Advancing precision dosing in solid organ transplantation

Kidney transplantation offers superior quality of life and longevity as compared to dialysis. However, whilst short term outcomes are typically excellent, issues remain, including from the immunosuppressant agents required to prevent organ rejection. These include incomplete effectiveness (with premature graft loss), intolerance, and serious acute and cumulative toxicities. Given substantial dose-response variability with current immunosuppressant dosing strategies, greater precision (individualisation) offers the ability to increase both safety and effectiveness and thus improve long-term patient outcomes. There already exist more sophisticated approaches to dose individualisation, using a target concentration intervention approach. Bayesian forecasting enriches interpretation of measured drug concentrations (or pharmacodynamic biomarkers) in the individual by leveraging against prior knowledge of the drugs population pharmacokinetic (or pharmacokinetic-pharmacodynamic) characteristics, stored within a pharmaco-statistical model. Robust evidence continues to accumulate of the superiority of such an approach to typical therapeutic drug monitoring. Nevertheless, barriers to implementation remain, including evidence for therapeutic targets, regulatory oversight, clinician understanding and acceptance, as well as practical aspects. Using a decade of real-world PK data as well as prospective trial data (genotype-informed Bayesian dosing of tacrolimus), our work is looking to fill in knowledge gaps required for broader implementation of precision dosing of mycophenolate and tacrolimus in organ transplantation.