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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Preclinical Studies to Predict the Disposition of Apo2L/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Humans: Characterization of in Vivo Efficacy, Pharmacokinetics, and Safety

Sean K. Kelley, Louise A. Harris, David Xie, Laura DeForge, Klara Totpal, Jeanine Bussiere and Judith A. Fox
Journal of Pharmacology and Experimental Therapeutics October 2001, 299 (1) 31-38;
Sean K. Kelley
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Louise A. Harris
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David Xie
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Laura DeForge
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Klara Totpal
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Jeanine Bussiere
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Judith A. Fox
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Abstract

Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a member of the tumor necrosis factor gene family known to induce apoptosis in a number of cancer cell lines and may have broad-spectrum activity against human malignancies. These studies have evaluated the potency of recombinant soluble human Apo2L/TRAIL in a mouse xenograft model and the disposition and safety of Apo2L/TRAIL in rodents and nonhuman primates. Mice with established COLO205 tumors were given daily i.v. injections of Apo2L/TRAIL (30–120 mg/kg/day). Control tumors doubled in size every 2 to 3 days, while time to tumor doubling in the treatment groups was significantly longer and related to dose (14–21 days). For pharmacokinetic studies, Apo2L/TRAIL was given as an i.v. bolus to mice (10 mg/kg), rats (10 mg/kg), cynomolgus monkeys (1, 5, and 50 mg/kg), and chimpanzees (1 and 5 mg/kg). Apo2L/TRAIL was rapidly eliminated from the serum of all species studied. Half-lives were ∼3 to 5 min in rodents and ∼23 to 31 min in nonhuman primates. Allometric scaling provided estimates of Apo2L/TRAIL kinetics in humans, suggesting that on a milligram per kilogram basis, doses significantly lower than those used in xenograft studies could be effective in humans. Apo2L/TRAIL clearance was highly correlated with glomerular filtration rate across species, indicating that the kidneys play a critical role in the elimination of this molecule. Safety evaluations in cynomolgus monkeys and chimpanzees revealed no abnormalities associated with Apo2L/TRAIL exposure. In conclusion, these studies have characterized the disposition of Apo2L/TRAIL in rodents and primates and provide information that will be used to predict the pharmacokinetics of Apo2L/TRAIL in humans.

Footnotes

  • Abbreviations:
    TNF
    tumor necrosis factor
    Apo2L/TRAIL
    tumor necrosis factor-related apoptosis-inducing ligand
    DR
    death receptor
    DcR
    decoy receptor
    OPG
    osteoprotegerin
    ELISA
    enzyme-linked immunosorbent assay
    OD
    optical density
    AUC
    area under the Apo2L/TRAIL serum concentration versus time curve
    Cmax
    model-predicted maximum serum Apo2L/TRAIL concentration
    Vss
    estimated steady-state volume of distribution
    GFR
    glomular filtration
    SBI
    Sierra Biomedical, Inc
    NIRC
    New Iberia Research Center
    • Received March 15, 2001.
    • Accepted June 14, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 1
1 Oct 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Preclinical Studies to Predict the Disposition of Apo2L/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Humans: Characterization of in Vivo Efficacy, Pharmacokinetics, and Safety

Sean K. Kelley, Louise A. Harris, David Xie, Laura DeForge, Klara Totpal, Jeanine Bussiere and Judith A. Fox
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 31-38;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Preclinical Studies to Predict the Disposition of Apo2L/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Humans: Characterization of in Vivo Efficacy, Pharmacokinetics, and Safety

Sean K. Kelley, Louise A. Harris, David Xie, Laura DeForge, Klara Totpal, Jeanine Bussiere and Judith A. Fox
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 31-38;
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