Pharmacokinetics of Intravenous CTLA4Ig (BMS-188667) in Cynomolgus Monkeys Following Single and Multiple Doses

The pharmacokinetics of CTLA4Ig, a novel immunosuppressive therapeutic protein, were investigated in cynomolgus monkeys following intravenous administration of single and multiple doses of CTLA4Ig. In the single-dose study, two monkeys of each sex received a dose of either 10 or 33 mg kg−1 CTLA4Ig by an intravenous bolus injection into a saphenous vein. In the multiple-dose study, three monkeys of each sex received either 10, 22.4, or 50 mg kg−1 of CTLA4Ig as an intravenous bolus injection once every other day for 15 doses over 29 days. Serial blood samples were collected at appropriate time points following the single dose and the last multiple dose. The serum samples were analysed for CTLA4Ig using an enzyme immunoassay procedure. The serum concentration data were evaluated by a noncompartmental method. Following single and multiple doses, both peak plasma concentration (Cmax) and area under the curve (AUC) values for CTLA4Ig increased in a proportion comparable with the dose increment ratio. The clearance values (CLT) for CTLA4Ig were not altered following the administration of single doses. The terminal elimination half-life values (t1/2) showed a tendency to increase as the administered dose increased. The steady-state volume of distribution (VdSS) of CTLA4Ig was about 2–3 times the blood volume in monkeys. On the basis of the derived and simulated pharmacokinetic parameters (using superposition principles), it was concluded that the pharmacokinetics of CTLA4Ig was not altered by repeated dosing.