caa a22 4500 477126456 CHVBK 20180405111651.0 cr unu---uuuuu 170330e19970701xx s 000 0 eng 10.1023/A:1012156001831 doi (NATIONALLICENCE)springer-10.1023/A:1012156001831 Assessment of Dose Proportionality, Absolute Bioavailability, and Immunogenicity Response of CTLA4Ig (BMS-188667), a Novel Immunosuppressive Agent, Following Subcutaneous and Intravenous Administration to Rats [Elektronische Daten] [Nuggehally Srinivas, Wen Shyu, Russell Weiner, Garvin Warner, Charles Comereski, Lee Tay, Douglas Greene, Rashmi Barbhaiya] 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. Plenum Publishing Corporation, 1997 CTLA4Ig nationallicence intravenous nationallicence subcutaneous nationallicence pharmacokinetics nationallicence immunogenicity nationallicence rats nationallicence Srinivas Nuggehally Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, 08543-4000, Princeton, New Jersey aut Shyu Wen Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, 08543-4000, Princeton, New Jersey aut Weiner Russell Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 191, 08903-0191, New Brunswick, New Jersey aut Warner Garvin Department of Drug Safety Evaluation, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4755, Syracuse, New York 13221-4775 aut Comereski Charles Department of Drug Safety Evaluation, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4755, Syracuse, New York 13221-4775 aut Tay Lee Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 191, 08903-0191, New Brunswick, New Jersey aut Greene Douglas Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, 08543-4000, Princeton, New Jersey aut Barbhaiya Rashmi Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, 08543-4000, Princeton, New Jersey aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/7(1997-07-01), 911-916 0724-8741 14:7<911 1997 14 11095 https://doi.org/10.1023/A:1012156001831 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012156001831 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Srinivas Nuggehally Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, 08543-4000, Princeton, New Jersey aut NATIONALLICENCE 700 1- Shyu Wen Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, 08543-4000, Princeton, New Jersey aut NATIONALLICENCE 700 1- Weiner Russell Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 191, 08903-0191, New Brunswick, New Jersey aut NATIONALLICENCE 700 1- Warner Garvin Department of Drug Safety Evaluation, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4755, Syracuse, New York 13221-4775 aut NATIONALLICENCE 700 1- Comereski Charles Department of Drug Safety Evaluation, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4755, Syracuse, New York 13221-4775 aut NATIONALLICENCE 700 1- Tay Lee Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 191, 08903-0191, New Brunswick, New Jersey aut NATIONALLICENCE 700 1- Greene Douglas Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, 08543-4000, Princeton, New Jersey aut NATIONALLICENCE 700 1- Barbhaiya Rashmi Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, 08543-4000, Princeton, New Jersey aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/7(1997-07-01), 911-916 0724-8741 14:7<911 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer