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

Comparative pharmacotoxicity studies in rats were performed to evaluat e the response to r-metHuIL-2[ala-125] following 2 or 4 weeks of daily intravenous or subcutaneous administration, as well as to evaluate ph armacokinetic and pharmacodynamic responses, Pharmacokinetic analysis indicated that r-metHuIL-2[ala-125] showed high bioavailability and no nlinear concentration profiles, Pharmacodynamic responses to intraveno us or subcutaneous dosing with r-metHuIL-2[ala-125], as measured by wh ite blood cell counts, were comparable, Preclinical safety studies (6, 30, and 150 pg kg(-1) day(-1)) indicated that r-metHuIL-2[ala-125], w hether given intravenously or subcutaneously, was associated with incr eased circulating and infiltrating levels of lymphocytes and eosinophi ls, Bone marrow lymphoid hyperplasia and splenic extramedullary hemato poiesis were similarly 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 histopathologic finding described as hepatocyte single cell necrosis which was observed following both int ravenous and subcutaneous administration and was considered to be a to xic 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 mu g kg(-1) day(-1), while that for subcutaneous administration was 30 mu g 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, b ased on NOAELs, suggest that subcutaneous administration may be a pref erred clinical route of administration.