Pharmacokinetics and pharmacodynamics of CTLA4lg (BMS-188667), a novel immunosuppressive agent, in monkeys following multiple doses.
The dose proportionality and multiple dose pharmacokinetics of CTLA4Ig, an immunosuppressive drug under development, were investigated in 12 cynomolgus monkeys in a parallel study. The activity of CTLA4Ig 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 CTLA4Ig. The monkeys in each dose level received the assigned intravenous dose of CTLA4Ig by a bolus injection into a saphenous vein on days 1, 4, 8, 11, 15, and 18. Immediately after the administration of CTLA4Ig on day 1, each monkey was challenged with SRBC. Serial blood samples were collected up to 720 h following administration of CTLA4Ig 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 CTLA4Ig using a validated ELISA method. The data obtained were subjected to noncompartmental pharmacokinetic analyses. The serum concentrations of CTLA4Ig attained steady state by day 11 regardless of the dose levels. The mean AUC0-720 values of CTLA4Ig 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 CTLA4Ig 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 CTLA4Ig were not altered as the dose increased. Dose-related immunosuppressive activity of CTLA4Ig (78-98% inhibition) was observed in monkeys immunized intravenously with SRBC. In conclusion, CTLA4Ig exhibits linear kinetics and demonstrates significant immunosuppressive activity over a dose range of 1.0-8.7 mg/kg in monkeys.
Srinivas
N R
NR
Department of Metabolism and Pharmacokinetics, Briston-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Weiner
R S
RS
Warner
G
G
Shyu
W C
WC
Davidson
T
T
Fadrowski
C G
CG
Tay
L K
LK
Lee
J S
JS
Greene
D S
DS
Barbhaiya
R H
RH
D000069594:Abatacept; D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D060908:CTLA-4 Antigen; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D012756:Sheep
D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept