subjects, generally healthy individuals but occasionally in patients. Serum/plasma samples are obtained at regular intervals and assayed for parent drug (or occasionally metabolite) concentration. Occasionally, blood concentration levels are neither feasible or possible to compare the two products (e.g. inhaled corticosteroids), then pharmacodynamic endpoints rather than pharmacokinetic endpoints (see below) are used for comparison. For a pharmacokinetic comparison, the plasma concentration data are used to assess key pharmacokinetic parameters such as area under the curve (AUC), peak concentration (C_max), time to peak concentration (T_max), and absorption lag time (t_lag). Testing should be conducted at several different doses, especially when the drug displays non-linear pharmacokinetics.

In addition to data from bioequivalence studies, other data may need to be submitted to meet regulatory requirements for bioequivalence. Such evidence may include:

analytical method validation
in vitro-in vivo correlation studies(IVIVC)

Regulatory definition

Australia

In Australia, the Therapeutics Goods Administration (TGA) considers preparations to be bioequivalent if the 90% confidence intervals (90% CI) of the rate ratios, between the two preparations, of C_max and AUC lie in the range 0.80-1.25. T_max should also be similar between the products.^[1]

There are tighter requirements for drugs with a narrow therapeutic index and/or saturable metabolism – thus no generic products exist on the Australian market for digoxin or phenytoin for instance.

Europe

According to regulations applicable in the European Economic Area^[3] two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same. This is considered demonstrated if the 90% confidence intervals (90% CI) of the ratios for AUC_0-t and C_max between the two preparations lie in the range 80.00 – 125.00%.

United States

The FDA considers two products bioequivalent if the 90% CI of the relative mean C_max, AUC_(0-t) and AUC_(0-∞) of the test (e.g. generic formulation) to reference (e.g. innovator brand formulation) should be within 80.00% to 125.00% in the fasting state. Although there are a few exceptions, generally a bioequivalent comparison of Test to Reference formulations also requires administration after an appropriate meal at a specified time before taking the drug, a so-called "fed" or "food-effect" study. A food-effect study requires the same statistical evaluation as the fasting study, described above.^[2]

References

^ ^a ^b Birkett DJ (2003). "Generics - equal or not?" (PDF). Aust Prescr 26: 85–7.
^ ^a ^b Center for Drug Evaluation and Research (2003). "Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations" (PDF). United States Food and Drug Administration.
^ Committee for Medicinal Products for Human Use (20 January 2010). "Guideline on the Investigation of Bioequivalence" (pdf). European Medicines Agency. Retrieved 21 April 2011.

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English Journal

A randomized, three-treatment, three-period, six-sequence-crossover, single-center, bioequivalence study to evaluate the impact of different 10-mg crystalline forms on the pharmacokinetics of lenvatinib in healthy volunteers.

Lee L, D'Angelo P, Verbel D, Martinez G, Aluri J, Brimhall D.
International journal of clinical pharmacology and therapeutics.Int J Clin Pharmacol Ther.2015 Feb;53(2):190-8. doi: 10.5414/CP202216.
OBJECTIVE: This study assessed the impact of varying lenvatinib crystalline forms in 10-mg lenvatinib capsules on drug bioavailability in healthy volunteers.MATERIALS: Lenvatinib 10-mg capsules (low C and high C forms).METHODS: This randomized, three-period- crossover study compared the pharmacokine
PMID 25600977

An open-label, randomized bioavailability study with alternative methods of administration of crushed ticagrelor tablets in healthy volunteers.

Teng R, Carlson G, Hsia J.
International journal of clinical pharmacology and therapeutics.Int J Clin Pharmacol Ther.2015 Feb;53(2):182-9. doi: 10.5414/CP202202.
OBJECTIVE: To compare the bioavailability and safety profile of crushed ticagrelor tablets suspended in water and administered orally or via nasogastric tube, with that of whole tablets administered orally.METHODS: In this single-center, open-label, randomized, three-treatment crossover study, 36 he
PMID 25500486

Demonstrating Comparative In Vitro Bioequivalence for Animal Drug Products Through Chemistry and Manufacturing Controls and Physicochemical Characterization: A Proposal.

Martinez MN1, Fahmy R.
The AAPS journal.AAPS J.2015 Jan 22. [Epub ahead of print]
The assessment of in vivo bioequivalence (BE) of nonsystemically absorbed drug products has been a longstanding challenge facing drug manufacturers and regulators of human or animal health products. Typically, in situations where blood level BE studies are not feasible, clinical endpoint BE trials h
PMID 25609223

Japanese Journal

Formulation and Optimization of Orally Disintegrating Tablets of Sumatriptan Succinate

Sheshala Ravi,Khan Nurzalina,Darwis Yusrida
CHEMICAL & PHARMACEUTICAL BULLETIN 59(8), 920-928, 2011
… The optimized formulation was found to be stable and bioequivalent with Suminat®. …
NAID 130000960921

Basic study of a diagnostic modality employing a new electrical impedance tomography (EIT) method for noninvasive measurement in localized tissue

Okazaki Kenji,Tangoku Akira,Morimoto Tadaoki,Kotani Ryosuke,Hattori Keigo,Yasuno Emiko,Akutagawa Masatake,Kinouchi Yohsuke,岡﨑憲二,丹黒章,森本忠興,小谷亮介,服部圭悟,安野恵実子,芥川正武,木内陽介
The journal of medical investigation : JMI 57(3-4), 205-218, 2010-08
… The objective of this study is to develop a device for noninvasive local tissueelectrical impedance tomography (EIT) using divided electrodes with guard electrodesand to validate its effectiveness using bioequivalent phantoms. … For this purpose, we prepareda measurement device and bioequivalent phantoms, measured the electrical characteristicsof the phantoms, and validated the method using the phantoms. …
NAID 120003596518