Evidence of Inverse Associations Between Mycophenolate, but Not Tacrolimus, Exposure and Absolute Neutrophil Count in Steroid-Free Adult Renal Transplant Recipients During the First Year Post-Transplant.

Purpose: Neutropenia frequently occurs (>50%) for renal transplant recipients in our center during the first year post engraftment while on mycophenolate (MPA) and tacrolimus (TAC) immunotherapy. Overexposure of MPA and/or TAC has been hypothesized to cause these neutropenic episodes. The purpose of this clinical study was to examine associations between MPA/TAC exposure and neutropenia in steroid-free kidney transplant patients. Methods: Age, absolute neutrophil count (ANC), MPA daily dose (g), TAC daily dose (mg), C1-C2-C4 MPA levels (mg/L), and C0-C2 TAC levels (μg/L) were collected prospectively in adult kidney recipients within 20-40 days(period 1), 4-7 months(period 2), and 11-13 months(period 3) post transplant (N=5-7). Area-under the curves of MPA and TAC, as measures of drug exposure, were determined using validated limited sampling strategies developed from steroid-free based regimens (Ther Drug Monit; 33:50-55, 2011). Spearman rank correlation analyses between dose-normalized area-under the curves of MPA or TAC and ANC were conducted (SigmaStat, v3.5 for Windows; significance set a priori at p<0.05). Results: Average study sample characteristics (mean baseline age 52 years) across 3 study periods included: ANC (3-4×103 cells/μL), MPA dose (1-2 g/D), TAC dose (5-8 mg/D), limited sampling strategy-predicted dose-normalized MPA exposures (27-36 mg*hr/L/g), and limited sampling strategy-predicted dose-normalized TAC exposures (20-25 μg*h/L/mg). Correlation analyses revealed inverse associations between ANC and MPA exposure within each study period (r2=0.26-0.47) and across the 3 visits, but no such associations were observed for TAC. Conclusions: To our knowledge, this is the first study to examine association between MPA or TAC exposure and neutropenia in steroid-free kidney transplant recipients using recently validated limited sampling strategies. Our novel findings suggest a potential association between MPA, but not TAC, exposure with ANC, which was consistent throughout all 3 study periods. The study is enrolling more patients to confirm these observations.