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Research ArticleArticle

Pharmacokinetics and Pharmacodynamics of SB-240563, a Humanized Monoclonal Antibody Directed to Human Interleukin-5, in Monkeys

P. Zia-Amirhosseini, E. Minthorn, L. J. Benincosa, T. K. Hart, C. S. Hottenstein, L. A. P. Tobia and C. B. Davis
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1060-1067;
P. Zia-Amirhosseini
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E. Minthorn
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L. J. Benincosa
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T. K. Hart
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C. S. Hottenstein
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L. A. P. Tobia
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C. B. Davis
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Abstract

The pharmacokinetics (PK) of SB-240563 have been investigated after i.v. and s.c. administration to cynomolgus monkeys. Approximately linear PK was observed following i.v. administration over a 6000-fold dose range (0.05–300 mg/kg). After i.v. dosing, SB-240563 concentration declined in a biexponential manner with a mean terminal half-life of 13 ± 2 days. The plasma clearance and volume of distribution at steady state were ∼0.2 ml/h/kg and 70 ml/kg, respectively. Following s.c. administration, SB-240563 was completely absorbed into the systemic circulation. Because interleukin-5 is known to stimulate production, activation, and maturation of eosinophils, eosinophil counts were measured to assess pharmacologic activity of SB-240563. The maximal response (81–96% decrease in eosinophil count relative to baseline) following a single s.c. administration occurred at 3 weeks postdosing. Suppression of eosinophil count also was observed following multiple monthly administrations of SB-240563 to monkeys. The pharmacokinetic/pharmacodynamic relationship was generally well described with an indirect pharmacologic response model with an estimated IC50 value of 1.43 μg/ml. The combination of a low IC50 value for reduction of circulating eosinophils and a long terminal half-life suggests the possibility of an infrequent dosing regimen for SB-240563 for treatment of diseases associated with increased eosinophil function such as asthma.

Footnotes

  • Send reprint requests to: Parnian Zia-Amirhosseini, 709 Swedeland Rd., UW2720, P.O. Box 1539, King of Prussia, PA 19406. E-mail:Parnian-Zia-Amirhosseini-1{at}sbphrd.com

  • Abbreviations:
    IL-5
    interleukin 5
    PK
    pharmacokinetic(s)
    ECL
    electrochemiluminescent
    PD
    pharmacodynamic(s)
    Cmax
    maximum plasma concentration
    Tmax
    time at whichCmax occurs
    AUC
    area under the plasma concentration-time curve
    Vss
    volume of distribution at steady state
    CL
    clearance
    T1/2
    terminal half-life
    • Received March 17, 1999.
    • Accepted August 18, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Pharmacokinetics and Pharmacodynamics of SB-240563, a Humanized Monoclonal Antibody Directed to Human Interleukin-5, in Monkeys

P. Zia-Amirhosseini, E. Minthorn, L. J. Benincosa, T. K. Hart, C. S. Hottenstein, L. A. P. Tobia and C. B. Davis
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1060-1067;

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Research ArticleArticle

Pharmacokinetics and Pharmacodynamics of SB-240563, a Humanized Monoclonal Antibody Directed to Human Interleukin-5, in Monkeys

P. Zia-Amirhosseini, E. Minthorn, L. J. Benincosa, T. K. Hart, C. S. Hottenstein, L. A. P. Tobia and C. B. Davis
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1060-1067;
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