A Model Mechanism Based Explanation of an In Vitro-In Vivo Disconnect for Improving Extrapolation and Translation

Smith, Andrew; Xu, Yanli; Ropella, Glen E. P.; Hunt, C. Anthony

doi:10.1101/216556

Cited by 2 publications

(9 citation statements)

References 21 publications

(24 reference statements)

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“…Results are presented from two vMouse and four vCulture experiments, each using 6 MC trials. For the two vMouse experiments, the first order "absorption" into Body and the transfer rate from Body to PV (maps to hepatic blood flow) are the same as in Smith et al (2016Smith et al ( , 2018 [7,3]. At the start of vCulture experiments, the Dose is introduced to Media Space using a rapid and prolonged process.…”

Section: Resultsmentioning

confidence: 99%

“…Verification of Translational Requirement 5 necessitated improving the vCulture architectures used previously [3,5]. To improve the credibility of current and future vCulture ⇔ vMouse translation experiments, we also made the vMouse architecture more physiomimetic.…”

Section: Virtual Liver and Virtual Componentsmentioning

confidence: 99%

“…Petersen et al (2016) used an early version of a vCulture to explore and challenge mechanismbased hypotheses about immune-mediated P450 down-regulation in vitro [5]. Smith et al (2018) used and updated, more biomimetic vCulture to demonstrate describe a virtual counterpart of an in vivo-in vitro disconnect [3]. For this work we use the enhanced version of their vCulture illustrated in Fig.…”

Section: Virtual Culturementioning

confidence: 99%

“…An improved understanding of in vivo ⇔ in vitro changes is crucial to interpreting in vitro data correctly and further improving hepatocyte-based IVIVEs to human targets. We argue that the vCulture ⇔ vMouse approach described by Smith et al (2018) can be used to identify and mitigate factors contributing to IVIVE inaccuracies in predicting the hepatic clearance of substances [3]. Credible applications of that approach will depend on evidence demonstrating that six translational requirements have been achieved.…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, it is well-understood that a major cause of these IVIVE disconnects is entanglement of different methodological and biological factors [2]. Smith et al (2018) suggest identifying factors contributing to and subsequently bridging IVIVE disconnects by instantiating then experimenting on concrete and scientifically challengeable model Mechanisms within validated virtual culture and virtual mouse contexts [3]. To distinguish virtual mouse and culture components, characteristics, and phenomena from real counterparts, we capitalize the former hereafter and, in several cases, append the prefix "v".…”

Section: Introductionmentioning

confidence: 99%

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Hepatocyte Organization Affects the Translation of Clearance from In Vitro to In Vivo

Dutta

Krishnan

Smith

et al.

EPiC Series in Computing

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An improved understanding of in vivo ⇔ in vitro changes is crucial in identifying and mitigating factors contributing to in vitro–in vivo extrapolation (IVIVE) inaccuracies in predicting the hepatic clearance of substances. We argue that a model mechanism-based virtual culture (vCulture) ⇔ virtual mouse (vMouse) (or vRat or vHuman) experiment approach can identify factors contributing to IVIVE disconnects. Doing so depends on having evidence that six Translational Requirements have been achieved. We cite evidence that the first four have been achieved. The fifth Requirement is that differences in measures of vCompound disposition between vCulture and vMouse are attributable solely to the micro-architectural, physiomimetic features, and uncertainties built into the vLiver and vMouse but are absent from the vCulture. The objective of this work is to first improve on a vCulture architecture used previously and then use results of virtual experiments to verify that its use enables the fifth Translational Requirement to be achieved. We employ two different idealized vCompounds, which map to highly permeable real compounds at the extreme ends of the intrinsic clearance spectrum. Virtual intrinsic clearance = Exposure rate per vHPC. At quasi-steady state, results for vCompound-1 are independent of the dosing rate. The average per-vHPC Exposure rates (taken over the whole vLiver in vMouse experiments) are the same (within the variance of the Experiments) as those in vCulture. However, they are location dependent within the vLiver. For vCompound-2, there are dosing rate differences and average per-vHPC Exposure rates within the vLiver are also location dependent. When we account for dosing rate differences, we see again that average per-vHPC Exposure rates averaged over the whole vLiver in vMouse experiments are the same as those in vCulture. Thus, the differences in per vHPC Exposure rate within the vLiver for both vCompounds are attributable solely to the micro-architectural and physiomimetic features built into the vLiver and vMouse but are absent from the vCulture. The results verify that the fifth Translational Requirement has been achieved.

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Section: Resultsmentioning

confidence: 99%

Section: Virtual Liver and Virtual Componentsmentioning

confidence: 99%

Section: Virtual Culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatocyte Organization Affects the Translation of Clearance from In Vitro to In Vivo

Dutta

Krishnan

Smith

et al.

EPiC Series in Computing

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Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-in vivo predictions of hepatic clearance

Krishnan¹,

Smith²,

Ropella

et al. 2020

Preprint

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We demonstrate how results of virtual experiments can suggest mechanism-based explanations for IVIVE underpredictions of hepatic clearance. We use agent-oriented, discrete-event methods. We experiment on software analogies of rats and hepatocyte cultures dosed identically with objects that mimic two idealized compounds, vC1 (not cleared) and vC2 (removal maximized). Hepatocytes in cultures and rat livers interact identically with vC1 and vC2. The rules governing vC1 and vC2 movements and interactions with hepatocytes are the same in both systems. The two software systems are independent; to be useful in discovering plausible explanations of IVIVE inaccuracies, we require that, in the absence of hepatocyte exposure differences, the culture-to-rat scaling factor = 1.0 for all corresponding measures. The probability of cell entry (pEnter) maps directly to the unbound-fraction of drug used by IVIVE methods. For vC1 (vC2), we achieve that validation target for pEnter = 0.05-1.0 (1.0). However, for pEnter = 0.05-0.8, vC2 removal rates during culture experiments underpredicted corresponding removal rates in rats. The magnitude of the underpredictions increases with decreasing pEnter. For example, using pEnter = 0.1 (0.3), peak vC2 removal rates in culture experiments underpredict corresponding removal rates in rats by 3.2 (1.4) fold. Underpredictions are a consequence of the biomimetic periportal-to-pericentral organization of hepatocytes within virtual livers are absent in virtual cultures. In rats, pericentral hepatocytes do more of the vC2 removal work. The results suggest that using IVIVE methods that abstract away influential features of hepatocyte organization within livers may contribute to IVIVE underpredictions.Significance StatementFrom experiments on virtual (software) counterparts of rats and hepatocyte cultures, we learned that IVIVE underpredictions are a consequence of the biomimetic periportal-to-pericentral organization of hepatocytes within virtual livers being absent in virtual cultures. Using IVIVE methods that abstract away influential features of hepatocyte organization within livers may contribute in part to some IVIVE underpredictions.Visual Abstract

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A Model Mechanism Based Explanation of an In Vitro-In Vivo Disconnect for Improving Extrapolation and Translation

Cited by 2 publications

References 21 publications

Hepatocyte Organization Affects the Translation of Clearance from In Vitro to In Vivo

Hepatocyte Organization Affects the Translation of Clearance from In Vitro to In Vivo

Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-in vivo predictions of hepatic clearance

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