Abstract
Aim
Provide proof of concept that dosing to free mycophenolic acid (MPA) concentrations will allow optimization 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 optimization 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 optimization 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 optimizing exposure to mycophenolic acid in the critical early phase post transplantation.
Provide proof of concept that dosing to free mycophenolic acid (MPA) concentrations will allow optimization 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 optimization 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 optimization 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 optimizing exposure to mycophenolic acid in the critical early phase post transplantation.
| Original language | English |
|---|---|
| Pages (from-to) | 89-90 |
| Number of pages | 2 |
| Journal | Nephrology |
| Volume | 22 |
| Issue number | S3 |
| DOIs | |
| Publication status | Published - Sept 2017 |
| Externally published | Yes |
| Event | Annual Scientific Meeting of the Australian-and-New-Zealand-Society-of-Nephrology 2017 - Darwin Convention Centre, Darwin, Australia Duration: 4 Sept 2017 → 6 Sept 2017 Conference number: 53rd https://onlinelibrary.wiley.com/toc/14401797/2017/22/S3 (Nephrology Vol 22, Issue S3) |