Background: Over the past 6 years we have prospectively used pharmacokinetic (PK) profiling of Tacrolimus (TAC) in “stable” RTR's to individualise future dosing. This study reports the results of TAC profiling in a large cohort of consecutive renal transplants in our unit. Diltiazem is a known inhibitor of CYP 3A4 and is routinely used in our unit to spare the TAC dose and protect against renal vasoconstrictive effects.

Methods: Stable RTR's had whole blood TAC levels measured (Architect CMIA, Abbott) at 6 time points (C0,0.5,1,2,3 and 4hours) from which a measured AUC0-4 was calculated by the Trapezoidal method and an AUC0-12 was derived using a published Bayesian equation based on four time points (C0, C1, C2 and C4). All patients were on prednisolone (0.3mg/kg) and Myfortic. 132 (82.3%) patients were also on daily Diltiazem (60mg -1.3%, 180 mg-66.0%, 240mg-15.0%, 360mg-3.9%). The correlation of each concentration time point with AUC's was measured by logistic regression. The dose/kg relationship to interquartile ranges for C0, AUC0-4 and AUC0-12 was determined and related to accepted therapeutic ranges from the published literature.

Results: 153 (103M:F50) consecutive RTRs were TAC PK profiled at a median of 33 POD's (IQR 27.3). Median for C0 = 9.5 (IQR 3.6 ng/ml); AUC0-4 = 69 ng.hr/ml (IQR 33); AUC 0-12 = 156.8 ng.hr/ml (IQR 69.11). 85/153( 55.56% ) of patients had C0 in the therapeutic range of 5-10 ng/ml, 4.6% (7/153) were below and 39.9% (61/153) were above. For AUC 0-12 the majority, 88/153 (57.5%), were above a recommended range of 100-150 ng.h/ml. 32/85 (36.4%) of patients with a C0 of 5-10 ng/ml had AUC0-12 of >150 ng.h/ml. 63/153(41.3%) of patients had Tmax=2hrs and 44(28.8%) had Tmax=1hr. In a linear regression model, C4 had the best correlation with AUC0-12 (r2= 0.90) whereas C0 was poorly correlated (r2= 0.625). C2 had best correlation with AUC0-4 (r2=0.78). Bioavailability measured by AUC0-4/dose_kg trended higher in females (p = 0.06)

Conclusions: PK profiling suggests 57.5% of our transplant population were overexposed to TAC despite acceptable C0 levels in the majority. Our study indicates a derived AUC measurement is a much better guide than C0 for future TAC dose adjustments in RTR's taking Diltiazem.

CITATION INFORMATION: Trevillian P, Heer M, Ainsworth S, Hibberd A. Population Pharmacokinetic Profiling of Tacrolimus in Renal Transplant Recipients (RTRs) Taking Diltiazem. Am J Transplant. 2017;17 (suppl 3).

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