Background: An increased incidence of acute rejection is seen with underexposure to mycophenolic acid (MPA) in the initial week post kidney transplantation, particularly in high immunological risk patients (1,2).
Up to 25% of individuals in contemporary drug regimens are below the proposed therapeutic range at this time (3), and these individuals cannot be identified a priori. There is ongoing interest in understanding changes in plasma protein binding of MPA occurring around the time of transplant (4).
Objectives: To quantify the change in MPA pharmacokinetics, and unexplained between-occasion variability, from pre- to post-kidney transplantation.
Methods: The ADOPT Trial (Dose Optimization Prior to Transplant) collected MPA and metabolite concentration data prior to kidney transplantation after steady-state dosing, and on multiple post-transplant occasions, from 45 transplant recipients. The pre-transplant and immediate post-transplant data was extracted, along with covariate data, to describe the pharmacokinetics. Analysis was performed using NONMEM 7.4.1.
Results: Total and unbound MPA concentration data were fit to a two-compartment pharmacokinetic model with first order absorption and lag-time, and first order elimination with allometric scaling using total body weight. There was no improvement in the fit when a post-transplant effect was used to predict clearance and protein binding. There was a -13% relative prediction error in model-predicted post-transplant clearance using the pre-transplant individual clearance estimate, which is an improvement compared with using the population clearance (40% relative prediction error).
Conclusion: Pre-transplant measurements of MPA can be used to improve the prediction of the dose required post-transplant to achieve target exposure.
References:
- Van Gelder T, Tedesco Silva H, De Fijter JW, Budde K, Kuypers D, Arns W, et al. Renal transplant patients at high risk of acute rejection benefit from adequate exposure to mycophenolic acid. Transplantation. 2010;89(5):595-9.
- Barraclough KA, Staatz CE, Johnson DW, Lee KJ, McWhinney BC, Ungerer JP, et al. Kidney transplant outcomes are related to tacrolimus, mycophenolic acid and prednisolone exposure in the first week. Transplant International. 2012;25(11):1182-93.
- van Gelder T, Hesselink DA. Mycophenolate revisited. Transplant international : official journal of the European Society for Organ Transplantation. 2015;28(5):508-15.
- Colom H, Andreu F, van Gelder T, Hesselink DA, de Winter BCM, Bestard O, et al. Prediction of Free from Total Mycophenolic Acid Concentrations in Stable Renal Transplant Patients: A Population-Based Approach. Clin Pharmacokinet. 2017;DOI:10.1007/s40262-017-0603-8.