Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Support Waivers of In Vivo Clinical Studies: Current Status, Challenges, and Opportunities

Abstract

Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling has been extensively applied to quantitatively translate in vitro data, predict the in vivo performance, and ultimately support waivers of in vivo clinical studies. In the area of biopharmaceutics and within the context of model-informed drug discovery and development (MID3), there is a rapidly growing interest in applying verified and validated mechanistic PBPK models to waive in vivo clinical studies. However, the regulatory acceptance of PBPK analyses for biopharmaceutics and oral drug absorption applications, which is also referred to variously as “PBPK absorption modeling” [CPT: Pharmacometrics Syst. Pharmacol.20176492], “physiologically based absorption modeling”, or “physiologically based biopharmaceutics modeling” (PBBM), remains rather low [J. Pharm. Sci.20161052723] [AAPS J.20192129]. Despite considerable progress in the understanding of gastrointestinal (GI) physiology, in vitro biopharmaceutic and in silico tools, PBPK models for oral absorption often suffer from an incomplete understanding of the physiology, overparameterization, and insufficient model validation and/or platform verification, all of which can represent limitations to their translatability and predictive performance. The complex interactions of drug substances and (bioenabling) formulations with the highly dynamic and heterogeneous environment of the GI tract in different age, ethnic, and genetic groups as well as disease states have not been yet fully elucidated, and they deserve further research. Along with advancements in the understanding of GI physiology and refinement of current or development of fully mechanistic in silico tools, we strongly believe that harmonization, interdisciplinary interaction, and enhancement of the translational link between in vitro, in silico, and in vivo will determine the future of PBBM. This Perspective provides an overview of the current status of PBBM, reflects on challenges and knowledge gaps, and discusses future opportunities around PBPK/PD models for oral absorption of small and large molecules to waive in vivo clinical studies

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

“…1) Rapid elimination 4,9,29,35 2) Inability of the in-vitro dissolution test to detect in-vivo relevant changes 27 29 3) Changing the levels of absorption modifying excipients in the formulation 28,30,35,36 4) Low permeability 4,14,37 5) Extensive first pass metabolism 9,22 4.1. BE Failures related to peak sharpness (t½Cmax), and gastric solubility In this analysis, drugs were categorised as to whether their t½Cmax was sharp or blunt depending on whether it was greater than or less than 5hrs.…”

“…Recently, an ICH harmonisation process led to globally harmonised guidance for BCS based biowaivers 7 . Although having globally harmonised BCS guidance is a welcome step, concerns have been expressed that the guidance in its current form is overly conservative in some aspects, such as strict dissolution requirements and the strict limits applied to excipient change [8][9][10] . There is therefore scope to improve and expand BCS biowaiver guidance in the future, based upon an improved scientific understanding of specific bioequivalence risks.…”

Proof of Concept in Assignment of Within-Subject Variability During Virtual Bioequivalence Studies: Propagation of Intra-Subject Variation in Gastrointestinal Physiology Using Physiologically Based Pharmacokinetic Modeling

“…While the WSV of some GI tract parameters have been unveiled by specialized studies measuring such parameters in more than one occasion in healthy volunteers (19)(20)(21), the WSV for most of the GI parameters and their co-variations are not known (22). Some investigators have used the conservative approach by assuming the WSV in these parameters to be similar to the respective BSV which can likely be the worst-case scenario in terms of impact of WSV on VBE outcome (3).…”

“…Several reports have highlighted the need for better handling and estimation of WSV (4,12,(22)(23)(24). However, a best practice approach is still lacking while clinical measures of WSV in most GI parameters are unavailable.…”

Developing Clinically Relevant Dissolution Specifications (CRDSs) for Oral Drug Products: Virtual Webinar Series

“…In the period since the first workshop, there has been significant activity in this area, particularly with the application of physiologically based biopharmaceutics modelling (PBBM), to support the development of CRDSs. In addition to publications describing the use of PBBM to support product development [ 2 , 3 , 4 , 5 , 6 ] and continued dialogue between academic, industrial, and regulatory scientists [ 7 , 8 , 9 ], the FDA has published a Draft Guidance document on the use of physiologically based pharmacokinetic (PBPK) analyses to support oral drug product development, manufacturing changes, and controls [ 10 ]. The aim of the 2021 webinar series was to continue the dialogue from the previous workshop and share and discuss progress and challenges through scientific presentations and Q&A sessions.…”