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Journal of Pharmacology and Experimental Therapeutics

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OtherDRUG METABOLISM AND DISPOSITION

Phase I Safety and Pharmacokinetic Profile of an Intercellular Adhesion Molecule-1 Antisense Oligodeoxynucleotide (ISIS 2302)

Josephine M. Glover, Janet M. Leeds, Timothy G. K. Mant, Dipti Amin, Daniel L. Kisner, Joan E. Zuckerman, Richard S. Geary, Arthur A. Levin and William R. Shanahan Jr.
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1173-1180;
Josephine M. Glover
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Janet M. Leeds
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Timothy G. K. Mant
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Dipti Amin
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Daniel L. Kisner
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Joan E. Zuckerman
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Richard S. Geary
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Arthur A. Levin
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William R. Shanahan Jr.
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Abstract

Healthy male volunteers received single or multiple intravenous infusions of an intercellular adhesion molecule-1 antisense phosphorothioate oligodeoxynucleotide, ISIS 2302, in a rising-dose (0.06–2.00 mg/kg infused over 2 hr), double-blind, placebo-controlled trial. Brief, dose-related increases in activated partial thromboplastin time were seen at the time of peak plasma concentration (C max). Clinically insignificant increases in C3a were seen after higher, repeated doses, but C5a, blood pressure and pulse were unaffected. No adverse events or other laboratory abnormalities were related to treatment with the drug. ISIS 2302C max was linearly related to dose and occurred at the end of infusion. Plasma half-life for intact drug (53–54 min) and total oligonucleotide (67–74 min) were similar at the two doses (0.5 and 2.0 mg/kg) at which extensive pharmacokinetic data were collected. Nonlinear changes in area under the plasma concentration/time curve and steady-state volume of distribution with increasing dose suggested a saturable component to disposition. Metabolites co-migrating with n-1, n-2 and n-3 chain-shortened versions of ISIS 2302 appeared very rapidly in plasma, and disposition and metabolism appeared unaltered by repeated dosing. ISIS 2302 was well tolerated and behaved reproducibly with respect to plasma pharmacokinetics and expected side effects.

Footnotes

  • Send reprint requests to: William R. Shanahan, Jr, Isis Pharmaceuticals Inc., 2292 Faraday Avenue, Carlsbad, CA 92008-7208.

  • ↵1 This study was funded by Isis Pharmaceuticals, Inc.

  • Abbreviations:
    ICAM-1
    intercellular adhesion molecule-1
    APTT
    activated partial thromboplastin time
    TT
    thrombin time
    PT
    prothrombin time
    CGE
    capillary gel electrophoresis
    • Received October 29, 1996.
    • Accepted May 12, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherDRUG METABOLISM AND DISPOSITION

Phase I Safety and Pharmacokinetic Profile of an Intercellular Adhesion Molecule-1 Antisense Oligodeoxynucleotide (ISIS 2302)

Josephine M. Glover, Janet M. Leeds, Timothy G. K. Mant, Dipti Amin, Daniel L. Kisner, Joan E. Zuckerman, Richard S. Geary, Arthur A. Levin and William R. Shanahan
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1173-1180;

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OtherDRUG METABOLISM AND DISPOSITION

Phase I Safety and Pharmacokinetic Profile of an Intercellular Adhesion Molecule-1 Antisense Oligodeoxynucleotide (ISIS 2302)

Josephine M. Glover, Janet M. Leeds, Timothy G. K. Mant, Dipti Amin, Daniel L. Kisner, Joan E. Zuckerman, Richard S. Geary, Arthur A. Levin and William R. Shanahan
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1173-1180;
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