PHARMACOKINETIC AND PHARMACODYNAMIC EVALUATION OF A TWO DOSE DACLIZUMAB REGIMEN IN LIVER TRANSPLANTATION

Abstract

100 Daclizumab (Zenapax®) is a humanized mAb directed to the α-chain of the IL-2 receptor (CD25). 1st pharmacokinetics and pharmacodynamics of a two dose regimen were characterized in an open-label, single center phase I/II trial in liver transplant patients. Methods: 26 de novo liver transplant patients received two doses of daclizumab intravenously at day 0, 1mg/kg and day 4, 0.5 mg/kg in addition to the microemulsion of cyclosporine and steroids. Serial blood samples were collected over 12 weeks for measurement of daclizumab serum and ascites concentrations (idiotype-specific ELISA) and the formation of anti-idiotypic antibodies. Flow cytometry (CD3, Cd4, CD8, CD20, CD25) was performed in parallel in all patients. The daily blodd loss and ascites fluid drainage were documented up to two weeks posttransplant. Absolute lymphocyte counts and differential blood pictures were performed by standard techniques. Results: (1) Peak serum concentrations after the first dose were 13.8 ± 5.8 μg/ml and 8.9 ± 4.1 μg/ml. (2) Concentrations higher than 1 μg/ml were measured until day 14 posttransplant (1.2 ± 1.1 μg/ml). (3) There were no relevant changes in CD3+, CD4+, CD8+ and CD20+ lymphocytes during exposure to daclizumab; whereas, CD25+ lymphocytes were not detectable during treatment (1.9 ± 0.9%) compared to pretransplant (21.4 ± 8.8%) and post-exposure (16 ± 14.1%). (4) Daclizumab demonstrated a concentration-effect relation, whereby concentrations exceeding 1 μg/ml were associated with CD25 suppression. (5) Daclizumab concentrations in ascites ranged from 2 to 6 μg/ml, but did not had an influence on serum levels. (6) No anti-idiotypic antibody response was seen. (7) 1/26 patients had a mild acute rejection on day 18 posttransplant and no side effects were seen after administration of daclizumab. Conclusions: Daclizumab was well tolerated in liver transplant recipients. Drainage of ascites fluid and postoperative bleeding contribute to the total body clearance of daclizumab, however there was no influence on the efficacy of CD25 coating. Therefore, daclizumab could be administered safely in a two dose regimen on day 0 and 4 after liver transplantation, achieving receptor saturation for 21 days.