In Vitro–In Vivo Correlation for Low-Clearance Compounds Using Hepatocyte Relay Method

Di, Li; Atkinson, Karen; Orozco, Christine C.; Funk, Carrie; Zhang, Hui; McDonald, Thomas S.; Tan, Beijing; Lin, Jian; Chang, Cheng; Obach, R. Scott

doi:10.1124/dmd.113.053322

Cited by 57 publications

(58 citation statements)

References 39 publications

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“…The in vitro clearances were then scaled by applying the well-stirred model using the conventional approach as described in BMATERIALS AND METHODS^(Eqs. [8][9][10][11][12]. Fraction unbound values in the incubation media and human plasma were experimentally determined and are listed in Table III together with the blood-to-plasma ratios.…”

Section: Resultsmentioning

confidence: 99%

“…[8][9][10][11][12][13][14][15][16]. For that, the fractions unbound in the incubation media and human plasma were experimentally determined and are listed in Table III together with the blood-to-plasma ratios.…”

Section: Ivive Of In Vitro Clearance Assessmentsmentioning

confidence: 99%

“…For example, models where the metabolic activity is prolonged for up to 2-4 weeks can extend the sensitive range for clearance determination. Longterm in vitro liver models, such as the hepatic stem cell line HepaRG™ (6), micropatterned HepatoPac® co-cultures of human hepatocytes with mouse embryonic 3T3 fibroblasts cells (7), and HμREL™ hepatocyte/fibroblast co-culture plates (8), as well as alternative approaches for low clearance determination, such as the relay method with suspension hepatocyte cultures (9), are being intensively explored. Chan et al (10) studied the Christophe Meille was a Roche employee during the conduct of this research.…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Profiling of Human Long-Term Liver Models and Hepatic Clearance Predictions from In Vitro Data Using Nonlinear Mixed-Effects Modeling

Kratochwil

Meille

Fowler

et al. 2017

AAPS J

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ABSTRACT.Early prediction of human clearance is often challenging, in particular for the growing number of low-clearance compounds. Long-term in vitro models have been developed which enable sophisticated hepatic drug disposition studies and improved clearance predictions. Here, the cell line HepG2, iPSC-derived hepatocytes (iCell®), the hepatic stem cell line HepaRG™, and human hepatocyte co-cultures (HμREL™ and HepatoPac®) were compared to primary hepatocyte suspension cultures with respect to their key metabolic activities. Similar metabolic activities were found for the long-term models HepaRG™, HμREL™, and HepatoPac® and the short-term suspension cultures when averaged across all 11 enzyme markers, although differences were seen in the activities of CYP2D6 and non-CYP enzymes. For iCell® and HepG2, the metabolic activity was more than tenfold lower. The micropatterned HepatoPac® model was further evaluated with respect to clearance prediction. To assess the in vitro parameters, pharmacokinetic modeling was applied. The determination of intrinsic clearance by nonlinear mixed-effects modeling in a long-term model significantly increased the confidence in the parameter estimation and extended the sensitive range towards 3% of liver blood flow, i.e., >10-fold lower as compared to suspension cultures. For in vitro to in vivo extrapolation, the well-stirred model was used. The micropatterned model gave rise to clearance prediction in man within a twofold error for the majority of low-clearance compounds. Further research is needed to understand whether transporter activity and drug metabolism by non-CYP enzymes, such as UGTs, SULTs, AO, and FMO, is comparable to the in vivo situation in these long-term culture models.KEY WORDS: in vitro clearance; in vitro liver models; IVIVE; nonlinear mixed-effects modeling.

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Section: Resultsmentioning

confidence: 99%

Section: Ivive Of In Vitro Clearance Assessmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metabolic Profiling of Human Long-Term Liver Models and Hepatic Clearance Predictions from In Vitro Data Using Nonlinear Mixed-Effects Modeling

Kratochwil

Meille

Fowler

et al. 2017

AAPS J

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“…2. IVIVC in Human, rat, and dog using the hepatocyte relay method (12,13). Open circles represent compounds having significant contribution of extra-hepatic metabolism or transporter-mediated clearance clearance pathway, since there was no turnover of the compound in the standard human liver microsome or hepatocyte suspension assays.…”

Section: Hepatocyte Relay Methodsmentioning

confidence: 99%

“…The assay has a straightforward format and can be utilized by typical drug metabolism laboratories with a minimal cost. The hepatocyte relay method is being used for intrinsic clearance determination (12,13) and metabolite identification (14) for humans and laboratory animal species. The method has been developed to conduct reaction phenotyping experiments with Transfer Supernatant Fig.…”

Section: Hepatocyte Relay Methodsmentioning

confidence: 99%

Addressing the Challenges of Low Clearance in Drug Research

Obach

2015

AAPS J

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Abstract. As a result of high-throughput ADME screening, early metabolite identification, and exploration of novel chemical entities, low-intrinsic-clearance compounds continue to increase in drug discovery portfolios. Currently available in vitro tools have limited resolution below a certain intrinsic clearance value, which can lead to overestimation of clearance and dose and underestimation of half-life. Significant advances have been made in recent years and novel approaches have been developed to address the challenges of low clearance in drug discovery, such as the hepatocyte relay method, use of qNMR-based standards of biosynthesized drug metabolites to permit monitoring metabolite formation, coculture hepatocyte systems, and the time depending modeling approach. Future development in the field will enable faster, more precise, and lower cost profiling of the properties of low-clearance compounds for intrinsic clearance, metabolite identification, and reaction phenotyping.

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ADMETInVitroProfiling – Utility and Applications in Lead Discovery

Kerns

Zhang²,

2021

Burger's Medicinal Chemistry and Drug Discovery

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In Vitro–In Vivo Correlation for Low-Clearance Compounds Using Hepatocyte Relay Method

Cited by 57 publications

References 39 publications

Metabolic Profiling of Human Long-Term Liver Models and Hepatic Clearance Predictions from In Vitro Data Using Nonlinear Mixed-Effects Modeling

Metabolic Profiling of Human Long-Term Liver Models and Hepatic Clearance Predictions from In Vitro Data Using Nonlinear Mixed-Effects Modeling

Addressing the Challenges of Low Clearance in Drug Research

ADMETInVitroProfiling – Utility and Applications in Lead Discovery

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