This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by LeBel, C. Articles by Wong, L. Search for Related Content PubMed PubMed Citation Articles by LeBel, C. Articles by Wong, L. Pubmed/NCBI databases Substance via MeSH Social Bookmarking                         What's this?

Pharmacokinetic, pharmacodynamic, and pharmacotoxic profiles of recombinant- methionyl human interleukin-2 [alanine- 125] (r-metHuIL-2[ala-125]) following intravenous and subcutaneous administration in rats

Department of Toxicology, Amgen Inc

L. Langlois

Department of Toxicology, Amgen Inc

DP Bell

Department of Pharmacology, Amgen Inc

JD Young

Department of Pharmacology, Amgen Inc

WC Kenney

and Department of Protein Chemistry, Amgen, Inc., Thousand Oaks, California 91320

BJ Payne

Midlantic Bio-Research Corporation, Temple Hills, Maryland 20748, USA

LE Sendelbach

Midlantic Bio-Research Corporation, Temple Hills, Maryland 20748, USA

Lck Wong

Department of Toxicology, Amgen Inc

Comparative pharmacotoxicity studies in rats were per formed to evaluate the response to r-metHuIL-2[ala-125] following 2 or 4 weeks of daily intravenous or sub cutaneous administration, as well as to evaluate pharmacokinetic and pharmacodynamic responses. Pharmacokinetic analysis indicated that r-metHuIL-2[ala- 125] showed high bioavailability and nonlinear concentra tion profiles. Pharmacodynamic responses to intravenous or subcutaneous dosing with r-metHuIL-2[ala-125], as measured by white blood cell counts, were comparable. Preclinical safety studies (6, 30, and 150 µg kg^-1 day ^-1) indi cated that r-metHuIL-2[ala-125], whether given intra venously or subcutaneously, was associated with increased circulating and infiltrating levels of lympho cytes and eosinophils. Bone marrow lymphoid hyperpla sia and splenic extramedullary hematopoiesis were simi larly observed in each study. This pattern of effects was considered an exaggerated pharmacodynamic response to r-metHuIL-2[ala-125]. Of further note was a histopatholog ic finding described as hepatocyte single cell necrosis which was observed following both intravenous and sub cutaneous administration and was considered to be a toxic response to high doses of r-metHuIL-2[ala-125]. The no observable adverse effect level (NOAEL) for r-metHuIL- 2[ala-125] via intravenous administration was 6 µg kg ^-1 day^-1, while that for subcutaneous administration was 30 µg kg^-1 day^-1. Data herein present a form of rHuIL-2 with pharmacokinetic and pharmacodynamic profiles that are similar when given by these two systemic routes. Pharmacotoxic data, based on NOAELs, suggest that sub cutaneous administration may be a preferred clinical route of administration.

Key Words: pharmacotoxicity • r-metHuIL-2 [ala-125] • rat • pharmacokinetic analysis

Human & Experimental Toxicology, Vol. 14, No. 11, 909-915 (1995)
DOI: 10.1177/096032719501401109


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?