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Research ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac

Tom S. Chan, Hongbin Yu, Amanda Moore, Salman R. Khetani and Donald Tweedie
Drug Metabolism and Disposition December 2013, 41 (12) 2024-2032; DOI: https://doi.org/10.1124/dmd.113.053397
Tom S. Chan
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (T.S.C., H.Y., D.T.); Hepregen Corporation, Medford, Massachusetts (A.M.); and Mechanical and Biomedical Engineering, Colorado State University, Fort Collins, Colorado (S.R.K.)
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Hongbin Yu
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (T.S.C., H.Y., D.T.); Hepregen Corporation, Medford, Massachusetts (A.M.); and Mechanical and Biomedical Engineering, Colorado State University, Fort Collins, Colorado (S.R.K.)
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Amanda Moore
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (T.S.C., H.Y., D.T.); Hepregen Corporation, Medford, Massachusetts (A.M.); and Mechanical and Biomedical Engineering, Colorado State University, Fort Collins, Colorado (S.R.K.)
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Salman R. Khetani
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (T.S.C., H.Y., D.T.); Hepregen Corporation, Medford, Massachusetts (A.M.); and Mechanical and Biomedical Engineering, Colorado State University, Fort Collins, Colorado (S.R.K.)
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Donald Tweedie
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut (T.S.C., H.Y., D.T.); Hepregen Corporation, Medford, Massachusetts (A.M.); and Mechanical and Biomedical Engineering, Colorado State University, Fort Collins, Colorado (S.R.K.)
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This article has corrections. Please see:

  • Correction to “Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac” - January 01, 2014
  • Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac - January 01, 2019

Abstract

Generating accurate in vitro intrinsic clearance data is an important aspect of predicting in vivo human clearance. Primary hepatocytes in suspension are routinely used to predict in vivo clearance; however, incubation times have typically been limited to 4–6 hours, which is not long enough to accurately evaluate the metabolic stability of slowly metabolized compounds. HepatoPac is a micropatterened hepatocyte-fibroblast coculture system that can be used for continuous incubations of up to 7 days. This study evaluated the ability of human HepatoPac to predict the in vivo clearance (CL) of 17 commercially available compounds with low to intermediate clearance (<12 ml/min per kg). In vitro half-life for disappearance of each compound was converted to hepatic clearance using the well stirred model, with and without correction for plasma protein binding. Hepatic CL, using three individual donors, was accurately predicted for 10 of 17 compounds (59%; predicted clearance within 2-fold of observed human in vivo clearance values). The accuracy of prediction increased to 76% (13 of 17 compounds) with an acceptance criterion defined as within 3-fold. When considering only low clearance compounds (<5 ml/min per kg), which represented 10 of the 17 compounds, the accuracy of prediction was 60% within 2-fold and 90% within 3-fold. In addition, the turnover of three slowly metabolized compounds (alprazolam, meloxicam, and tolbutamide) in HepatoPac was directly compared with turnover in suspended hepatocytes. The turnover of alprazolam and tolbutamide was approximately 2-fold greater using HepatoPac compared with suspended hepatocytes, which was roughly in line with the extrapolated values (correcting for the longer incubation time and lower cell number with HepatoPac). HepatoPac, but not suspended hepatocytes, demonstrated significant turnover of meloxicam. These results demonstrate the utility of HepatoPac for prediction of in vivo hepatic clearance, particularly with low clearance compounds.

Footnotes

    • Received June 20, 2013.
    • Accepted August 15, 2013.
  • S.R.K. is an equity holder in Hepregen Corporation.

  • T.S.C. and H.Y. contributed equally to this work.

  • dx.doi.org/10.1124/dmd.113.053397.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (12)
Drug Metabolism and Disposition
Vol. 41, Issue 12
1 Dec 2013
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Research ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

Clearance Prediction Using HepatoPac

Tom S. Chan, Hongbin Yu, Amanda Moore, Salman R. Khetani and Donald Tweedie
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2024-2032; DOI: https://doi.org/10.1124/dmd.113.053397

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Research ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

Clearance Prediction Using HepatoPac

Tom S. Chan, Hongbin Yu, Amanda Moore, Salman R. Khetani and Donald Tweedie
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2024-2032; DOI: https://doi.org/10.1124/dmd.113.053397
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