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□The dose proportionality and multiple dose pharmacokinetics of CTLA4lg, an immunosuppressive drug under development, were investigated in 12 cynomolgus monkeys in a parallel study. The activity of CTLA4lg in suppressing the immunoresponses to sheep red blood cell (SRBC) was also assessed. Two monkeys per gender were randomly assigned to one of the three dose levels, 1.0, 2.9, and 8.7 mg/kg of CTLA4lg. The monkeys in each dose level received the assigned intravenous dose of CTLA4lg by a bolus injection into a saphenous vein on days 1, 4, 8, 11, 15, and 18. Immediately after the administration of CTLA4lg on day 1, each monkey was challenged with SRBC. Serial blood samples were collected up to 720 h following administration of CTLA4lg on day 18 (last dose). In addition, predose blood samples were obtained on days 1, 4, 8,11,15, and 18. Serum samples were analyzed for the concentrations of CTLA4lg using a validated ELISA method. The data obtained were subjected to noncompartmental pharmacokinetic analyses. The serum concentrations of CTLA4lg attained steady state by day 11 regardless of the dose levels. The mean AUC0 -720 values of CTLA4lg increased in a dose proportional manner. The mean values of Cmax increased in a ratio of 1:3.3:8.5 while the dose administered increased in a ratio of 1:3:9. Predose serum concentrations (Cmin) of CTLA4lg increased in a dose proportional manner. The mean T1/2 values were not significantly different among the dose groups, suggesting that the elimination characteristics of CTLA4lg were not altered as the dose increased. Dose-related immunosuppressive activity of CTLA4lg (78–98% inhibition) was observed in monkeys immunized intravenously with SRBC. In conclusion, CTLA4lg exhibits linear kinetics and demonstrates significant immunosuppressive activity over a dose range of 1.0–8.7 mg/ kg in monkeys.

After administration of a drug or exposure to an environmental chemical, the body’s anatomical, physiological, and biochemical parameters act upon the drug or chemical resulting in absorption into the systemic circulation, distribution to organs and tissues, metabolism to other active or inactive chemical species, and elimination from the body. The rate and extent of each process is dependent upon both the biology of the organism and the physiochemical properties of the drug or chemical. The study of the processes of absorption, distribution, metabolism, and elimination or ADME is known as pharmacokinetics for pharmaceuticals and toxicokinetics for toxicants. These ADME processes contribute to the overall exposure of the body to drugs and chemicals. The processes of absorption and metabolism are discussed in detail in other chapters in this volume (Chapters 1.01, 1.03, 1.04, and 1.06).