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.
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 language | English |
|---|---|
| Number of pages | 1 |
| Publication status | Published - 24 Jan 2018 |
| Event | Population Analysis Group of Australia and New Zealand 2018 - Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Australia Duration: 5 Feb 2018 → 7 Feb 2018 Conference number: 19th https://www.paganz.org/melbourne-2018/ https://www.paganz.org/tag/2018/ (Abstracts) |
Conference
| Conference | Population Analysis Group of Australia and New Zealand 2018 |
|---|---|
| Abbreviated title | PAGANZ 2018 |
| Country/Territory | Australia |
| City | Melbourne |
| Period | 5/02/18 → 7/02/18 |
| Internet address |