Z. Daher Abdi (1), M. Essig (1,2), Y. Le Meur (3), P. Marquet (1,4), A. Rousseau (1)
(1) UMR S-850 National Institute of Health and Medical Research (Inserm), Limoges, France;(2) Department of Nephrology, University Hospital, Limoges, France; (3) Department of Nephrology, University Hospital, Brest, France; (4) Department of Pharmacology, University Hospital, Limoges, France
Objectives: Previous studies have reported conflicted results concerning the relationships between mycophenolic acid (MPA) exposure and the risk of acute rejection in the first year post-transplantation1. A recent randomized clinical trial2 concluded to a significant association between very early (i.e on day 3) MPA inter-dose area under the plasma concentration vs time curve (AUC) and acute rejection. The present study aimed at modelling the effect of MPA exposure on rejection free survival by comparing two approaches: i) a survival model with independent-time covariate(s) and ii) a joint model for longitudinal and survival data so as to take into account the time-course of MPA exposure.
Methods: We analyzed data from adult kidney transplant recipients enrolled in the randomized clinical trial APOMYGRE3. All patients received mycophenolate mofetil associated with cyclosporine. MPA AUC0-12h were previously estimated using Bayesian methods4; 126 patients provided between 2 and 6 AUC values estimated at different postgrafting periods. 22 patients experienced acute rejection(s). An exponential baseline hazard model implemented in NONMEM VII was used to predict the risk of rejection with an interval censored approach. MPA exposure was incorporated in the survival model using either i) a single MPA AUC value estimated within the first week (i.e. AUCw1) or ii) the longitudinal MPA exposure modelled by a non-linear mixed effect model (then the joint likelihood was maximized using the laplacian approximation). Visual predictive checks (VPC) based on simulated vs non-parametric estimates of survival (Kaplan-Meier plots) were used for model evaluation.
Results: The predicted time course of MPA AUC described rejection free survival better than AUCw1. In this joint model, the time-course of MPA AUCs over the first year post-transplantation was fitted using an exponential model with intercept. The number of HLA mismatches was the only significant independent-time covariate. The VPC based on the final joint model showed that the simulated survival curves matched the Kaplan-Meier survival estimates.
Conclusions: The developed joint model suggested that optimum MPA exposure is critical over the first year and not only in the very early post-transplantation period, highlighting the utility of monitoring MPA levels throughout the first year post-transplantation. Using this joint model, simulations can be performed leading to MPA target levels minimizing the risk of rejection.
References:
[1] Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007;46(1):13-58.
[2] van Gelder T, Silva HT, de Fijter JW, et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation. 2008;86(8):1043-1051.
[3] Le Meur Y, Büchler M, Thierry A, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am. J. Transplant. 2007;7(11):2496-2503.
[4] Prémaud A, Le Meur Y, Debord J, et al. Maximum a posteriori bayesian estimation of mycophenolic acid pharmacokinetics in renal transplant recipients at different postgrafting periods. Ther Drug Monit. 2005;27(3):354-361.
Reference: PAGE 21 (2012) Abstr 2469 [www.page-meeting.org/?abstract=2469]
Poster: New Modelling Approaches