Pharmacokinetics, pharmacodynamics, and immunodynamics of daclizumab in a two-dose regimen in liver transplantation.
BACKGROUND
The humanized anti-interleukin 2 receptor (IL-2R) monoclonal antibody daclizumab (Zenapax) has been shown to be safe and effective for preventing acute allograft rejection in renal transplantation. The aim of this study was to evaluate pharmacokinetics and pharmacodynamics of daclizumab in a two-dose regimen (1.5 mg/kg total) after liver transplantation.


METHODS
Twenty-eight patients were enrolled in this study. Patients were evaluated for outcome, postoperative blood and ascites loss, serum levels of daclizumab, and corresponding changes in peripheral blood. Patients were also checked for development of anti-daclizumab antibodies.


RESULTS
CD25+ cells in patients' blood were significantly reduced for 28 days after daclizumab application. Elimination half-life of the antibody was 99 hr with a total body clearance of 57 ml/hr. Blood loss was not statistically significant and loss of ascites was weakly correlated to the monoclonal antibody clearance. One episode of mild acute rejection occurred. Although there was no significant decrease in absolute counts of CD3+, CD4+, and CD8+ lymphocytes, we were not able to show constant coating of IL-2Ralpha with daclizumab. IL-2Ralpha was not detectable on cell surface with two different antibodies and IL-2Rbeta was clearly reduced. Low titers of neutralizing anti-daclizumab antibodies in 3 of 13 patients were not of clinical significance and without influence on the pharmacokinetics.


CONCLUSIONS
A two-dose regimen with daclizumab in liver transplantation leads to effective blockade of the IL-2Ralpha for at least 14 days after transplantation. Daclizumab seems to affect not only IL-2Ralpha but also IL-2Rbeta and may lead to an impairment of other cytokine pathways, such as the IL-15 pathway.
Koch
Martina
M
Klinik für Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Germany.
Niemeyer
Gerit
G
Patel
Indravadan
I
Light
Susan
S
Nashan
Bjoern
B
D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000097:blood; D001201:Ascites / Q000453:epidemiology; D001707:Biopsy, Needle; D016063:Blood Loss, Surgical; D002102:Cadaver; D016572:Cyclosporine / Q000627:therapeutic use; D000077561:Daclizumab; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000453:epidemiology* / Q000473:pathology; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D016031:Liver Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D008657:Metabolic Clearance Rate; D011183:Postoperative Complications / Q000145:classification; D015375:Receptors, Interleukin-2 / Q000097:blood; D014019:Tissue Donors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D016572:Cyclosporine; D000077561:Daclizumab