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Bioequivalence Studies
Published in Nusrat Rabbee, Biomarker Analysis in Clinical Trials with R, 2020
Bioequivalence is the study of two drugs for comparability (as stated above) of their bioavailability at the site of action. For example, two drugs with the same active ingredient may have different routes of administration and may need to be compared for bioequivalence. Another example is a drug, which may have changed its formulation during the drug development process and needs to be compared to the original formulation. In these cases, a bioequivalence study can be part of an NDA submission. PK parameters, like AUC, Cmax, and Tmax (time at which Cmax is achieved), are measured and analyzed for this purpose. The variables assume log normal distribution for analysis.
Generics and Biosimilars
Published in Shein-Chung Chow, Innovative Statistics in Regulatory Science, 2019
In the United States, for traditional chemical (small molecule) drug products, when an innovative (brand-name) drug product is going off patent, pharmaceutical and/or generic companies may file an abbreviated new drug application (ANDA) for approval of generic copies of the brand-name drug product. In 1984, the FDA was authorized to approve generic drug products under the Drug Price Competition and Patent Term Restoration Act, which is also known as the Hatch-Waxman Act. For approval of small molecule generic drug products, the FDA requires that evidence of average bioavailability, in terms of the rate and extent of drug absorption, be provided. The assessment of bioequivalence as a surrogate endpoint for quantitative evaluation of drug safety and efficacy is based on the Fundamental Bioequivalence Assumption that if two drug products are shown to be bioequivalent in average bioavailability, it is assumed that they will reach the same therapeutic effect or they are therapeutically equivalent and hence can be used interchangeably. Under the Fundamental Bioequivalence Assumption, regulatory requirements, study design, criteria, and statistical methods for assessment of bioequivalence have been well established (see, e.g., Schuirmann, 1987; EMEA, 2001; FDA 2001, 2003a, 2003b; WHO, 2005; Chow and Liu, 2008).
Bioequivalence of Orally Inhaled Drug Products: Challenges and Opportunities
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Jayne E. Hastedt, Elise Burmeister Getz
Bioequivalence is defined 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.”3 That is, when the chemical entity that exerts a biological effect appears at its site of action in a similar amount, and with similar kinetics, in two formulations or products, these two formulations or products will be assumed to “have the same clinical effect and no greater chance of adverse effect.”4
Determination of galantamine in human plasma by LC-MS/MS using carbamazepine as an internal standard: Method validation and application to a pharmacokinetic study of galantamine hydrobromide prolonged-release capsules in healthy Thai volunteers
Published in Cogent Medicine, 2020
Darunee Hongwiset, Songwut Yotsawimonwat, Chokchai Wongsinsup, Saowarunee Sangsrijan, Chuleegone Sornsuvit
Galantamine, a cholinergic agent, is one of the approved drugs for the treatment of mild to moderate Alzheimer’s disease (AD). With a dual mechanism of action, reversible competitive inhibitor of acetylcholinesterase and allosteric modulator of nicotinic receptor, galantamine is an effective drug which was widely used. Various formulations of galantamine are available in forms of oral solutions, tablets and capsules. Since the use of galantamine is increased, new formulations and/or generic formulations are required. Pharmacokinetic and bioequivalence studies are also essential as a tool in drug development. These studied required a sensitive and robust bioanalytical method. In this study, a rapid HPLC-MS/MS method for quantification of galantamine in human plasma with simple solvent-solvent extraction was developed, validated and applied in the pharmacokinetic study of 8 mg galantamine hydrobromide release capsules in healthy Thai volunteers.
Bioavailability testing of a newly developed clindamycin oral suspension in a pediatric porcine model
Published in Pharmaceutical Development and Technology, 2019
Grace A. Goode, Santosh J. Wagh, David J. Irby, Dejian Ma, Richard F. Jacobs, Gregory L. Kearns, Hassan Almoazen
The mean ± SD as well as a 95% confidence interval was computed for each pharmacokinetic parameter under study. A two-tailed, paired Student t test was used to compare the difference in each parameter between the test and reference oral formulations for all animals. A post hoc power test was used to assess the relevance of any observed statistically significant differences in any of the pharmacokinetic paramemters evaluated. The percent relative bioavailability was computed based on the ratio of AUC∞ for the test and reference formulations. A two one-sided test (TOST) was accomplished using SAS software (Statistical Analysis Software version 3.7, 2012–2017) to assess bioequivalence according to the FDA’s definition. Bioequivalence was determined if the 90% confidence interval for the geometric least square ratio of test/reference was within the range 0.8–1.25 (U.S. Department of Health and Human Services, Food and Drug Administration, and Center for Drug Evaluation and Research (CDER) 2001).
Is Bioequivalence a Sufficient Measure of Equivalence?
Published in Journal of Legal Medicine, 2019
Since the Food, Drug, and Cosmetic Act of 1938 (FDCA),15 the FDA has required every new drug introduced into United States commerce to undergo an approval process to ensure drug safety and efficacy.16 To obtain approval, manufacturers must submit to the FDA a New Drug Application (NDA).17 The Abbreviated New Drug Application (ANDA) process, on the other hand, enables generic drug sponsors to bypass the safety and efficacy testing already established by the brand drug (or “Reference Listed Drug”) through its NDA.18 In lieu of the safety and efficacy testing, a generic drug sponsor alternatively must prove pharmaceutical equivalence and bioequivalence to the brand drug.19 To establish pharmaceutical equivalence, the sponsor must show that “the active ingredient of the new drug is the same as that of the listed drug” and that the “route of administration, dosage form, and the strength of the new drug are the same as those of the listed drug.”20 Then, the sponsor must “show that the new drug is bioequivalent to the listed drug.”21 The FDA considers the combination of pharmaceutical equivalence and bioequivalence to establish therapeutic equivalence, which means that the drugs “can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.”22 Bioequivalence thus plays a pivotal role in the FDA’s approval of generic drugs.