Last updated 27 July 2021
The recommended target
concentration is an average steady state of 50 mcg/L unbound mycophenolic acid.
This is equivalent to 600 mcg/L*h AUC0-12. 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 This model is superceded by Metz2019.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.
Copyright All rights
reserved | Developed by Sam Holford & Nick Holford 2012-2021
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.