INDUCTION IMMUNOSUPPRESSION

S. Lin¹, A.K. Henning², F. Akhlaghi³, R. Reisfield⁴, A. Vergara-silva⁴, M.R. First^4
1Department Of Pharmacy Practice, University of Rhode Island, Kingston/RI/UNITED STATES OF AMERICA, ², The EMMES Corporation, Rockville/MD/UNITED STATES OF AMERICA, ³Biomedical & Pharmaceutical Sciences, University of Rhode Island, Kingston/RI/UNITED STATES OF AMERICA, ⁴, Astellas Pharma Global Development, Inc, Deerfield/IL/UNITED STATES OF AMERICA

Body: Introduction: Calcineurin inhibitors are known cytochrome P450 (CYP) enzyme substrates. CYP enzyme activity can be modulated via activation of IL-2 receptors (IL-2R) expressed on hepatocytes and intestinal cells. IL-2R antagonists (IL-2RA) may promote preferential binding of circulating IL-2 to IL-2Rs on these cells by blocking IL-2Rs on activated T-cells. This down-regulates CYP enzyme activity, leading to increased CNI levels. This analysis evaluates the significance of this drug-drug interaction in kidney transplant recipients. Methods: Data was utilized from a 5-year randomized, double-blinded, placebo-controlled study comparing outcomes associated with maintenance immunosuppression using 2 corticosteroid regimens: long-term therapy (CCS; n=195) versus early withdrawal (CSWD; n=191) after 7 days. Patients received either IL-2RAs or anti-thymocyte globulin (rATG) for induction therapy. Serial tacrolimus trough levels and doses used in the first 2 months were compared between induction agents within each corticosteroid arm. Tacrolimus adverse effects, as well as acute rejection rate and patient/graft survival at 12 months, were also evaluated. Results: No differences were observed in demographics between induction groups within each of the corticosteroid treatment arms. In the first week post-transplantation, IL-2RA-treated patients achieved significantly higher tacrolimus trough levels than rATG-treated patients. On day 3, of the patients who received continued corticosteroid therapy, tacrolimus levels were 11.6 vs 7.3 ng/mL in the IL-2RA and rATG induction groups (p=0.003), respectively. Corresponding levels were 14.0 vs 7.0 ng/mL in the CSWD cohort (p<0.001). Significantly lower doses (mg/kg) were required by IL-2RA-treated patients to achieve target levels, regardless of the corticosteroid treatment regimen. Differences in tacrolimus levels remained significant when levels were normalized to daily doses (see Figure 1a and 1b). No differences in acute rejection rates, graft function, patient/graft survival or rate of adverse effects were observed. Figure 1a. TAC blood levels (ng/mL) normalized to dose (mg/kg) – CCS group Figure 1b. TAC blood levels (ng/mL) normalized to dose (mg/kg) – CSWD group Conclusions: IL-2RA administration with tacrolimus results in significantly increased tacrolimus levels in the short term period post-kidney transplantation. This did not have an impact on rejection rates, graft function or patient/graft survival at 12 months.

Disclosure: All authors have declared no conflicts of interest.