Pharmacokinetics, Biologic Activity, and Tolerability of Alefacept by Intravenous and Intramuscular Administration.

Alefacept, human LFA-3/IgGz[sub 1] fusion protein, is currently under clinical development for the treatment of chronic plaque psoriasis and other T cell mediated disorders. This recombinant protein binds CD2 on T cells and FcγRIII on accessory cells (e.g., natural killer cells, macrophages), inhibiting T cell activation/proliferation and inducing selective T cell apoptosis. These effects are associated with selective reductions in memory-effector (CD4[sup +]CD45RO[sup +] and CD8[sup +]CD45RO[sup +]) T cells. Two open-label studies were conducted in healthy male volunteers to evaluate the pharmacokinetics, biologic activity, and tolerability of a single dose of alefacept when administered as a 0.15 mg/kg 30-sec i.v. bolus (n=12), 0.04 mg/kg intramuscular (i.m.) injection (n=8), or 0.04mg/kg 30-min intravenous (i.v.) infusion (n=8). I.V. infusion produced a higher C[sub max] (0.96 ± 0.26 mcg/ml vs. 0.36 ± 0.19 mcg/ml) and a shorter T[sub max] (2.8 ± 1.9 hr vs. 86 ± 60 hr) when compared to i.m. injection. Based on A UC[sub 0-last] and A UC[sub 0-∞] values, the relative bioavailability of i.m. to i.v. infusion was approximately 60%. After absorption from the i.m. injection was complete, the rate of alefacept elimination from the serum appeared consistent with the i.v. infusion half-life (approximately 12 days). Biologic activity was demonstrated by transient reductions in absolute number of CD2[sup +] lymphocytes, with notable specificity for memory T-cell subsets. Alefacept was well tolerated; the most common adverse effects were headache, pharyngitis, rash, and myalgia. IM administration was not associated with significant local reactions. Results of these studies support i.v. bolus or i.m. administration of alefacept. An i.m. dose of approximately 150 to 200% of the i.v. dose is an appropriate and convenient alternative to i.v. administration. [ABSTRACT FROM AUTHOR]