POPULATION PHARMACOKINETICS AND DEMOGRAPHIC-CLINICAL COVARIATES OF BASILIXIMAB (SIMULECT) IN RENAL TRANSPLANTATION

Abstract

621 Basiliximab is an IL-2 receptor (CD25) chimeric mAb which significantly reduced the incidence of acute rejection episodes by 33% compared to placebo in the US Phase 3 renal transplant trial when added to a regimen of Neoral and steroids. In the context of this trial, the population PK of basiliximab was characterized and potential demographic-clinical covariates were screened. Methods:De novo patients received 40 mg Simulect (20 mg on days 0 and 4). Serial blood samples (n=1418; 8.2 ± 1.3 per patient) were collected over 12 weeks in 169 patients. Serum drug concentrations were determined by an idiotype-specific ELISA. Individual empirical Bayes estimates of the disposition parameters were derived based on population priors from 46 intensively sampled Phase 2 patients evaluated by nonlinear mixed-effects modeling. The relationships between PK parameters and covariates were explored by linear and nonlinear regression techniques for continuous variables and by unpaired t-tests for categorical variables. Pharmacokinetics: Basiliximab clearance (CL) was 36.7 ± 15.9 ml/hr, distribution volume (Vss) 8.0 ± 2.4 L, and half life 7.4 ± 3.0 days. Coefficients of between-patient variability were 41.4% for CL and 30.0% for Vss. Demographic covariates: Weight (range, 44-131 kg) and age (range, 20-69 yrs) each contributed ≤ 7% to the variability in CL and Vss. CL did not differ between genders (p=0.932) but there was a slightly larger Vss in men (8.2 ± 2.5 L, n=107) compared to women (7.5 ± 2.2 L, n=62), p=0.053. There was no influence of race on Vss (p=0.101); however, there was a trend toward lower CL in whites (35.5 ± 15.6 ml/hr, n=107) compared to blacks (40.2 ± 13.8 ml/hr, n=47), p=0.064. Clinical covariates: Patients with any notable proteinuria in the first posttransplant month did not have a more rapid CL (33.3 ± 13.1 ml/hr, n=17) compared to the remainder without proteinuria (37.1 ± 15.4 ml/hr), p=0.291. There was a trend toward faster CL in patients who were hemodialyzed in the first week due to delayed graft function (42.2 ± 14.0 ml/hr, n=23) compared to those with functioning grafts (35.9 ± 15.2 ml/hr), p=0.056. Patients experiencing an acute rejection episode after basiliximab was eliminated from serum (n=33) had not cleared the mAb at a faster rate than their peers who remained rejection-free: 38.1 ± 15.3 vs 35.1 ± 14.9 ml/hr, p=0.322. Conclusions: (1) Basiliximab disposition and variability were similar to those reported for other chimeric mAbs. (2) Individualizing doses based on weight (mg/kg) would bring no benefit to the regimen. (3) No special demographic or clinical subpopulations were identified for which an alteration in the standard adult dosing regimen appears necessary.