Volume 67, Issue 6, Pages 2440-2447 (June 2005) AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients  Eduard M. Scholten, Serge C.L.M. Cremers, R.I.K. C. Schoemaker, Ajda T. Rowshani, Erik J. van Kan, J.A.N. den Hartigh, Leendert C. Paul, Johan W. de Fijter  Kidney International  Volume 67, Issue 6, Pages 2440-2447 (June 2005) DOI: 10.1111/j.1523-1755.2005.00352.x Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 1 Tacrolimus blood concentration time curve according to the population-based model (continuous line), the measured tacrolimus blood concentrations at t = 0h, 2h, 3h in a patient (•), and the tacrolimus blood concentration time curve according to the model after fitting the population parameters to the measured concentrations (dotted line), after which the AUC0-12h is calculated by the model. Kidney International 2005 67, 2440-2447DOI: (10.1111/j.1523-1755.2005.00352.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 2 Relationship between either (A) predose level (Ctrough, ng/mL), (B) a single sample at 3 hours postdose (C3h, ng/mL), or (C) Bayesian estimates of AUC0-12h using blood concentrations at 0 and 3 hours postdose (AUC 0h +3h, ng.h/mL) and the AUC0-12h calculated by trapezoidal rule. The inner lines (–·–) demonstrate the 95% confidence interval, the outer lines the 95% prediction interval. Kidney International 2005 67, 2440-2447DOI: (10.1111/j.1523-1755.2005.00352.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 3 AUC-guided tacrolimus dosing in de novo kidney transplant recipients. Upper: Mean tacrolimus AUCs (± SD) in ng.h/mL and target AUC (dotted line) ± 20% (gray dotted lines). Lower: Dose corrections (± SD and range) in mg, calculated by the model, to reach these targets. Beyond 6 weeks (according to the protocol), the target AUC was lowered, which was implemented gradually between 6 and 10 weeks post-transplantation for safety reasons. For this reason, the dose corrections at these time points are shown in gray. Kidney International 2005 67, 2440-2447DOI: (10.1111/j.1523-1755.2005.00352.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 4 Tacrolimus concentrations (mean ± SE) (A, C) and dose-corrected tacrolimus curves (B, D) in the early phase post-transplant (target AUC: 210 ng.h/mL) (A, B), and in the “steady” phase (target AUC: 125 ng.h/mL) (C, D) in de novo kidney transplant recipients. Kidney International 2005 67, 2440-2447DOI: (10.1111/j.1523-1755.2005.00352.x) Copyright © 2005 International Society of Nephrology Terms and Conditions