Emmanuelle Comets (1,2), Marie-Clémence Verdier (1), Jing Wang (1), Eric Bellissant (1), Claire Fougerou (1)
(1) CIC 1414, CHU Pontchaillou, Université Rennes 1, 35000 Rennes, France (2) INSERM, IAME, UMR 1137; Univ Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France
Objectives: The objective of this work was to develop a pharmacokinetic (PK) model for mycophenolate acid (MPA) and its main active metabolite, phenolic glucuronide metabolite (MPAG), in patients given mycophenolate mofetil (MMF) in association with low doses of tacrolimus and steroids, to prevent graft rejection after hepatic transplantation.
Methods: The MMF-FK clinical trial was designed to investigate the benefits of co-administering MMF to reduce daily doses of tacrolimus in liver transplant recipients1. Patients were randomised to receive either tacrolimus therapy in conventional doses, or half doses of tacrolimus in combination with oral MMF, given as 1.5g twice daily for 6 weeks, then 1g twice daily. PK samples were collected 3 weeks (PK1) and 3 months (PK2) after transplantation. The Kehr drain implanted in the bile duct after transplantation was declamped at PK1 and clamped at PK2. The data were analysed through nonlinear mixed effect models, using Monolix 4.2.22.
Results: PK was collected in 27 patients, 20 of which had measurements on both occasions. The PK was well described by a 2 compartment model for MPA and a one-compartment model for MPAG, with enterohepatic recycling. The parameters defining MPAG recycling were estimated by a grid approach. MPA was mainly eliminated after metabolism to MPAG. At PK2 the amount of MPAG recycled was 10%, and decreased by about 50% at PK1 when the Kehr drain was declamped. Interindividual variability ranged from 20 to 70%; there was significant interoccasion variability for several parameters, even when the drain effect was taken into account, reflected in the large diversity of PK profiles.
Conclusions: This study confirms the difficulty of dose adjustment of MMF, due to the large variability of MPA/MPAG concentrations both between and within subjects, especially in these patients with possible renal and hepatic impairment receiving several co-medications. Although we could identify the enterohepatic cycle, its low contribution to overall exposure suggests a simpler PK model can be used for drug adjustment.
References:
[1] Boudjema K, Camus C, Saliba F, et al. Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: a randomized study. Am J Transplant. 2011;11:965-76.
[2] Monolix User Guide, version 4.2.2. Lixoft 2013. http://www.lixoft.eu/wp-content/resources/docs/UsersGuide.pdf
Reference: PAGE 23 (2014) Abstr 3116 [www.page-meeting.org/?abstract=3116]
Poster: Drug/Disease modeling - Other topics