Improving Prediction of Metabolic Clearance Using Quantitative Extrapolation of Results Obtained From Human Hepatic Micropatterned Cocultures Model and by Considering the Impact of Albumin Binding

Da-Silva, Franck; Boulenc, Xavier; Vermet, Hélène; Compigne, Pauline; Gerbal‐Chaloin, Sabine; Daujat-Chavanieu, Martine; Klieber, Sylvie; Poulin, Patrick

doi:10.1016/j.xphs.2018.03.001

Cited by 32 publications

(29 citation statements)

References 56 publications

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“…To apply this methodology to different experimental procedures with varied albumin concentrations, the PLR value can be changed to the actual concentration ratio of HSA in the buffer/plasma/perfusate and the organ material, and if an assay has albumin at a similar level to that in vivo , the PLR should be 1 (Poulin and Haddad, 2015). This has recently been confirmed to improve prediction accuracy for naproxen and bisphenol A in isolated perfused rat livers with different albumin concentrations (Bounakta et al, 2018; Poulin et al, 2017) and in the HepatoPac ® system with 25 compounds (Da-Silva et al, 2018).…”

Section: Protein Facilitated Uptakementioning

confidence: 76%

“…The PLR values mentioned earlier are for protein-free incubations, where it is assumed that protein-facilitated uptake is not occurring, and “the CL int determined in vitro should represent only a measure of the hepatic uptake of the free drug moiety by contrast to the in vivo condition in liver where the bound drug moiety is also assumed to be available for uptake” (Da-Silva et al, 2018). To apply this methodology to different experimental procedures with varied albumin concentrations, the PLR value can be changed to the actual concentration ratio of HSA in the buffer/plasma/perfusate and the organ material, and if an assay has albumin at a similar level to that in vivo , the PLR should be 1 (Poulin and Haddad, 2015).…”

Section: Protein Facilitated Uptakementioning

confidence: 99%

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An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation

Bowman

Benet

2018

European Journal of Pharmaceutical Sciences

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As explained by the free drug theory, the unbound fraction of drug has long been thought to drive the efficacy of a molecule. Thus, the fraction unbound term, or f, appears in equations for fundamental pharmacokinetic parameters such as clearance, and is used when attempting in vitro to in vivo extrapolation (IVIVE). In recent years though, it has been noted that IVIVE does not always yield accurate predictions, and that some highly protein bound ligands have more efficient uptake than can be explained by their unbound fractions. This review explores the evolution of f terms included when implementing IVIVE, the concept of protein-facilitated uptake, and the mechanisms that have been proposed to account for facilitated uptake.

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Section: Protein Facilitated Uptakementioning

confidence: 76%

Section: Protein Facilitated Uptakementioning

confidence: 99%

An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation

Bowman

Benet

2018

European Journal of Pharmaceutical Sciences

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“…37 The long-term hepatocyte co-cultures also have the advantage that a broader range of intrinsic clearance values can be determined, with accurate measurement down to ~0.2 µL/min/10 6 cells, approximately 10-fold lower than attained in classical suspension culture experiments. 14 A comprehensive study by Da-Silva et al showed the benefit of long-term co-cultures in human clearance prediction: 38 Using the same batch of primary human hepatocyte cells, they determined the intrinsic clearances for 15 drugs in suspension, monolayer, and HepatoPac cultures. Here the HepatoPac system clearly outperformed the other culture systems in prediction accuracy.…”

Section: Clearance Determination For High-stability Compoundsmentioning

confidence: 99%

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

et al. 2019

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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.

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“…They reported that CL int, in vitro estimated using the relay method showed excellent predictions of human CL int, in vivo . Further, novel in vitro systems such as HepatoPac 44,45) and HμREL, 46,47) which are micropatterned hepatocyte coculture systems, and cell systems such as upcyte, 48) which is derived from human hepatocytes, have been used to estimate low CL int, in vitro and predict in vivo CL in humans.…”

Section: Prediction Of Human Pk Using Ivivementioning

confidence: 99%

Utility of Chimeric Mice with Humanized Liver for Predicting Human Pharmacokinetics in Drug Discovery: Comparison with <i>in Vitro</i>–<i>in Vivo</i> Extrapolation and Allometric Scaling

Naritomi

Sanoh

Ohta

2019

Biological & Pharmaceutical Bulletin

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Predicting human pharmacokinetics (PK) such as clearance (CL) and volume of distribution (Vd) is a critical component of drug discovery. These predictions are mainly performed by in vitro-in vivo extrapolation (IVIVE) using human biological samples, such as hepatic microsomes and hepatocytes. However, some issues with this process have arisen, such as inconsistencies between in vitro and in vivo findings; the integration of predicted CYP, non-CYP and transporter-mediated human PK; and the difficulty of evaluating very metabolically stable compounds. Various approaches to solving these issues have been reported. Allometric scaling using experimental animals has also often been used. However, this method has also shown many problems due to interspecies differences, albeit that various correction methods have been proposed. Another approach involves the production of chimeric mice with humanized liver via the transplantation of human hepatocytes into mice. The livers of these mice are repopulated mostly with human hepatocytes and express human drug-metabolizing enzymes and drug transporters, suggesting that these mice are useful for solving the issues of IVIVE and allometric scaling, and more reliably predicting human PK. In this review, we summarize human PK prediction methods using IVIVE, allometric scaling and chimeric mice with humanized liver, and discuss the utility of predicting human PK in drug discovery by comparing these chimeric mice with IVIVE and allometric scaling.

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Improving Prediction of Metabolic Clearance Using Quantitative Extrapolation of Results Obtained From Human Hepatic Micropatterned Cocultures Model and by Considering the Impact of Albumin Binding

Cited by 32 publications

References 56 publications

An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation

An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation

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

Utility of Chimeric Mice with Humanized Liver for Predicting Human Pharmacokinetics in Drug Discovery: Comparison with <i>in Vitro</i>–<i>in Vivo</i> Extrapolation and Allometric Scaling

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