Background: In a prior Phase 2b study in de novo KT pts, a CNI-free tofacitinib fixed-dose regimen achieved comparable rate of biopsy-proven acute rejection (BPAR), higher GFR, and lower incidence of allograft interstitial fibrosis and tubular atrophy (IF/TA) compared with CsA. However, higher rates of serious infection and PTLD were observed with tofacitinib. In this ad hoc analysis, we evaluated tofacitinib exposure as a prognosticator of clinical outcomes.
Methods: 322 KT pts received randomized treatment with either CsA or 1 of 2 tofacitinib fixed-dose regimens. All pts received basiliximab induction, MPA, and corticosteroids. Cox proportional hazards model was first used to identify the factors affecting clinical outcomes. Of the 213 tofacitinib-treated pts, 186 (87%) had evaluable tofacitinib exposure (time-weighted 2-hour postdose concentrations) and were re-categorized to above-median or below-median exposure groups (AME vs BME). Clinical outcomes were compared between each tofacitinib group and CsA.
Results: Tofacitinib pharmacokinetics were found to be statistically associated with serious infection rate (p<0.05).
|Results at Month 12||AME (n=93)||BME (n=93)||CsA (n=109)|
|First BPAR rate, KM%||9.3||18.5||18.8|
|First clinical BPAR rate (BPAR with increase in serum creatinine), KM%||5.6||9.1||9.0|
|Graft loss (death censored), KM%||0.0||2.5||0.9|
|Mean measured GFR, mL/min||61.2*||67.9*||53.9|
|IF/TA in allograft, %||20.5*||27.8*||48.3|
|Serious infection, KM%||53.0*||28.4||25.5|
|CMV disease, KM%||23.5*||9.6||4.5|
|BKV nephritis, KM%||3.8||2.8||1.1|
|Number of pts with PTLD||3#||0||0|
|*p<0.05 vs CsA; KM, Kaplan-Meier estimate|
|#Two additional cases of PTLD occurred in the AME group after Month 12|
Conclusions: Similar to the analyses of tofacitinib fixed-dose regimens, both AME and BME groups showed similar efficacy, better renal function, and a lower incidence of allograft IF/TA compared to CsA. However, increased incidences of serious infections and PTLD were observed only in the AME group. The BME group had a similar safety profile to CsA while preserving the advantage of better allograft function and histology. These findings suggest the balance of efficacy and safety of tofacitinib in KT pts may be improved by concentration-controlled dosing.
Vincenti, F.: Grant/Research Support, Pfizer Inc. Tedesco Silva, H.: Grant/Research Support, Pfizer Inc. O'Connell, P.: Other, Pfizer Inc. International Advisory Board. Tortorici, M.: Employee, Pfizer Inc. Stockholder, Pfizer Inc. Lawendy, N.: Employee, Pfizer Inc. Stockholder, Pfizer Inc. Wang, W.: Employee, Pfizer Inc. Stockholder, Pfizer Inc. Chan, G.: Employee, Pfizer Inc. Stockholder, Pfizer Inc.
To cite this abstract in AMA style:Busque S, Vincenti F, Silva HTedesco, O'Connell P, Tortorici M, Lawendy N, Wang W, Chan G. Adverse Events of Over-Immunosuppression Are Dependent on Tofacitinib Exposure in Kidney Transplant (KT) Patients [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/adverse-events-of-over-immunosuppression-are-dependent-on-tofacitinib-exposure-in-kidney-transplant-kt-patients/. Accessed October 27, 2020.
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