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Research ArticleArticle

Physiologically Based Pharmacokinetic Models Can Be Used to Predict the Unique Nonlinear Absorption Profiles of Vismodegib

Louis Lin, Matthew R. Wright, Cornelis E.C.A. Hop and Harvey Wong
Drug Metabolism and Disposition September 2022, 50 (9) 1170-1181; DOI: https://doi.org/10.1124/dmd.122.000885
Louis Lin
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (L.L., H.W.) and Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (M.R.W., C.E.C.A.H.)
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Matthew R. Wright
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (L.L., H.W.) and Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (M.R.W., C.E.C.A.H.)
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Cornelis E.C.A. Hop
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (L.L., H.W.) and Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (M.R.W., C.E.C.A.H.)
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Harvey Wong
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (L.L., H.W.) and Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (M.R.W., C.E.C.A.H.)
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Abstract

Predicting human pharmacokinetics (PK) during the drug discovery phase is valuable to assess doses required to reach therapeutic exposures. For orally administered compounds, however, this can be especially difficult, since the absorption process is complex. Vismodegib is a compound with unique nonlinear oral PK characteristics in humans. Oral physiologically based pharmacokinetic (PBPK) models were built using preclinical in vitro and in vivo data and successfully predicted the oral PK profiles in rats, dogs, and monkeys. Simulated drug exposures (area under the concentration-time curve from time 0 to infinity and Cmax) following oral administration were within twofold of observed values for dogs and monkeys, and close to twofold for rats, providing validation to the model structure. Adaptation of this oral PBPK model to humans, using human physiologic parameters coupled with predicted human PK, resulted in underpredictions of vismodegib exposure following both single and multiple doses. When observed human PK was used to drive the oral PBPK model, oral PK profiles in humans were well predicted, with fold errors in predicted versus observed drug exposures being close to 1. Importantly, the oral PBPK model captured the unique nonlinear, nondose-dependent PK of vismodegib at a steady state. The mechanism responsible for nonlinearity was consistent with oral absorption being influenced by nonsink permeation conditions. We introduce a new parameter, the permeation gradient factor, to characterize the effect of nonsink conditions on permeation. Using vismodegib as an example, we demonstrate the value of using oral PBPK models in drug discovery to predict the oral PK of compounds with nonlinear absorption characteristics in human.

SIGNIFICANCE STATEMENT A physiologically based pharmacokinetic (PBPK) model was built to demonstrate the value of these models early in the drug discovery stage for the prediction of human pharmacokinetics for compounds with unusual oral pharmacokinetics. In this study, our PBPK model could successfully capture the unique steady-state oral pharmacokinetics of our model compound, vismodegib. The mechanism for nonlinearity can be attributed to nonsink permeation conditions in vivo. We introduce the permeation gradient factor as a parameter to assess this effect.

Footnotes

    • Received March 2, 2022.
    • Accepted June 23, 2022.
  • This work was performed under a research collaboration and by Genentech, Inc and UBC.

  • H.W. is an employee of the University of British Columbia and is a consultant for Genentech. M.R.W. and C.E.C.A.H. are employees of Genentech.

  • dx.doi.org/10.1124/dmd.122.000885.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (9)
Drug Metabolism and Disposition
Vol. 50, Issue 9
1 Sep 2022
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Research ArticleArticle

Oral PBPK Modeling of Vismodegib

Louis Lin, Matthew R. Wright, Cornelis E.C.A. Hop and Harvey Wong
Drug Metabolism and Disposition September 1, 2022, 50 (9) 1170-1181; DOI: https://doi.org/10.1124/dmd.122.000885

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Research ArticleArticle

Oral PBPK Modeling of Vismodegib

Louis Lin, Matthew R. Wright, Cornelis E.C.A. Hop and Harvey Wong
Drug Metabolism and Disposition September 1, 2022, 50 (9) 1170-1181; DOI: https://doi.org/10.1124/dmd.122.000885
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