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Research ArticleArticle

Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Inhibition and Biomarker Modulation by the Novel Phosphatidylinositol 3-Kinase Inhibitor GDC-0941

Laurent Salphati, Harvey Wong, Marcia Belvin, Delia Bradford, Kyle A. Edgar, Wei Wei Prior, Deepak Sampath and Jeffrey J. Wallin
Drug Metabolism and Disposition September 2010, 38 (9) 1436-1442; DOI: https://doi.org/10.1124/dmd.110.032912
Laurent Salphati
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Harvey Wong
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Marcia Belvin
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Delia Bradford
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Kyle A. Edgar
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Wei Wei Prior
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Deepak Sampath
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Jeffrey J. Wallin
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Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is a major determinant of cell cycling and proliferation. Its deregulation, by activation or transforming mutations of the p110α subunit, is associated with the development of many cancers. 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) is a novel small molecule inhibitor of PI3K currently being evaluated in the clinic as an anticancer agent. The objectives of these studies were to characterize the relationships between GDC-0941 plasma concentrations and tumor reduction in MCF7.1 breast cancer xenografts and to evaluate the association between the tumor pharmacodynamic biomarker [phosphorylated (p) Akt and phosphorylated proline-rich Akt substrate of 40 kDa (pPRAS40)] responses and antitumor efficacy. MCF7.1 tumor-bearing mice were treated for up to 3 weeks with GDC-0941 at various doses (12.5–200 mg/kg) and dosing schedules (daily to weekly). An indirect response model fitted to tumor growth data indicated that the GDC-0941 plasma concentration required for tumor stasis was approximately 0.3 μM. The relationship between GDC-0941 plasma concentrations and inhibition of pAkt and pPRAS40 in tumor was also investigated after a single oral dose of 12.5, 50, or 150 mg/kg. An indirect response model was fitted to the inhibition of Akt and PRAS40 phosphorylation data and provided IC50 estimates of 0.36 and 0.29 μM for pAkt and pPRAS40, respectively. The relationship between pAkt inhibition and tumor volume was further explored using an integrated pharmacokinetic biomarker tumor growth model, which showed that a pAkt inhibition of at least 30% was required to achieve stasis after GDC-0941 treatment of the MCF7.1 xenograft.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.032912.

  • ABBREVIATIONS:

    PI3K
    phophatidylinositol 3-kinase
    PRAS40
    proline-rich Akt substrate of 40kDa
    mTor
    mammalian target of rapamycin
    XL147
    N-(3-(benzo[c][1,2,5]thiadiazol-5-ylamino)quinoxalin-2-yl)-4-methylbenzenesulfonamide
    BKM120
    5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine
    GSK1059615
    (Z)-5-((4-(pyridin-4-yl)quinolin-6-yl)methylene)thiazolidine-2,4-dione
    GDC-0941
    2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
    PK
    pharmacokinetic
    PD
    pharmacodynamic
    MCT
    0.5% methylycellulose/0.2% Tween 80
    TGI
    tumor growth inhibition
    TV
    tumor volume
    p
    phosphorylated
    PF02341066
    (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine.

  • Received February 23, 2010.
  • Accepted June 10, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (9)
Drug Metabolism and Disposition
Vol. 38, Issue 9
1 Sep 2010
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Research ArticleArticle

Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Inhibition and Biomarker Modulation by the Novel Phosphatidylinositol 3-Kinase Inhibitor GDC-0941

Laurent Salphati, Harvey Wong, Marcia Belvin, Delia Bradford, Kyle A. Edgar, Wei Wei Prior, Deepak Sampath and Jeffrey J. Wallin
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1436-1442; DOI: https://doi.org/10.1124/dmd.110.032912

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Research ArticleArticle

Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Inhibition and Biomarker Modulation by the Novel Phosphatidylinositol 3-Kinase Inhibitor GDC-0941

Laurent Salphati, Harvey Wong, Marcia Belvin, Delia Bradford, Kyle A. Edgar, Wei Wei Prior, Deepak Sampath and Jeffrey J. Wallin
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1436-1442; DOI: https://doi.org/10.1124/dmd.110.032912
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