Predicting model-informed precision dosing: A test-case in tacrolimus dose adaptation for kidney transplant...

Before investing resources into the development of a precision dosing (model-informed precision dosing [MIPD]) tool for tacrolimus, the performance of the tool was evaluated in silico. A retrospective dataset of 315 de novo kidney transplant recipients was first used to identify a one-compartment pharmacokinetic (PK) model with time-dependent clearance. MIPD performance was subsequently evaluated by calculating errors to predict future concentrations, which is directly related to dosing precision and probability of target attainment (PTA). Based on the identified model residual error, the theoretical upper limit was 45% PTA for a target of 13.5 ng/ml and an acceptable range of 12-15 ng/ml. Using empirical Bayesian estimation, this limit was reached on day 5 post-transplant and beyond. By incorporating correlated within-patient variability when predicting future individual concentrations, PTA improved beyond the theoretical upper limit. This yielded a Bayesian feedback dosing algorithm accurately predicting future trough concentrations and adapting each dose to reach a target concentration. Simulated concentration-time profiles were then used to quantify MIPD-based improvement on three end points: average PTA increased from 28% to 39%, median time to three concentrations in target decreased from 10 to 7 days, and mean log-squared distance to target decreased from 0.080 to 0.055. A study of 200 patients was predicted to have sufficient power to demonstrate these nuanced PK end points reliably. These simulations supported our decision to develop a precision dosing tool for tacrolimus and test it in a prospective trial.