Scientific considerations to move towards biowaiver for biopharmaceutical classification system class III drugs: How modeling and simulation can help

Abstract

The 2017 Guidance by U.S. Food and Drug Administration (FDA) has recommended the criteria to qualify for a Biopharmaceutical Classification System (BCS)-based biowaiver that includes high solubility of the drug across the physiological pH range as well as the formulation considerations, e.g., being qualitatively the same and quantitatively very similar to the reference product. These were ratified by the International Council for Harmonization (ICH) in 2018. The FDA has used the similar verbiage when referring to the BCS-based biowaiver option for BCS class III drugs (highly soluble but poorly permeable). However, establishing in vitro-in vivo correlations (IVIVC) using conventional mass balance deconvolution approaches, which assumes a single absorption compartment, is not likely for very rapidly dissolving dosage forms containing BCS III drugs. Unlike conventional mass balance deconvolution techniques, physiologically based pharmacokinetic models are able to disentangle different processes contributing to the input function, e.g., dissolution, gastrointestinal transit, and permeation and to establish IVIVC using variants of the compartmental absorption and transit model, supporting biowaiver for formulations containing BCS III drugs. However, there are knowledge gaps that need to be filled.This review provides a systematic assessment of the advancements in applications of physiologically based pharmacokinetic (PBPK) models for IVIVC and biowaiver for such cases with the aim of identifying the most important gaps and hurdles. It concludes by calling for research efforts on the impact of excipients on dissolution and permeation, alongside the development of PBPK modeling to link these in vitro characteristics to in vivo bioequivalence outcomes through simulations of virtual clinical studies

Regulatory utility of physiologically‐based pharmacokinetic modeling to support alternative bioequivalence approaches and risk assessment: A workshop summary report

“…Considering the above challenges, research opportunities related to oral PBPK modeling have been conducted through both internal and external projects and resulted in several publications. [5][6][7][8] She concluded her presentation by encouraging generic pharmaceutical industry to submit alternative BE proposals with modeling and simulation data and to hold early discussions with the Agency via pre-ANDA meeting and controlled correspondences.…”

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

“…PBBM can be used in the justification and setting of clinically relevant dissolution specifications through the establishment of a dissolution safe space, within which in vitro dissolution changes have no detrimental impact on in vivo performance, or by establishing an edge of failure beyond which changes in in vitro dissolution have an unacceptable impact on PK. Coupling such approaches with virtual bioequivalence analysis (VBE) [ 18 , 19 ] can be used to obtain biowaivers for generic products or used by originators during product development, for example, to assess impact after scale-up and post-approval changes (SUPAC), or changes in supplier or grade of excipients. Best practice guidelines for wider PBPK applications beyond the biopharmaceutic area have been published [ 20 ], and there is recent interest in the setting of best practice guidelines for PBPK modelling in the biopharmaceutic area [ 10 , 21 ].…”

“…An inherent requirement to demonstrate BE, or non-bioequivalence, using widely applied crossover studies, is to be able to handle both between-subject (population) variability and within-subject variability (BSV and WSV, respectively) of PK (FDA Guidance, 2003 and 2021, for example). WSV is also often referred to as inter-occasion variability (IOV) or intrasubject variability; Wu et al (2021) [ 19 ] provide a discussion of the nuances of these terms.…”

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

“…Although no trend to an increased risk of inequivalence is seen in our assessment, the oral absorption of poorly permeable BCS 3 drugs is complex, with a stronger dependence on transit time and GI region dependent permeability than for highly permeable drugs due to slower absorption being spread over a larger proportion of the GI tract. Given this complexity, physiologically based pharmacokinetic modelling (PBPK) may be especially useful in determining factors influencing their absorption and therefore could prove to be an invaluable tool for future assessment of excipient change on pharmacokinetic performance 73 .…”