NextDose: A web-based Bayesian dose forecasting tool

Last updated 17 June 2024

Mycophenolate

A target concentration intervention (TCI) approach using mycophenolic acid concentrations (MPA) have been shown to reduce renal transplant rejection in two separate randomized concentration controlled trials (Hale, Nicholls et al. 1998, Le Meur, Buchler et al. 2007). The cost-effectiveness of target concentration intervention has also been established (Rousseau, Laroche et al. 2010).

Target Concentration

The recommended target concentration is an average steady state of 50 mcg/L unbound mycophenolic acid. This is equivalent to 600 mcg/L*h AUC_0-12. This target is derived from a target concentration based on total MPA concentrations.

The target concentration for MPA has been proposed to be 45 mg/L*h total MPA (Le Meur, Buchler et al. 2007). This is based on the use of TCI over a 12 month period after renal transplantation. Patients also received cyclosporine which increases unbound MPA clearance but not MPA plasma protein binding. Thus cyclosporine is not expected to change the relationship between MPA total (or unbound) concentration and response.

The use of total concentrations rather than unbound concentrations poses important problems for using TCI because even if the unbound target concentration remained constant the total concentration would rise because of improvement in renal function and increases in serum albumin. Renal function is associated with accumulation of presumably acidic substances which displace MPA from binding sites to albumin. As renal function improves MPA binding increases and total concentrations rise. Binding is directly proportional to serum albumin so increases in albumin also contribute to increased total concentrations.

Colom et al. (Colom, Andreu et al. 2018) have proposed using total MPA concentrations to predict unbound MPA concentrations based on creatinine clearance but did not account for changes in serum albumin. Data from the ADOPT trial (Metz, Holford et al. 2018) has been used to develop a model for the PK of unbound MPA and to predict total MPA using a binding parameter (KB) that changes with renal function and serum albumin. This model is based on MPA concentrations measured before and for 3 months after renal transplantation. It has been implemented in NextDose as Metz2019. An earlier version of the model was developed based only up to 2 weeks post transplant (Metz2018). This model is superceded by Metz2019. Versions of the models with and without between occasion variability for dose prediction are available.

Colom, H., F. Andreu, T. van Gelder, D. A. Hesselink, B. C. M. de Winter, O. Bestard, J. Torras, J. M. Cruzado, J. M. Grinyo and N. Lloberas (2018). "Prediction of Free from Total Mycophenolic Acid Concentrations in Stable Renal Transplant Patients: A Population-Based Approach." Clin Pharmacokinet 57(7): 877-893.

Hale, M., A. Nicholls, R. Bullingham, R. Hene, A. Hoitsman, J. Squifflet and et al. (1998). "The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation." Clinical Pharmacology and Therapeutics 64: 672-683.

Le Meur, Y., M. Buchler, A. Thierry, S. Caillard, F. Villemain, S. Lavaud, I. Etienne, P. F. Westeel, B. H. de Ligny, L. Rostaing, E. Thervet, J. C. Szelag, J. P. Rerolle, A. Rousseau, G. Touchard and P. Marquet (2007). "Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation." Am J Transplant 7(11): 2496-2503.

Metz, D., N. Holford, N. Cranswick, J. Kanellis, P. Trnka, A. Walker and F. Ierino (2018). "Total and unbound mycophenolic acid pharmacokinetics before and after kidney transplantation." PAGANZ Auckland.

Rousseau, A., M.-L. Laroche, N. Venisse, C. Loichot-Roselmac, A. Turcant, G. Hoizey, P. Compagnon, L. Hary, D. Debruyne, S. Saivin, E. Jacqz-Aigrain, M. Buchler, C. Villeneuve, A. Vergnenègre, Y. Le Meur and P. Marquet (2010). "Cost-Effectiveness Analysis of Individualized Mycophenolate Mofetil Dosing in Kidney Transplant Patients in the APOMYGRE Trial." Transplantation 89(10): 1255-1262.