Bridging the Gap between Preclinical and Clinical Studies Using Pharmacokinetic–Pharmacodynamic Modeling: An Analysis of GDC-0973, a MEK Inhibitor
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- Harvey Wong
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Laurent Vernillet
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Amy Peterson
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Joseph A. Ware
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Lillian Lee
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Jean-Francois Martini
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Peiwen Yu
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Congfen Li
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Geoffrey Del Rosario
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Edna F. Choo
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Klaus P. Hoeflich
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Yongchang Shi
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Blake T. Aftab
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Ron Aoyama
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Sanh Tan Lam
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- Marcia Belvin
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
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- John Prescott
- Authors' Affiliations: Departments of 1Drug Metabolism and Pharmacokinetics, 2Clinical Pharmacology, 3Exploratory Clinical Development, and 4Cell Signaling Pathways, Genentech Inc.; and 5Exelixis, South San Francisco, California
Abstract
<jats:title>Abstract</jats:title> <jats:p>Purpose: GDC-0973 is a potent and selective mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) inhibitor. Pharmacokinetic–pharmacodynamic (PK–PD) modeling was used to relate GDC-0973 plasma and tumor concentrations, tumor pharmacodynamics and antitumor efficacy to establish pharmacokinetic endpoints and predict active doses in the clinic.</jats:p> <jats:p>Experimental Design: A PK–PD model was used to characterize GDC-0973 tumor disposition and in vivo potency in WM-266-4 xenograft mice. Simulations were conducted using the PK–PD model along with human pharmacokinetics to identify a target plasma concentration and predict active doses. In vivo potency and antitumor efficacy were characterized in A375 melanoma xenograft mice, and a population-based integrated PK–PD-efficacy model was used to relate tumor pharmacodynamics (%pERK decrease) to antitumor activity.</jats:p> <jats:p>Results: GDC-0973 showed a sustained tumor pharmacodynamic response due to longer residence in tumor than in plasma. Following single doses of GDC-0973, estimated in vivo IC50 values of %pERK decrease based on tumor concentrations in xenograft mice were 0.78 (WM-266-4) and 0.52 μmol/L (A375). Following multiple doses of GDC-0973, the estimated in vivo IC50 value in WM-266-4 increased (3.89 μmol/L). Human simulations predicted a minimum target plasma concentration of 83 nmol/L and an active dose range of 28 to 112 mg. The steep relationship between tumor pharmacodynamics (%pERK decrease) and antitumor efficacy suggests a pathway modulation threshold beyond which antitumor efficacy switches on.</jats:p> <jats:p>Conclusions: Clinical observations of %pERK decrease and antitumor activity were consistent with model predictions. This article illustrates how PK–PD modeling can improve the translation of preclinical data to humans by providing a means to integrate preclinical and early clinical data. Clin Cancer Res; 18(11); 3090–9. ©2012 AACR.</jats:p>
Journal
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- Clinical Cancer Research
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Clinical Cancer Research 18 (11), 3090-3099, 2012-05-31
American Association for Cancer Research (AACR)
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Details 詳細情報について
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- CRID
- 1361981470960056704
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- ISSN
- 15573265
- 10780432
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- Data Source
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- Crossref