Limited Sampling Strategy for Tacrolimus Area Under the Curve in Renal Transplant Patients

The area under the blood concentration versus time curve (AUC) is a good measure of patient drug exposure. In clinical practice trough blood concentrations are routinely measured instead of A U C , because full pharmacokinetic profile is expensive and not always practicable. Recent studies have shown that in renal transplant patients receiving tacrolimus pre-dose monitoring is not the most reliable method to assess body drug exposure. The aim of this study was to evaluate the better association of time sampling in a limited sample strategy for AUC; in addiction the study involved the relationship between tacrolimus trough blood concentration and corresponding AUC. Steady state pharmacokinetic study for tacrolimus was carried out over a 12 hour dosing interval in 12 renal transplant patients. The study population was aged 46±8.3 (mean±SD) years, transplant age 585±1109 days, creatinine clearance 36.9±18.1 mL/ min, tacrolimus dose 0.10±0.05 mg/Kg/day. Thirteen blood samples, the first just before drug administration (CO), others at one-hour interval (CI...CI2), were analysed for tacrolimus concentrations with microparticle-enzyme-immunoassay (MEIA) technology applied to IMx analytical platform (Abbott Diagnostics). The AUC was calculated by linear trapezoidal rule. Single and associated point measurements were evaluated for correlation with AUC by multiple (stepwise) regression. The tacrolimus peak (mean±SD) was at the CI sample (32.2±18.1 ng/mL). The C10 sample conelated best with AUC (r=0.976). The correlation coeffìcient of the other isolated time points ranged from 0.730 to 0.969. Multiple regression analysis demonstrated the best predictive power of A U C for a six sampling strategy including CI, C2, C5, C6, C8, and C10 (adjusted r2= 0.9999). The trough concentration had the lowest correlation with the AUC (r=0.730, r2=0.534), although the correlation was statistically significant (p<0.01). A two-point model including CO and C3 greatly improved the predictive power (r2=0.969). So CO is a suitable although poor indicator of AUC; other abbreviated AUC measurements may be a more accurate tool for therapeutic monitoring of tacrolimus exposure in renal transplant recipients.