Article Title

Assessing the potential bioequivalence requirement for oral immediate release dosage form: Post approval changes for cardiovascular drugs


Formulation changes can occur during drug development before approval or after approval. Recently, the FDA issued several guidances regarding scale up and post approval changes (SUPAC). The first of the series addresses the requirements for determining and evaluating those changes for immediate release (IR) oral dosage form. In that guidance, the concepts of Biopharmaceutical Classification System (BCS) were introduced. Based on their solubility (S) and permeability (P), the drugs are classified as high (H) and low (L), and thus are divided into four classes (HS/HP, HS/LP, LS/HP, and LS/LP). Only LS/LP drugs are required to perform a bioequivalence (BE) study. The other classes of drugs are required to perform a BE study only when they fail their dissolution testing, under level 3 changes in manufacturing process, components and composition. In addition, only a handful of drugs were classified under the BCS system. In order for the industry to extensively apply the BCS system, more drugs need to be classified. The objective of this study is to compile the pertinent information relating to the drug release from the formulation and absorption through the gut wall. By evaluating the information collectively, an educational guess can be made as to whether the formulation can be rapidly converted to solution in the gastrointestinal tract and therefore behave as such. Under those conditions, a BE study may not be needed if in vitro dissolution performance can be demonstrated. Cardiovascular drugs were studied for their vastly different safety profiles, physicochemical properties and pharmacokinetic behaviors. This report is written for the Taiwan regulatory authority (Bureau of Pharmaceutical Affairs, Department of Health) considering the uniqueness of the Asian pharmaceutical environment. The final judgement was made based on the following information: 1) effective and toxic concentrations; 2) solubility and pKa; 3) total % absorption as both drug and metabolite(s); 4) half-life and its peak time as indication of in vivo solubility and permeability of drug; and 5) German BA list, WHO list, and the FDA narrow therapeutic index drug list. The reason(s) for the judgement was provided.

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