Abstract
Mycophenolic acid (MPA) underexposure in the immediate post-transplant period occurs in ~25% of kidney transplant recipients receiving tacrolimus. In high-risk candidates this is associated with over twice the rejection rate (23.9% versus 10.4%, p=0.012). Optimising mycophenolate dose based on a pre-transplant PK assessment could ameliorate this risk.
Aim
To describe the period effect – pre- to post-transplant – on MPA pharmacokinetics (PK), and the ability to predict post-transplant mycophenolate mofetil (MMF) dose requirement.
Methods
45 kidney transplant recipients had PK profiles for total MPA (MPAt) and unbound MPA (MPAu) on steady-state dosing both pre- and post-transplant. MPA AUC was estimated using the log-linear trapezoid method over a 12 h period. Change in MPA exposure was tested using the Wilcoxon signed-rank test. After adjustment for median change in exposure, the precision of pre-transplant AUC to predict post-transplant AUC was tested by median absolute percentage prediction error (MAPE), and the proportion within 20% of the observed post-transplant AUC, equivalent to a range of 36mg/L*h to 54mg/L*h around an MPAt target of 45mg/L*h.
Results
Estimated MPA AUC (0-12) values were significantly higher pre-transplant for both MPAt (median 63.05mg/L*h versus 42.53mg/L*h, p<0.001) and MPAu AUC (1067.4mcg/L*h versus 520.9mcg/L*h, p=<0.00001). MAPE was 31.4% for MPAt and 42.9% for MPAu. Only 19.4% of MPAt and 33.3% of MPAu exposure predictions were within 20% of observed post-transplant predictions.
Conclusions
Exposure to both MPAt and MPAu was significantly higher pre- versus post kidney transplantation. Pre-transplant PK profile was not highly predictive using the trapezoidal method. This could be in part be due to this method calculating AUC. A model-based Bayesian prediction method may be more useful, with pharmacometric analysis of ADOPT data underway.
Aim
To describe the period effect – pre- to post-transplant – on MPA pharmacokinetics (PK), and the ability to predict post-transplant mycophenolate mofetil (MMF) dose requirement.
Methods
45 kidney transplant recipients had PK profiles for total MPA (MPAt) and unbound MPA (MPAu) on steady-state dosing both pre- and post-transplant. MPA AUC was estimated using the log-linear trapezoid method over a 12 h period. Change in MPA exposure was tested using the Wilcoxon signed-rank test. After adjustment for median change in exposure, the precision of pre-transplant AUC to predict post-transplant AUC was tested by median absolute percentage prediction error (MAPE), and the proportion within 20% of the observed post-transplant AUC, equivalent to a range of 36mg/L*h to 54mg/L*h around an MPAt target of 45mg/L*h.
Results
Estimated MPA AUC (0-12) values were significantly higher pre-transplant for both MPAt (median 63.05mg/L*h versus 42.53mg/L*h, p<0.001) and MPAu AUC (1067.4mcg/L*h versus 520.9mcg/L*h, p=<0.00001). MAPE was 31.4% for MPAt and 42.9% for MPAu. Only 19.4% of MPAt and 33.3% of MPAu exposure predictions were within 20% of observed post-transplant predictions.
Conclusions
Exposure to both MPAt and MPAu was significantly higher pre- versus post kidney transplantation. Pre-transplant PK profile was not highly predictive using the trapezoidal method. This could be in part be due to this method calculating AUC. A model-based Bayesian prediction method may be more useful, with pharmacometric analysis of ADOPT data underway.
| Original language | English |
|---|---|
| Pages (from-to) | 54 |
| Number of pages | 1 |
| Journal | Nephrology |
| Volume | 23 |
| Issue number | S3 |
| DOIs | |
| Publication status | Published - Sept 2018 |
| Event | Annual Scientific Meeting of the Australian-and-New-Zealand-Society-of-Nephrology 2018 - International Convention Centre, Sydney, Australia Duration: 8 Sept 2018 → 12 Sept 2018 Conference number: 54th https://onlinelibrary.wiley.com/doi/10.1111/nep.13441 |