Pharmacokinetics and Pharmacodynamics of CTLA4Ig (BMS‐188667), a Novel Immunosuppressive Agent, After Subcutaneous and Intravenous Administration to Mice

Abstract

The objectives of this study were to describe the pharmacodynamics of CTLA4Ig (BMS-188667)after single intravenous and subcutaneous doses in mice challenged with sheep red blood cells (SRBC), the pharmacokinetics of CTLA4Ig after intravenous and subcutaneous doses, and to assess the subcutaneous absolute bioavailability. Pharmacodynamic assessments were performed at 0.01, 0.04, 0.11, and 0.33 mg (i.v.) and 0.06, 0.17, 0.5, 1.6, and 3.3 mg (s.c.) dose levels. In separate groups, pharmacokinetics were assessed at 0.33 mg (i.v.) and 0.5, 1.6, and 3.3 mg (s.c.) dose levels. Immediately before dosing, each mouse was challenged with SRBC (1 × 108 cells). Serial blood samples, in a staggered manner, were collected from the pharmacokinetic groups up to 15 days after dosing. Three blood samples were collected from the pharmacodynamic groups. Serum samples were analysed for either CTLA4Ig (pharmacokinetic groups) or anti-SRBC antibodies (pharmacodynamic groups) using enzyme-linked immunosorbent assays. CTLA4Ig suppressed the formation of antibodies to SRBC in mice, in a dose dependent manner. Complete suppression was observed between day 12 and 29 regardless of route of administration. The ED50 value for the intravenous dose (0.034 mg) was threefold lower than that of the subcutaneous treatment (0.112 mg). The subcutaneous bioavailability decreased with the increment of dose, from 110% (0.5 mg) to 98% (1.6mg) to 78% (3.3 mg). The absorption after subcutaneous administration was prolonged with tmax values ranging from 9 to 24 h; while, t½ (87–124 h) values appeared to be comparable. CTLA4Ig exhibited dose related immunosuppressive responses. At the same dose level, CTLA4Ig was more immunosuppressive following intravenous administration than subcutaneous and the subcutaneous absolute bioavailability decreased as the administered dose increased.