![Bupropion bioequivalency comparison](https://upload.wikimedia.org/wikipedia/commons/7/7d/Bupropion_bioequivalency_comparison.svg)
Bioequivalence is a term in
pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
used to assess the expected
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
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."
For
The World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
(WHO) "two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives, and their bioavailabilities, in terms of rate (Cmax and tmax) and extent of absorption (area under the curve), after administration of the same molar dose under the same conditions, are similar to such a degree that their effects can be expected to be essentially the same".
The
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(
FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
) 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."
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
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
General ...
)
Regulatory definition
The World Health Organization
The World Health Organization considers two formulation bioequivalent if the 90% confidence interval for the ratio multisource (generic) product/comparator lie within 80.00-125.00% acceptance range for AUC
0–t and C
max. For high variable finished pharmaceutical products, the applicable acceptance range for C
max can be 69.84-143.19%.
Australia
In
Australia
Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...
, the
Therapeutics Goods Administration (TGA) considers preparations to be bioequivalent if the 90%
confidence interval
In frequentist statistics, a confidence interval (CI) is a range of estimates for an unknown parameter. A confidence interval is computed at a designated ''confidence level''; the 95% confidence level is most common, but other levels, such as 9 ...
s (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.
There are tighter requirements for drugs with a narrow
therapeutic index
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
and/or saturable metabolism – thus no generic products exist on the Australian market for
digoxin
Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is on ...
or
phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The intr ...
for instance.
Europe
According to regulations applicable in the
European Economic Area
The European Economic Area (EEA) was established via the ''Agreement on the European Economic Area'', an international agreement which enables the extension of the European Union's single market to member states of the European Free Trade Ass ...
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 interval
In frequentist statistics, a confidence interval (CI) is a range of estimates for an unknown parameter. A confidence interval is computed at a designated ''confidence level''; the 95% confidence level is most common, but other levels, such as 9 ...
s (90% CI) of the ratios for AUC
0–t and ''C''
max between the two preparations lie in the range 80–125%.
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% to 125% 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.
Bioequivalence issues
While the FDA maintains that approved generic drugs are equivalent to their branded counterparts, bioequivalence problems have been reported by physicians and patients for many drugs.
Certain classes of drugs are suspected to be particularly problematic because of their chemistry. Some of these include chiral drugs, poorly absorbed drugs, and cytotoxic drugs. In addition, complex delivery mechanisms can cause bioequivalence variances.
Physicians are cautioned to avoid switching patients from branded to generic, or between different generic manufacturers, when prescribing anti-epileptic drugs,
warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent strok ...
, and
levothyroxine
Levothyroxine, also known as -thyroxine, is a manufactured form of the thyroid hormone thyroxine (T4). It is used to treat hypothyroidism, thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also ...
.
Major issues were raised in the verification of bioequivalence when multiple generic versions of FDA-approved generic drug were found not to be equivalent in efficacy and side effect profiles. In 2007, two providers of consumer information on nutritional products and supplements,
ConsumerLab.com
ConsumerLab.com, LLC. is a privately held American company registered in White Plains, NY. It is a publisher of test results on health, wellness, and nutrition products. Consumer Labs is not a laboratory, but contracts studies to outside laborator ...
and The People's Pharmacy, released the results of comparative tests of different brands of bupropion.
The People's Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, which prompted it to ask ConsumerLab.com to test the products in question. The tests showed that some generic versions of Wellbutrin XL 300 mg didn't perform the same as the brand-name pill in laboratory tests.
The FDA investigated these complaints and concluded that the generic version is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL.
After several years of denying patient reports, in 2012 the FDA reversed this opinion, announcing that "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg."
The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300 mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013. As of October 2013, the FDA has made determinations on the formulations from some manufacturers not being bioequivalent.
In 2004,
Ranbaxy
Ranbaxy Laboratories Limited was an Indian multinational pharmaceutical company that was incorporated in India in 1961 and remained an entity until 2014. The company went public in 1973. Ownership of Ranbaxy changed twice over the course of its ...
was revealed to have been falsifying data regarding the generic drugs they were manufacturing. As a result, 30 products were removed from US markets and Ranbaxy paid $500 million in fines. The FDA investigated many Indian drug manufacturers after this was discovered, and as a result at least 12 companies have been banned from shipping drugs to the US.
In 2017, The European Medicines Agency recommended suspension of a number of nationally approved medicines for which bioequivalence studies were conducted by Micro Therapeutic Research Labs in India, due to inspections identifying misrepresentation of study data and deficiencies in documentation and data handling.
See also
*
Generic drug
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
*
Pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
*
Clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
*
Abbreviated New Drug Application
An Abbreviated New Drug Application (ANDA) is an application for a U.S. generic drug approval for an existing licensed medication or approved drug.
The ANDA is submitted to Food and Drug Administration, FDA's Center for Drug Evaluation and Resea ...
References
External links
* Hussain AS, et al
The Biopharmaceutics Classification System: Highlights of the FDA's Draft GuidanceOffice of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration.
* Mills D (2005)
International Biopharmaceutical Association: IBPA Publications.
– further U.S. information on bioequivalence testing and generic drugs
Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms WHO Technical Report Series, No. 937, 2006, Annex 8.
Guidance for organizations performing in vivo bioequivalence studies (revision) WHO Technical Report Series 996, 2016, Annex 9.
General background notes and list of international comparator pharmaceutical products WHO Technical Report Series 1003, 2017, Annex 5.
WHO List of International Comparator products(September 2016)
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Pharmacokinetics
Clinical research
Life sciences industry