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

Abstract

SummaryAn increased basiliximab dose may saturate T-cell CD25 receptors in kidney transplant patients receiving calcineurin inhibitor (CNI)-free immunosuppression. In a 12-week study, 16 de novo kidney transplant patients were randomized to (i) 40 mg basiliximab with cyclosporine [n = 3] (controls), (ii) 80 mg basiliximab with cyclosporine [n = 6], or (iii) 80 mg basiliximab with everolimus (CNI-free) [n = 7], all with mycophenolic acid and steroids. Recruitment was stopped prematurely due to increased biopsy-proven acute rejection (BPAR) in the basiliximab 80 mg CNI-free group. BPAR occurred in 1/3, 1/6, and 4/7 patients in the three treatment groups, respectively. The primary endpoint, area under the effect curve of CD25 saturation to week 12, was 8.4(1.6) % 9 weeks in the control group, 11.1(1.1) % 9 weeks with basiliximab 80 mg + cyclosporine, and 9.7(0.7) % 9 weeks in the basiliximab 80 mg CNI-free group (P = 0.020 for basiliximab 80 mg + cyclosporine versus controls; P = 0.119 for basiliximab 80 mg CNI-free versus controls). Although small patient numbers prohibit robust conclusions, these results suggest that doubling the cumulative basiliximab dose to 80 mg does not provide adequate immunosuppression during the first 3 months after kidney transplantation in the absence of CNI therapy (ClinicalTrials.gov number: NCT01596062). 184

Efficacy and Safety of Everolimus for Maintenance Immunosuppression of Kidney Transplantation: A Meta-Analysis of Randomized Controlled Trials

“…We performed sensitivity analysis excluding 2 trials [22, 35] that reported GFR estimates based on MDRD and a similar effect to the original meta analysis was observed (MD, 5.18; 95% CI, 2.07–8.30; I 2 , 56%). We performed additional sensitivity analysis excluding 2 trials [19, 24] that did not specify just which methods used to estimate GFR and a similar effect to the original meta analysis was observed (MD, 6.30; 95% CI, 3.06–9.53; I 2 , 42%).…”

“…After examining the titles and abstracts and eliminating identical publications, 67 possibly qualified articles were determined. Fifteen reports [22–36] of 11 trials, including a total of 1,633 randomized patients, were chosen for inclusion in the meta-analysis (Fig 1). One of these trials was available in abstract form only by Wolfgang et al 2012 [31].…”

“…GFR was estimated by Nankivell formula in 5 trails [24–27, 29–33], modification of diet in renal disease (MDRD) formula in 3 trails [22, 34, 35], and was unclear in 3 studies [23, 28, 36]. Early conversion to EVR (defined as ≤3 months after transplantation) was evaluated in 5 studies [22, 23, 25, 28, 30, 31], whereas 6 studies evaluated the late conversion to EVR [24, 26, 27, 31, 32–36]. There was a difference in baseline renal function, both within and between the trials, but most of the patients had mild or moderate renal dysfunction at the time of randomization.…”

“…There were 3 trials [23, 28, 31] that added to the meta-analysis examining the link between conversion from CNI to EVR and renal allograft loss while in the 5 other trials [22, 27, 30, 33, 35], no renal allografts were lost up to the first year posttransplantation. Patients converted to EVR had a similar risk of graft loss compared with the patients remaining on CNI (RR, 1.43; 95% CI, 0.44–4.68; I 2 , 37%; Fig 5).…”

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

“…The absence of first-order elimination term lead to apparent VM and KM values that may be superior than "actual" values. In studies where KM was not identifiable, either KM value was fixed to low values,as done for brodalumab [77] (anti-IL-17R) and dupilumab [78] (IL-4Rα), with values of 0.02 and 0.01 mg/L, respectively, or the Michaelis-Menten term was replaced by a zero-order elimination rate constant, as done for cetuximab [79,80] and basiliximab [81] (anti-CD25). However, MichaelisMenten models allow a quantification of the relationship between antigen mass and pharmacokinetic parameters only if antigen mass is added as a covariate on Michaelis-Menten term parameters.…”