Application of New Cellular and Microphysiological Systems to Drug Metabolism Optimization and Their Positioning Respective to In Silico Tools

Abstract

New cellular model systems for drug metabolism applications, such as advanced 2D liver co-cultures, spheroids, and microphysiological systems (MPSs), offer exciting opportunities to reproduce human biology more closely in vitro with the aim of improving predictions of pharmacokinetics, drug–drug interactions, and efficacy. These advanced cellular systems have quickly become established for human intrinsic clearance determination and have been validated for several other absorption, distribution, metabolism, and excretion (ADME) applications. Adoption will be driven through the demonstration of clear added value, for instance, by more accurate and precise clearance predictions and by more reliable extrapolation of drug interaction potential leading to faster progression to pivotal proof-of-concept studies. New experimental systems are attractive when they can (1) increase experimental capacity, removing optimization bottlenecks; (2) improve measurement quality of ADME properties that impact pharmacokinetics; and (3) enable measurements to be made that were not previously possible, reducing risk in ADME prediction and candidate selection. As new systems become established, they will find their place in the repository of tools used at different stages of the research and development process, depending on the balance of value, throughput, and cost. In this article, we give a perspective on the integration of these new methodologies into ADME optimization during drug discovery, and the likely applications and impacts on drug development.

Application of the Extended Clearance Classification System (ECCS) in Drug Discovery and Development: Selection of Appropriate In Vitro Tools and Clearance Prediction

“…For compounds with CLint,h ≤ 3 µL/min/10 6 cells in suspended hepatocytes (low clearance), re-assessment of CLint,h using HepatoPac® should be considered to achieve a reasonable IVIVE. With 3 < CLint,h ≤ 30 µL/min/10 6 cells (moderate clearance), CLint,h in suspended hepatocytes can be used for the clearance prediction (Docci et al, 2019). However, it is noted that a >3-fold under-estimation of up-scaled CLint,h,u (mL/min/kg) in hepatocyte suspension relative to the reference in vivo CLint,h,u is likely, when CLint,h is ≤ 10 µL/min/10 6 (Table 2; Figure 3(A)).…”

“…HepatoPac® is an example of a long-term human hepatocyte coculture systems which maintain viability and functional expression of drug metabolizing enzymes for up to seven days and are now well established (Khetani and Bhatia, 2008;Lin and Khetani, 2016), while the other assay approaches as Hurel microliver platform® and relay method are also available (Hultman et al, 2016;Murgasova, 2019). HepatoPac® has been shown to provide improved accuracy and precision of hepatic intrinsic metabolic clearance predictions compared to hepatocytes in monoculture (Kratochwil et al, 2017;Chan et al, 2019;Docci et al, 2019).…”

Using Physicochemical Measurements to Influence Better Compound Design

“…78 Following these principles, driven by judicious predictions in the design phase, will expedite the small-molecule discovery process and lead to improvements at all stages of the process, 106 from less false positives (or negatives) in vitro to better ADME outcomes, 107 fewer developability risks, 97 and better harmonization of in vitro versus in silico data. 108 This will ultimately lead to the progression of compounds into the clinic with better physical properties, which will lead to better predictability of outcomes 109 and, ultimately, a greater chance of success in the costly clinical development phases. The use of predictive physicochemical design is not yet universal in drug discovery, but it is one computational method with tangible and demonstrable impact.…”

Addressing Today’s Absorption, Distribution, Metabolism, and Excretion (ADME) Challenges in the Translation of In Vitro ADME Characteristics to Humans: A Case Study of theSMN2mRNA Splicing Modifier Risdiplam

“…In addition, reduced error in the in vivo intrinsic clearance prediction was observed using the HepatoPac® system when compared with hepatocytes in suspension culture (Umehara et al, 2020). The HepatoPac® long-term incubation system substantially lowers the intrinsic clearance quantification limit to 0.1-0.3 µL/min/million cells (Da-Silva et al, 2018;Docci et al, 2019;Umehara et al, 2020), and this improved sensitivity enabled risdiplam CL int of 0.7 µL/min/million cells to be determined. These data were then scaled to predict the in vivo clearance, the result of which was in excellent agreement (34% higher) with that observed in vivo (Section 4).…”

“…However, these primary cells lose function over a time span of ~4-6 h (Hutzler et al, 2015), and the lower limit of intrinsic clearance measurement is only ~3 µL/min/million cells in suspension culture (Docci et al, 2019).…”