Bioequivalency advantage

Discuss the issues regarding levothyroxine product bioequivalence and the advantages of maintaining patients on the same product. 

In recent years pharmaceutical scientists have participated in lively discussions about how present methods of bioequivalency determination might legitimately and advantageously be modified. For example, the question of whether it is necessary to always take plasma samples so that AUC at the end of the test is at least 90% of AUC at time infinity has been explored [7,8], Statistical aspects of this and other possible methods of modifying protocol design are covered in a most useful book published in 1999 and in several papers [8-10,22],... 

There are in general, two t5rpes of equivalence trials in clinical development, bio- and clinical equivalence. In the former, certain pharmacokinetic variables of a new formulation have to fall within specified (and regulated) margins of the standard formulation of the same active entity. The advantage of this type of trial is that, if bioequivalence is proven then proof of clinical equivalence is not required. Proof of clinical equivalence of a generic product to the marketed product can be much more difficult to demonstrate. 

Other concerns have been expressed. ° These include the observation that vehicle components of the products to be evaluated may have different effects on the adhesive properties of the tape. In addition, it is important to appreciate that because the dermatopharmacokinetic bioequivalence studies will most likely be carried out on normal disease-free human volunteers, the generated data may show little resemblance to the actual drug distribution within the stratum corneum of patients. Non-etheless, following further validation, the technique will have several advantages. For example, basic pharmacokinetic parameters, such as AUC, Craax, max, Tud half-Hfc, may be approximated from the data obtained. In addition, the approach could be applicable to all types of topical preparation. 

Blume H, Elze M, Potthast H, et al. Practical strategies and design advantages in highly variable drag studies multiple dose and replicate administration design. In Blume H, Midha K, eds. Bio-intemational 2 Bioavailability, Bioequivalence and Hiarmacokinetic studies. Stuttgart Medpharm Scientific Publishers, 1995 117-122. 

By definition, sustained release formulations differ pharmaceutically and pharmacokinetically from the innovator drug. Delayed or sustained release oral formulations are used for chronic therapy, and may have two principal advantages (a) reduction in dose frequency (and thus, hopefully, improved compliance see Chapter 21) and (b) reduction of Cmax for a standard AUC, which can improve tolerability when adverse events are plasma concentration-related. The demonstration of bioequivalence usually hinges on the following factors (a) equivalence of AUC to an innovator drug at steady state (b) the absence of any chance of dose dumping (c) consistency of performance from dose to dose [see 21CFR320.25(f)]. 

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