We assessed the incidence of post-transplant biopsy-proven acute rejection (BPAR), graft loss and other adverse events (AEs) associated with everolimus (EVR) and tacrolimus (TAC) exposure at 12 months in a Phase IIIb, multi-center, randomized, open-label non inferiority study (US92).

De novo renal transplant recipients (n=309) received EVR 0.75 mg b.i.d. as starting dose, which was adjusted to maintain a trough level of 3–8 ng/mL. Patients received TAC and prednisone per local guidelines, with TAC dosing adjusted to achieve trough levels of 4–7 ng/mL (0–2 Months [M]), 3–6 ng/mL (2–6 M) and 2–5 ng/mL (6–12 M). Efficacy failure rates (BPAR, graft loss, death, loss to follow-up) and incidence of AEs were assessed at 12 months post-transplant to investigate relationships to time-normalized EVR and TAC exposure.

At 12 months post-transplant, BPAR, graft loss and death had occurred in 19.1%, 1.3% and 1.9% of patients, respectively, and 2.9% were lost to follow-up. The highest rates of BPAR occurred in patients with EVR <3 ng/mL (64.7% vs. 14.0% at 3–8 ng/mL) and in those with TAC <2 ng/mL (50.0% vs. 19.3% at ≥2 ng/mL). The lowest BPAR rates were associated with EVR 6–8 ng/mL (7.8%), regardless of TAC concentration. Graft loss also occurred most frequently in patients with the lowest EVR and TAC concentrations (10.5% and 100%, respectively). BK viral infection was less frequent at higher EVR (≥6 ng/mL) and lower TAC (<5 ng/mL) levels. Wound healing and peripheral edema rates were less frequent with intermediate-to-high TAC or EVR concentrations. New onset diabetes occurred most often at EVR <3 ng/mL and TAC <2 ng/mL, but also at the highest TAC level (≥8 ng/mL). Hypertriglyceridemia and stomatitis were most common at higher levels of TAC (≥5 ng/mL), regardless of EVR trough levels.

These results demonstrate a low incidence of BPAR and graft loss at an EVR trough level of ≥3 ng/mL with TAC concentration above 2 ng/mL in de novo kidney transplant patients at 12 months post-transplant. In addition, the lowest incidence of AEs were observed with EVR concentrations ≥6 ng/mL with TAC concentrations below 5 ng/mL.

CITATION INFORMATION: Shihab F, Qazi Y, Mulgaonkar S, McCague K, Patel D, Peddi V, Shaffer D. Relationship Between Clinical Events and Everolimus Exposure at 12 Months in De Novo Renal Transplant Recipients. Am J Transplant. 2016;16 (suppl 3).

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