Electronic Patient File-Embedded Model-Informed Precision Dosing Compared with Physician Dosing of Tacrolimus in Kidney Transplantation.

Model-informed precision dosing (MIPD) of tacrolimus in renal allograft recipients, evaluated in silico, demonstrated improved (time to and) probability of target concentration attainment and smaller deviations from target range. Using simulated tacrolimus concentration-time profiles, a study of 200 patients was predicted to have sufficient power to demonstrate superior performance of MIPD for these exposure end points compared with physician-based dosing. A fully automated tacrolimus MIPD application integrated in the electronic patient file was tested in 293 de novo recipients in the first 14 days after transplantation in a prospective randomized controlled clinical validation study. More patients dosed with the MIPD application reached the primary study end point of three in-target tacrolimus pre-dose trough concentrations by Day 8, compared with physician-dosed patients: 52.2% (95% CI: 45.3-59.6) vs. 35.7% (95% CI: 27.4-45.6); HR: 1.64 (95% CI: 1.10-2.43) (P = 0.015). The mean fraction of samples per patient in target during the complete study period was higher in the MIPD arm: 0.38 ± 0.14 compared with the physician-dosed arm: 0.28 ± 0.14 (P < 0.001). The mean distance from target window was significantly lower in MIPD-treated patients: 0.022 (95% CI: 0.019-0.024) vs. 0.040 (95% CI: 0.036-0.044) (P < 0.001). On 19 occasions (< 1%), MIPD tacrolimus dose suggestions were actively overruled by physicians. A fully automated MIPD application for tacrolimus in de novo renal recipients, integrated in the electronic patient file, demonstrated superior performance in achieving tacrolimus exposure targets with limited active overruling of MIPD dose executions by physicians. Automated MIPD can be tested in larger trials to evaluate the impact of dosing decision support on clinical outcomes after renal transplantation.