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Research ArticleArticle

Learning and Confirming with Preclinical Studies: Modeling and Simulation in the Discovery of GDC-0917, an Inhibitor of Apoptosis Proteins Antagonist

Harvey Wong, Stephen E. Gould, Nageshwar Budha, Walter C. Darbonne, Edward E. Kadel III, Hank La, Bruno Alicke, Jason S. Halladay, Rebecca Erickson, Chia Portera, Anthony W. Tolcher, Jeffery R. Infante, Michael Mamounas, John A. Flygare, Cornelis E. C. A. Hop and Wayne J. Fairbrother
Drug Metabolism and Disposition December 2013, 41 (12) 2104-2113; DOI: https://doi.org/10.1124/dmd.113.053926
Harvey Wong
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Stephen E. Gould
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Nageshwar Budha
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Walter C. Darbonne
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Edward E. Kadel III
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Hank La
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Bruno Alicke
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Jason S. Halladay
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Rebecca Erickson
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Chia Portera
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Anthony W. Tolcher
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Jeffery R. Infante
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Michael Mamounas
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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John A. Flygare
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Cornelis E. C. A. Hop
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Wayne J. Fairbrother
Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.)
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Abstract

The application of modeling and simulation techniques is increasingly common in the preclinical stages of the drug development process. GDC-0917 [(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-(2-(oxazol-2-yl)-4-phenylthiazol-5-yl)pyrrolidine-2-carboxamide] is a potent second-generation antagonist of inhibitor of apoptosis (IAP) proteins that is being developed for the treatment of various cancers. GDC-0917 has low to moderate clearance in the mouse (12.0 ml/min/kg), rat (27.0 ml/min/kg), and dog (15.3 ml/min/kg), and high clearance in the monkey (67.6 ml/min/kg). Accordingly, oral bioavailability was lowest in monkeys compared with other species. Based on our experience with a prototype molecule with similar structure, in vitro–in vivo extrapolation was used to predict a moderate clearance (11.5 ml/min/kg) in humans. The predicted human volume of distribution was estimated using simple allometry at 6.69 l/kg. Translational pharmacokinetic-pharmacodynamic (PK-PD) analysis using results from MDA-MB-231-X1.1 breast cancer xenograft studies and predicted human pharmacokinetics suggests that ED50 and ED90 targets can be achieved in humans using acceptable doses (72 mg and 660 mg, respectively) and under an acceptable time frame. The relationship between GDC-0917 concentrations and pharmacodynamic response (cIAP1 degradation) was characterized using an in vitro peripheral blood mononuclear cell immunoassay. Simulations of human GDC-0917 plasma concentration-time profile and cIAP1 degradation at the 5-mg starting dose in the phase 1 clinical trial agreed well with observations. This work shows the importance of leveraging information from prototype molecules and illustrates how modeling and simulation can be used to add value to preclinical studies in the early stages of the drug development process.

Footnotes

    • Received July 28, 2013.
    • Accepted September 16, 2013.
  • dx.doi.org/10.1124/dmd.113.053926.

  • 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 ArticleArticle

Preclinical Modeling and Simulation of GDC-0917

Harvey Wong, Stephen E. Gould, Nageshwar Budha, Walter C. Darbonne, Edward E. Kadel, Hank La, Bruno Alicke, Jason S. Halladay, Rebecca Erickson, Chia Portera, Anthony W. Tolcher, Jeffery R. Infante, Michael Mamounas, John A. Flygare, Cornelis E. C. A. Hop and Wayne J. Fairbrother
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2104-2113; DOI: https://doi.org/10.1124/dmd.113.053926

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Research ArticleArticle

Preclinical Modeling and Simulation of GDC-0917

Harvey Wong, Stephen E. Gould, Nageshwar Budha, Walter C. Darbonne, Edward E. Kadel, Hank La, Bruno Alicke, Jason S. Halladay, Rebecca Erickson, Chia Portera, Anthony W. Tolcher, Jeffery R. Infante, Michael Mamounas, John A. Flygare, Cornelis E. C. A. Hop and Wayne J. Fairbrother
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2104-2113; DOI: https://doi.org/10.1124/dmd.113.053926
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