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Phase I Trial of WuTac, A Murine Anti-CD25 Monoclonal Antibody, Tolerance and Pharmacokinetics of Multiple Doses in Renal Transplant Patients

Author: YangHua
Tutor: LiHeng
School: Huazhong University of Science and Technology
Course: Surgery
Keywords: Anti-CD25 monoclonal antibody Kidney transplant Tolerated Security Pharmacokinetics Pharmacodynamic
CLC: R96
Type: Master's thesis
Year: 2010
Downloads: 45
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Abstract

Purpose independent research and development of biological agents Wuhan Institute of Biological Products China Pharmaceutical Group New Drug \and pharmacokinetics the test the (SFDA Approval Document No.: 2003L03465), evaluation WuTac in renal transplant patient application security, a preliminary exploration of the efficacy and provide a safe dose range for the development of Phase II clinical trial of the drug dosing regimen. Methods 18 cases of living-donor renal transplant recipients, and 0.1 mg / kg (n = 8) and 0.2 mg / kg (n = 10) two-dose group, two hours before renal transplantation administration, intraoperative a day, seven days in a row after administration, intravenous infusion WuTac 0.1 mg · kg ^{-1 · d ^{-10 0.2 mg · kg ^{-1 < / sup> · d ^{-10 ; the underlying immunosuppression with mycophenolate mofetil (MMF) prednisone triple immunosuppressive regimen of cyclosporine (CsA). The evaluation of renal transplant patients WuTac the maximum tolerated dose and adverse events characteristics; double antibody sandwich ELISA blood concentration, pharmacology software the DAS the 2.0 processing plasma concentration data and calculate the pharmacokinetic parameters, to evaluate WuTac in kidney transplant patients in vivo pharmacokinetic characteristics; indirect ELISA postoperative titers of anti-mouse antibody (HAMA), monitoring of renal transplant patients produce HAMA the law; the flow cytometry continuous detection of peripheral blood lymphocyte subsets, preliminary explore the characteristics of WuTac immunosuppressive effects. Data entry, verification, analysis EpiData 3.1, SPSS 15.0 software, the significance level α chosen 0.05, Origin Pro8.0 software drawing. Results All subjects were not there the first dose response, cytokine release syndrome and acute rejection. 0.1 mg / kg dose group included eight subjects after renal transplantation smooth recovery, no serious adverse events occurred; 10 subjects were included in accordance with the needs of the confirmatory test WuTac the maximum tolerated dose, 0.2 mg / kg dose group one case, in which subjects serum creatinine increase due to medication observation period after three days withdrew to disable WuTac and supplemented after hemodialysis graft function recovery; nine subjects completed the trial graft function recovery, the occurrence of delayed graft function recovery one cases, medication observation period elevated serum creatinine cases, two cases of subjects were supplemented hemodialysis treatment; medication observation period pulmonary Aspergillus fumigatus infection one cases, symptomatic treatment and adjust the immunosuppressant after lung infection cure; This three cases subjects and dropouts test subjects were greater than 50 kg body weight daily WuTac medication doses greater than 10 mg, 0.2 mg / kg group and the remaining subjects after renal transplantation smooth recovery. Pharmacokinetic parameters t1 / 2, the tmax, Vd CL AUCss / D AUC0-t / D, AUC0-∞ / D two groups was no difference (P gt; 0.05), Cmax / D were significantly different ( P lt; 0.05). When WuTac plasma concentration greater than 1000μg · L-1, WuTac significantly inhibit CD25 lymphocytes, while the total number of peripheral blood T lymphocytes (CD3 CD19-T lymphocytes), helper T lymphocytes (CD3 CD4 T lymphocytes) cytotoxic T lymphocytes (CD3 CD8 T lymphocytes), B lymphocytes (CD3-CD19 lymphocytes), the proportion of NK cells (CD3-CD16 CD56 cells) no effect. -1 0.1 mg · kg ^{· d ^{10 the administration, WuTac and activation of T lymphocytes combination play enclosing about 10 ^{1 four days; 0.2 mg · kg ^{-1 · d ^{-10 administration, WuTac play with a combination of activated T lymphocytes the enclosing of about 14 ^{2 < / sup> 1 Tian; 0.1 mg / kg group subjects 14 days after HAMA tested positive, 0.2 mg / kg group subjects after 35 days HAMA tested positive. Conclusion WuTac two hours before surgery administered once for seven consecutive days after daily administration once the maximum tolerated dose of 0.2 mg · kg ^{-1 · d ^{-10 and the total daily dose does not exceed 10 mg; recommended safe dose range, WuTac not increase the incidence of adverse events. Pharmacokinetic trials: WuTac distribution in the plasma, and less tissue or plasma protein binding. WuTac combination of activated T lymphocytes play closed, rather than destruction or clear role. Effective therapeutic concentrations WuTac kidney transplant patients the 1000μg · L-1, when WuTac plasma concentrations greater than 1000μg · L-1, will be able to completely block the IL-2 receptor and stability; When WuTac blood concentration of small in 1000μg · L-1, CD25 lymphocyte proportion began to rise, ^{2 week recovery to pretreatment levels. Kidney transplant patients WuTac, generate the HAMA proportion is low affect WuTac efficacy.}}}}}}}}}}}}}

Phase I Trial of WuTac, A Murine Anti-CD25 Monoclonal Antibody, Tolerance and Pharmacokinetics of Multiple Doses in Renal Transplant Patients

Abstract

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