Tacrolimus and Mycophenolic Acid Exposure Are Associated with Biopsy-Proven Acute Rejection: A Study to Provide Evidence for Longer-Term Target Ranges

Evidence to define target ranges for tacrolimus (Tac) and mycophenolic acid (MPA) exposure after the first year of kidney transplantation is limited. We investigated the association of measurements at 1 year and repeated measurements of real-world Tac-trough levels (C₀) and abbreviated area under the curve from zero to 12 hours (AUC_0-12h) of Tac and MPA with biopsy-proven acute rejection (BPAR) between years 1 and 3 post-transplant in 968 kidney transplant recipients (KTRs). Thirty-five (3.6%) out of 968 KTRs experienced BPAR. Both Tac-AUC_0-12h (hazard ratio (HR): 0.39, 95% confidence interval (CI): 0.30–0.50, P < 0.001), Tac-C₀ (HR: 0.46, 95% CI: 0.38–0.57, P < 0.001) and MPA-AUC_0-12h at 1 year (HR: 0.80, 95% CI: 0.68–0.94, P = 0.006), as well as repeated measurements of Tac-C₀ (HR: 0.70, 95% credibility interval (CrI): 0.61–0.82, P < 0.001), and of MPA-AUC_0-12h (HR: 0.75, 95% CrI: 0.62–0.93, P < 0.001) were associated with BPAR. In our population, the recommended target range for Tac-AUC_0-12h at 1 year would be 75–95 ng*hour/mL and a Tac-C₀ 5–7 ng/mL. The Tac-AUC_0-12h predicted BPAR better than Tac-C₀ and identified KTRs with over- or underexposure despite supposedly adequate Tac-C₀. We did not find evidence to recommend another target than the consensus range of 30–60 mg*hour/L for MPA-AUC_0-12h after the first year of transplantation. To our knowledge, this is a first study on the simultaneous exposure of Tac and MPA at year 1 and subsequent BPAR up to year 3, which may help define the therapeutic target window for the longer term.