THE ADOPT TRIAL: A PHARMACOMETRIC STUDY OF THE BETWEEN-OCCASION VARIABILITY IN FREE MYCOPHENOLIC ACID PHARMACOKINETICS PRIOR TO AND IN THE EARLY PHASE POST KIDNEY TRANSPLANT IN SIXTY PROSPECTIVELY RECRUITED ADULTS AND CHILDREN

D METZ¹, A WALKER¹, N CRANSWICK¹, J KAUSMAN¹, N HOLFORD², F IERINO³

¹Royal Children’s Hospital, Melbourne; ²Univerisity of Auckland, Auckland New Zealand; ³ St Vincent’s Hospital, Melbourne

Aim: Provide proof of concept that dosing to free mycophenolic acid (MPA) concentrations will allow optimisation of mycophenolate mofetil (MMF) prior to kidney transplantation and negate the need for repeated AUC estimation in the early months.

Background: The free drug principle, established for a broad range of therapeutic drugs, holds that it is the free drug concentration in plasma most directly linked with biophase concentration and hence drug effect.

To safely perform concentration-controlled dosing of MMF in the initial phase post kidney transplant, repeated AUC estimation is required, because of enterohepatic recycling and time-dependant clearance. However, assuming the free drug principle holds for MPA, as has been shown in vitro, it is likely that much of the increase in MPA exposure over time is related to clinically irrelevant plasma protein binding changes. This would reduce the need for repeated estimation and, we hypothesize, providing an opportunity for dose optimisation prior to kidney transplant.

Methods: The ADOPT trial, completing recruitment in 2017, is a national, multi-site pharmacokinetic trial examining the relationship between total and free MPA pharmacokinetics before and at several points after kidney transplantation, and of covariates known to influence MPA plasma protein binding. Pharmacometric mixed effect modelling will be used for analysis, including examining whether the between-occasion variability in free MPA is small enough to allow for precise concentration-controlled dosing.

Conclusions: If precision and practicality of free MPA dose optimisation can be shown, this would provide a compelling case for a larger interventional trial targeting mycophenolate dose to free MPA concentration. This would overcome the major practical challenges to optimising exposure to mycophenolic acid in the critical early phase post transplantation.