An Assessment of Occasional Bio-Inequivalence for BCS1 and BCS3 Drugs: What are the Underlying Reasons?

Despite having adequate solubility properties, bioequivalence (BE) studies performed on immediate release formulations containing BCS1/3 drugs occasionally fail. By systematically evaluating a set of 17 soluble drugs where unexpected BE failures have been reported and comparing to a set of 29 drugs where no such reports have been documented, a broad assessment of the risk factors leading to BE failure was performed. BE failures for BCS1/3 drugs were predominantly related to changes in C-max rather than AUC. C-max changes were typically modest, with minimal clinical significance for most drugs. Overall, drugs with a sharp plasma peak were identified as a key factor in BE failure risk. A new pharmacokinetic term (t1/2C(max)) is proposed to identify drugs at higher risk due to their peak plasma profile shape. In addition, the analysis revealed that weak acids, and drugs with particularly high gastric solubility are potentially more vulnerable to BE failure, particularly when these features are combined with a sharp C-max peak. BCS3 drugs, which are often characterised as being more vulnerable to BE failure due to their potential for permeation and transit to be altered, particularly by excipient change, were not in general at greater risk of BE failures. These findings will help to inform how biowaivers may be optimally applied in the future. (C) 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.