Denileukin is a fusion protein designed to direct the cytocidal action of diphtheria toxin to cells which express the IL-2 receptor. Ex vivo studies report that after binding to the IL-2 receptor on the cell surface, denileukin is internalized by receptor-mediated endocytosis. The fusion protein is subsequently cleaved, releasing diphtheria toxin enzymatic and translocation domains from the IL-2 fragment, resulting in the inhibition of protein synthesis and ultimately, cell death.
Pharmacokinetic parameters associated with denileukin were determined over a range of doses (3 to 31 mcg/kg/day) in patients with lymphoma. Denileukin was administered as an IV infusion following the schedule used in the clinical trials. Following the first dose, denileukin displayed 2-compartment behavior with a distribution phase (half-life approximately 2 to 5 minutes) and a terminal phase (half-life approximately 70 to 80 minutes).
Systemic exposure was variable but proportional to dose. Mean clearance was approximately 0.6 to 2.0 mL/min/kg and the mean volume of distribution was similar to that of circulating blood (0.06 to 0.09 L/kg). The mean clearance increased approximately 2- to 8-fold from course 1 to course 3 corresponding to a decrease in exposure of approximately 75%. No accumulation was evident between the first and fifth doses. Gender and age have no effect on pharmacokinetics of denileukin.
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