A population pharmacokinetic screen to identify demographic-clinical covariates of basiliximab in liver transplantation.
BACKGROUND
Basiliximab is a high-affinity interleukin-2 receptor (CD25) chimeric monoclonal antibody used for immunoprophylaxis in organ transplantation. It was assessed in a randomized, double-blind, placebo-controlled efficacy trial in de novo liver allograft recipients who received 40 mg of basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppression with cyclosporine (INN, ciclosporin) microemulsion and corticosteroids.


METHODS
Serial blood samples (8.3 +/- 1.4 per patient) were collected during 12 weeks after transplantation from 184 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. Demographic-clinical covariates were explored with regression methods.


RESULTS
Basiliximab clearance was 55 +/- 26 mL/h, the distribution volume was 9.7 +/- 4.2 L, and the half-life was 8.7 +/- 6.7 days. Patient weight, age, sex, ethnicity, history of alcoholism, hepatitis C seropositivity, and notable postoperative bleeding had no clinically relevant influences on basiliximab disposition; however, the cumulative volume of drained ascites fluid in the first week was positively correlated with clearance. Receptor-saturating basiliximab concentrations (> or =0.1 microg/mL) were maintained for 38 +/- 16 days, and this was negatively correlated with the cumulative volume of drained ascites fluid in week 1. Patients who experienced an acute rejection episode did not clear basiliximab at a faster rate than their rejection-free peers nor did they maintain CD25-saturating concentrations for a shorter period.


CONCLUSIONS
Although the standard dose regimen of 20 mg of basiliximab on days 0 and 4 after transplantation appears to be appropriate for the majority of patients with liver transplants, a supplemental dose at the end of the first week may be considered for those with substantial (>10 L) postoperative ascites fluid drainage.
Kovarik
J M
JM
Novartis Pharmaceuticals, Medizinische Hochschule, Universitäts Klinikum Rudolf Virchow, Switzerland.
Nashan
B
B
Neuhaus
P
P
Clavien
P A
PA
Gerbeau
C
C
Hall
M L
ML
Korn
A
A
D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D001202:Ascitic Fluid / Q000378:metabolism; D000077552:Basiliximab; D003710:Demography; D004311:Double-Blind Method; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016031:Liver Transplantation / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000276:immunology; D011993:Recombinant Fusion Proteins; D023001:Transplantation Tolerance
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab