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Research ArticleArticle

Interplay of Dissolution, Solubility, and Nonsink Permeation Determines the Oral Absorption of the Hedgehog Pathway Inhibitor GDC-0449 in Dogs: An Investigation Using Preclinical Studies and Physiologically Based Pharmacokinetic Modeling

Harvey Wong, Frank-Peter Theil, Yong Cui, James C. Marsters Jr., S. Cyrus Khojasteh, Laurent Vernillet, Hank La, Xiling Song, Hong Wang, Eric J. Morinello, Yuzhong Deng and Cornelis E. C. A. Hop
Drug Metabolism and Disposition July 2010, 38 (7) 1029-1038; DOI: https://doi.org/10.1124/dmd.110.032680
Harvey Wong
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Frank-Peter Theil
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Yong Cui
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James C. Marsters Jr.
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S. Cyrus Khojasteh
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Laurent Vernillet
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Hank La
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Xiling Song
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Hong Wang
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Eric J. Morinello
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Yuzhong Deng
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Cornelis E. C. A. Hop
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Abstract

Factors determining the pharmacokinetics of 2-chloro-N-(4-chloro-3-(pyridine-2-yl)phenyl)-4-(methylsulfonyl)benzamide (GDC-0449) were investigated using preclinical studies and physiologically based pharmacokinetic (PBPK) modeling. Multiple-dose studies where dogs were given twice-daily oral doses of either 7.5 or 25 mg/kg GDC-0449 showed less than dose-proportional increases in exposure on day 1. At steady state, exposures were comparable between the two dose groups. Oral administration of activated charcoal to dogs receiving oral or intravenous GDC-0449 (25 mg) showed a more rapid decrease in plasma concentrations, suggesting that the concentration gradient driving intestinal membrane permeation was reversible. The biliary clearance of GDC-0449 in dogs was low (0.04 ml/min/kg) and did not account for the majority of the estimated systemic clearance (∼19% of systemic clearance). Likewise, in vitro studies using sandwich-cultured human hepatocytes showed negligible biliary excretion. The effect of particle size on oral absorption was shown in a single-dose study where 150 mg of GDC-0449 of two particle sizes was administered. An oral PBPK model was used to investigate mechanisms determining the oral pharmacokinetics of GDC-0449. The overall oral absorption of GDC-0449 appears to depend on the interplay between the dissolution and intestinal membrane permeation processes. A unique feature of GDC-0449 distinguishing it from other Biopharmaceutical Classification System II compounds was that incorporation of the effects of solubility rate-limited absorption and nonsink permeation on the intestinal membrane permeation process was necessary to describe its pharmacokinetic behavior.

Footnotes

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

    doi:10.1124/dmd.110.032680.

  • ABBREVIATIONS:

    Hh
    hedgehog
    PTCH1
    Patched
    SMO
    Smoothened
    GDC-0449
    2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide
    PBPK
    physiologically based pharmacokinetic
    K2EDTA
    potassium EDTA
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    SI
    small intestine
    GI
    gastrointestinal
    FASSIF
    fasted state simulated intestinal fluid
    SRLA
    solubility rate-limited absorption
    MPER
    maximum permeation extraction ratio
    BEI
    biliary excretion index
    CLbiliary
    biliary clearance
    AUC
    area under the concentration-time curve
    CL
    plasma clearance
    Vss
    volume of distribution at steady state
    AUC0–168
    area under the plasma concentration-time profile from time 0 to 168 h postdose
    AUC0–24
    area under the plasma concentration-time profile from time 0 to 24 h postdose
    BCS
    Biopharmaceutical Classification System.

  • Received February 10, 2010.
  • Accepted April 20, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Research ArticleArticle

Interplay of Dissolution, Solubility, and Nonsink Permeation Determines the Oral Absorption of the Hedgehog Pathway Inhibitor GDC-0449 in Dogs: An Investigation Using Preclinical Studies and Physiologically Based Pharmacokinetic Modeling

Harvey Wong, Frank-Peter Theil, Yong Cui, James C. Marsters, S. Cyrus Khojasteh, Laurent Vernillet, Hank La, Xiling Song, Hong Wang, Eric J. Morinello, Yuzhong Deng and Cornelis E. C. A. Hop
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1029-1038; DOI: https://doi.org/10.1124/dmd.110.032680

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Research ArticleArticle

Interplay of Dissolution, Solubility, and Nonsink Permeation Determines the Oral Absorption of the Hedgehog Pathway Inhibitor GDC-0449 in Dogs: An Investigation Using Preclinical Studies and Physiologically Based Pharmacokinetic Modeling

Harvey Wong, Frank-Peter Theil, Yong Cui, James C. Marsters, S. Cyrus Khojasteh, Laurent Vernillet, Hank La, Xiling Song, Hong Wang, Eric J. Morinello, Yuzhong Deng and Cornelis E. C. A. Hop
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1029-1038; DOI: https://doi.org/10.1124/dmd.110.032680
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