Virtual Bioequivalence - New Developments, Applications and Pitfalls

The impact and acceptance of Physiologically-Based Pharmacokinetic (PBPK) modelling is growing strongly within the pharmaceutical industry, and such model informed approaches are increasingly advocated by regulatory agencies to help streamline drug product development. PBPK modelling, or Physiologically-Based Biopharmaceutics modelling (PBBM) as it is sometimes referred to, of new drugs (both during development or post-approval (eg SUPAC)) and generics has demonstrated value in saving time and budget, while strengthening internal decision-making. PBPK models/PBBM with built-in Virtual Bioequivalence (VBE) analysis tools are now available and have been used to waive a number of clinical BE studies.

The novel VBE tools currently available require integrated systems information regarding between (inter) and within (intra) subject variability (BSV and WSV respectively) of relevant physiological parameters preferably including their covariation. Such tools, coupled to appropriate mechanistic models, enable the propagation of physiological BSV and WSV of luminal pH, fluid volumes, bile salt concentration, gastric emptying etc. to the BSV/WSV of BE PK endpoints (AUC, Cmax). For VBE analysis, this approach reduces both the associated assumptions and the need to apply WSV derived from prior clinical BE studies but at the same time raises issues in relation to knowing the BSV/WSV and covariation of all required physiological parameters. However, many, but not all, of these values are now being collected and added to the PBPK model "Systems" information whence the values can be readily applied as required. Consideration of the necessity for and benefits of mechanistic models of dissolution, solubilisation, and permeation within the gut will be discussed. This relates both to the need for models sensitive to BSV/WSV of physiology in order to propagate this to simulation outcomes and to introducing connectivity between parameters such that, for example, an individual with high luminal fluid volume relative to other subjects may, through dilution effects, also have reduced bile salt concentration or increased bulk fluid pH. This approach then begins to address the covariation of gut physiological parameters for which knowledge is limited but which ultimately is crucial for realistic PBPK simulations of clinical trials including VBE analyses. The presentation will briefly touch on best practice for developing robust PBPK and VBE analyses including potential pitfalls and limitations.