Bioequivalence and Bioavailability

Bioavailability studies play a critical role in the evaluation of product formulations throughout the entire development process. 

Bioavailahility is defined 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. 

Bioavailahility studies are used to compare different formulations of the drug product, or different batches of the same formulation and, as discussed in Chapter 8, generic copies of a reference drug. Their comparative value is based on the premise that, if similar amounts of identical active substance are delivered to the site of action at similar rates, then a similar biological response can be expected, which leads to the conclusion that the two preparations are bioequivalent. 

In-vitro bioavailahility tests usually form part of the criteria for evaluating the individual batches of a product. These are based on monitoring the rate of release of the drug substance from the pharmaceutical form, usually by observing the dissolution rates of tablets or capsules. 

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Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms based on a biopharmaceutics classification system. Center for Drug Evaluation and Research, Food and Drug Administration, issued 8/2000, posted 8/31/2000. http //www.fda.gov/cder/guidance/ index, htm... 

J. Zha and L. Endrenyi, Variation of the peak concentration following single and repeated drug administration in investigations of bioavailability and bioequivalence, J. Biopharm. Stat., 7, 191 (1997). 

CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98 Draft), Dec. 1998. 

FDA Guidance for Industry Waiver of in vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Containing Certain Active Moieties/ Active Ingredients Based on a Biopharmaceutics Classification System, CDER-GUID 2062dft.wpd Draft, Jan. 1999. 

CDER Waiver of in vivo bioavailability and bioequivalence studies for... 

Crison, G. L. Amidon. pH and surfactant-facilitated in vitro solubilization and dissolution of ketoprofen, a class II drug. Implications for waiver of bioavailability and bioequivalence studies (Unpublished). 

CDER Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system Food and Drug Administration, 2000. 

H. M. Abdou, Dissolution, Bioavailability, and Bioequivalence, Mack Pub., Easton, 1989. 

Bioavailability and bioequivalence are also usually assessed in animals. Such studies are undertaken as part of pharmacokinetic and/or pharmacodynamic studies. Bioavailability relates to the proportion of a drug that actually reaches its site of action after administration. As most biopharmaceuticals are delivered parenterally (e.g. by injection), their bioavailability is virtually 100 per cent. On the other hand, administration of biopharmaceuticals by mouth would, in most instances, yield a bioavailability at or near 0 per cent. Bioavailability studies would be rendered more complex if, for example, a therapeutic peptide was being administered intranasally. 

Christians U, First MR, Benet LZ (2000) Recommendations for bioequivalence testing of cyclosporine generics revisited. Ther Drug Monit 22 330-335 CPMP (2000) European Medicines Agency. Committee for Proprietary Medicinal Products. Note for guidance on the investigation on bioavailability and bioequivalence. CPMP/EWP/QWP/1401/98.http //www.emea.europa.eu/pdfs/human/qwp/140198en.pdf. Cited 30 Dec 2008... 

Guidance for Industry Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations. Oct. 2000. 

FDA. Guidance for Industry Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations (Revised) (I). Rockville MD, USA U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2003. 

In a series of papers (23-26), Polli and colleagues proposed alternative direct curve comparison metrics on this level. In their papers, attention was focused on two aspects (i) are means or medians more suitable for comparison and (ii) how can symmetric confidence intervals be constructed that are invariant when exchanging reference and test In addition, this work was devoted to bioavailability and bioequivalence, i.e., time profiles in vivo, but the conclusions apply likewise to in vitro-release profiles. 

Marston SA, Polli JE. Evaluation of direct curve comparison metrics applied to pharmacokinetic profiles and relative bioavailability and bioequivalence. Pharm Res 1997 14 1363-1369. 

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