Screening for basiliximab exposure–response relationships in renal allotransplantation

Abstract

The immunosuppressant basiliximab--a chimeric monoclonal antibody specific to the interleukin-2 receptor on activated T-lymphocytes--significantly reduces the incidence of acute cellular rejection following renal transplantation. Screening for exposure-response relationships was performed within a randomized, blinded, placebo-controlled efficacy trial in which patients received 40 mg basiliximab (20 mg on days 0 and 4) by intravenous infusion in addition to cyclosporine and corticosteroids. In a subset of patients, serum samples were collected pre-transplant and once in weeks 2, 3 and 4 for determination of basiliximab concentrations. A population pharmacostatistical model was used to derive individual empirical Bayes estimates of each patient's pharmacokinetic parameters. Biopsy-confirmed acute rejection episodes were recorded to month 6 post-transplant. Forty basiliximab-treated patients were evaluated, 30 men and 10 women, aged 48 +/- 12 yr (range, 24-73) and weighing 72.4 +/- 12.9 kg (range, 52.5-107.5). The basiliximab distribution volume was 7.5 +/- 1.7 L, the half-life 7.5 +/- 2.5 d and the clearance 33 +/- 12 mL/h. There was no clinically relevant influence of weight, age, or gender on basiliximab disposition. Receptor-saturating serum basiliximab concentrations (> 0.2 microgram/mL) were maintained for 41 +/- 23 d. Twenty-five patients remained rejection-free over the 6-month observation period, while a total of 26 biopsy-confirmed acute rejection episodes occurred in the remaining 14 patients. Of these episodes, 12 occurred during receptor blockade. No apparent relationship to basiliximab concentration on the day of onset was observed range, 0.1-9.0 microgram/mL) nor did the time of suppression offset represent a period of increased risk for rejection episodes. Fourteen rejection episodes occurred after basiliximab had cleared from the serum. The durations of receptor suppression preceding these events did not differ compared with those in patients who remained rejection-free: 32 +/- 11 versus 45 +/- 26 d, respectively (p = 0.1269). Given the durations of receptor saturation achieved with the chosen basiliximab regimen, this screen for exposure-response relationships did not identify the duration of receptor saturation in peripheral blood as a predictive factor for acute rejection episodes. Further exploration for exposure-effect relationships in a larger population is warranted.

Efficacy and tolerability of interleukin‐2 receptor blockade with basiliximab in pediatric renal transplant recipients

“…The effect of basiliximab was monitored using anti‐CD25 antibodies, and saturation of the α‐chain of the IL‐2R was demonstrated to last for up to 6 weeks. No relationship between CD25 saturation and rejection was observed, similar to the results obtained in adult renal transplant recipients (14). The two patients who experienced a steroid‐resistant rejection during this time frame exhibited reduced CD25 saturation several days after clinical signs of rejection developed.…”

CD25 blockade in kidney transplant patients randomized to standard-dose or high-dose basiliximab with cyclosporine, or high-dose basiliximab in a calcineurin inhibitor-free regimen

“…A nonlinear relation was apparent between dose and AUC: Doubling the dose of basiliximab led to approximately a threefold increase in AUC, a finding that has not been observed previously at lower doses (up to 60 mg in total) . Clearance, that is, the linear component of basiliximab elimination, was lower in the current study (0.245L/day) than in previous reports (0.4–1.1L/day) , and the elimination half‐life (t 1/2β ) was 25.6 days compared to 6.5–14.4 days in other pharmacokinetic trials in kidney transplant patients . These findings could be accounted for by different analytical techniques or by the observed nonlinear elimination.…”

“…Among the five patients in this group who provided data to the end of the 12‐week study, T‐cell CD25 saturation was total in four cases (and 71% in the remaining case) at day 56 but was below 50% in all patients by day 84. Despite this extended saturation period as compared to previous pharmacodynamic studies , an entirely CNI‐free regimen with basiliximab induction at an increased cumulative dose of 80 mg did not appear to prevent early acute rejection adequately. The increased rate of acute rejection observed in the CNI‐free regimen is in agreement with the absence of synergistic benefit described between T‐cell receptor‐mediated production of IL‐2 blocked by CNI agents and the effect of IL‐2 receptor antibodies to limit IL‐2 mediated T‐cell proliferation.…”

A population pharmacokinetic screen to identify demographic-clinical covariates of basiliximab in liver transplantation

“…This regimen provides CD25 saturation on peripheral blood T lymphocytes for an average of 36 ± 14 days, which covers the period in which the majority of acute rejection episodes occur. Pharmacokinetic‐pharmacodynamic evaluations in both phase 3 trials for this transplant indication supported the dose regimen and indicated that those patients who experienced an acute rejection episode did not have a shorter duration of CD25 saturation compared with their rejection‐free peers 5 , 6 . Therefore the period of CD25 saturation achieved with this regimen appears to be appropriate, and prolonging the period would not likely improve the efficacy outcome.…”