PMID- 9244149
OWN - NLM
STAT- MEDLINE
DCOM- 19970922
LR  - 20190818
IS  - 0724-8741 (Print)
IS  - 0724-8741 (Linking)
VI  - 14
IP  - 7
DP  - 1997 Jul
TI  - Assessment of dose proportionality, absolute bioavailability, and immunogenicity 
      response of CTLA4Ig (BMS-188667), a novel immunosuppressive agent, following 
      subcutaneous and intravenous administration to rats.
PG  - 911-6
AB  - PURPOSE: The objectives of this study were: to delineate the pharmacokinetics of 
      CTLA4Ig in rats after single and multiple intravenous (IV) and subcutaneous (SC) 
      doses; to assess the relationship of the pharmacokinetic parameters of CTLA4Ig vs 
      dose; to calculate the SC absolute bioavailability; and to assess the antibody 
      response of CTLA4Ig. METHODS: A total of 48 (24 male and 24 female) Sprague 
      Dawley rats were divided into eight treatments with 3 rats per gender in each 
      group: a single dose of 10, 80, or 200 mg/kg of CTLA4Ig given either IV or SC and 
      a repeated dose of 10 mg/kg (once every other day for 7 doses over 13 days) given 
      either SC or IV. Serial blood samples were collected up to 43 days after single 
      dose administration and up to 50 days following the administration of the last 
      multiple dose on day 13. The serum concentration of CTLA4Ig and anti-CTLA4Ig 
      antibodies were measured using ELISA assays. RESULTS: After single IV doses, Cmax 
      and AUCinf increased in a dose proportional manner; CL appeared to be dose 
      independent, while both Vss and T1/2 increased as the administered dose 
      increased. Following single SC doses, Cmax and AUCinf increased in a linear 
      manner but not proportionally; mean Tmax values were prolonged but similar among 
      the three dose levels, while T1/2 increased as the administered dose increased. 
      The absolute SC bioavailability of CTLA4Ig decreased as the dose increased from 
      10 (62.5%), 80 (55.7%), and 200 mg/kg (41.1%). Comparison of the AUCtau values 
      between the first and last doses suggested an accumulation (3.1-4.7) of CTLA4Ig. 
      However, regardless of the route of dosing, AUCtau after the last dose were 
      comparable to AUCinf values following the single dose. Anti-CTLA4Ig antibodies 
      were detected at the 10 mg/kg dose level after single or multiple doses for both 
      routes of administration. However, regardless of single or multiple doses, 
      antibody titers were relatively greater for the SC compared to the IV 
      administration. CONCLUSIONS: The key findings of this study were: (i) the 
      elimination characteristics of CTLA4Ig were comparable between the SC and IV 
      routes; (ii) the repeated dosing did not alter the pharmacokinetics of CTLA4Ig; 
      (iii) the SC absolute bioavailability tended to decrease as the administered dose 
      increased; and (iv) a greater formation of anti-CTLA4Ig antibodies was observed 
      after SC compared to IV at a single 10 mg/kg dose level; however, after multiple 
      dosing, the formation of antibodies from either of the two routes was relatively 
      slower, and (v) during the study period, no antibodies were observed at either 
      the 80 or 200 mg/kg dose levels regardless of the route of administration.
FAU - Srinivas, N R
AU  - Srinivas NR
AD  - Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb 
      Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
FAU - Shyu, W C
AU  - Shyu WC
FAU - Weiner, R S
AU  - Weiner RS
FAU - Warner, G
AU  - Warner G
FAU - Comereski, C
AU  - Comereski C
FAU - Tay, L K
AU  - Tay LK
FAU - Greene, D S
AU  - Greene DS
FAU - Barbhaiya, R H
AU  - Barbhaiya RH
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Pharm Res
JT  - Pharmaceutical research
JID - 8406521
RN  - 0 (Antibodies)
RN  - 0 (Antigens, CD)
RN  - 0 (Antigens, Differentiation)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (Immunoconjugates)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 7D0YB67S97 (Abatacept)
SB  - IM
MH  - Abatacept
MH  - Animals
MH  - Antibodies/blood/immunology
MH  - Antigens, CD
MH  - Antigens, Differentiation/*administration & dosage/immunology
MH  - Area Under Curve
MH  - Biological Availability
MH  - CTLA-4 Antigen
MH  - Female
MH  - *Immunoconjugates
MH  - Immunosuppressive Agents/*administration & dosage/immunology/pharmacokinetics
MH  - Injections, Intravenous
MH  - Injections, Subcutaneous
MH  - Male
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recombinant Fusion Proteins/administration & dosage/immunology/pharmacokinetics
EDAT- 1997/07/01 00:00
MHDA- 1997/07/01 00:01
CRDT- 1997/07/01 00:00
PHST- 1997/07/01 00:00 [pubmed]
PHST- 1997/07/01 00:01 [medline]
PHST- 1997/07/01 00:00 [entrez]
AID - 10.1023/a:1012156001831 [doi]
PST - ppublish
SO  - Pharm Res. 1997 Jul;14(7):911-6. doi: 10.1023/a:1012156001831.