Total and unbound mycophenolic acid pharmacokinetics before and after kidney transplantation

David Kieran Metz, Nick Holford, Noël Edward Cranswick, John Kanellis, Peter Trnka, Amanda M. Walker, Frank Ierino

Research output: Contribution to conferenceAbstractpeer-review

Abstract

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.
Original languageEnglish
Number of pages1
Publication statusPublished - 24 Jan 2018
EventPopulation Analysis Group of Australia and New Zealand 2018 - Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Australia
Duration: 5 Feb 20187 Feb 2018
Conference number: 19th
https://www.paganz.org/melbourne-2018/
https://www.paganz.org/tag/2018/ (Abstracts)

Conference

ConferencePopulation Analysis Group of Australia and New Zealand 2018
Abbreviated titlePAGANZ 2018
Country/TerritoryAustralia
CityMelbourne
Period5/02/187/02/18
Internet address

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