A pharmacokinetic study of intravenous CTLA4Ig, a novel immunosuppressive agent, in mice.
Three skin-intact mice in each group received a single 0.07-, 0.29-, or 0.57-mg dose of CTLA4Ig intravenously (i.v.). Three skin-grafted mice received a single 0.29-mg dose i.v. and another three skin-grafted mice received a 0.29-mg dose once daily for 7 days (the dose was administered via the tail vein). Serial blood samples (0.15 mL) were obtained by retro-orbital bleeds up to 240 h after all single doses and up to 360 h after the last multiple dose. Serum samples were analyzed for CTLA4Ig by a validated enzyme immunoassay method. The concentration data were subjected to noncompartmental pharmacokinetic analysis. Both Cmax and AUCinf values increased in a dose-proportional manner in skin-intact mice. The CLT values were dose independent. The MRT, t1/2, and Vdss values at the 0.07-mg dose level were significantly lower than those obtained for both the 0.29- and 0.57-mg dose levels; however, the respective values between the 0.29- and 0.57-mg dose levels were not significantly different. No significant differences were found in the pharmacokinetic parameters between the skin-intact and skin-grafted mice.
Srinivas
N R
NR
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Weiner
R S
RS
Shyu
W C
WC
Calore
J D
JD
Tritschler
D
D
Tay
L K
LK
Lee
J S
JS
Greene
D S
DS
Barbhaiya
R H
RH
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D060908:CTLA-4 Antigen; D004305:Dose-Response Relationship, Drug; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D051379:Mice; D008815:Mice, Inbred Strains; D012867:Skin / Q000187:drug effects*; D013997:Time Factors
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept