Mycophenolate, clinical pharmacokinetics, formulations, and methods for assessing drug exposure

• Published in: Transplantation reviews (Philadelphia, Pa.) Pa.), 2011-04, Vol.25 (2), p.47-57
• Main Authors: Tett, Susan E, Saint-Marcoux, Franck, Staatz, Christine E, Brunet, Merce, Vinks, Alexander A, Miura, Masatomo, Marquet, Pierre, Kuypers, Dirk R, van Gelder, Teun, Cattaneo, Dario
• Format: Article
• Language: English
• Subjects: Chemistry, Pharmaceutical; Graft Rejection - prevention & control; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacokinetics; Mycophenolic Acid - administration & dosage; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - pharmacokinetics; Organ Transplantation; Surgery
• ISSN: 0955-470X; 1557-9816
• DOI: 10.1016/j.trre.2010.06.001

Abstract This article summarizes part of a consensus meeting about mycophenolate (MPA) therapeutic drug monitoring held in Rome under the auspices of The Transplantation Society in November 2008 ( Clin J Am Soc Nephrol . 2010;5:341–358). This part of the meeting focused on the clinical pharmacokinetics of MPA and included discussion on how to measure MPA (active drug) exposure and the differences between the currently available formulations. Summary points • Because of variability in the dose-concentration relationship, MPA exposure should be measured and doses should be adjusted accordingly to achieve optimal clinical outcomes. • Suggested therapeutic exposures derived for MPA from mycophenolate mofetil (MMF) may differ to those that could be useful for MPA from enteric-coated mycophenolate sodium (EC-MPS), particularly if limited sampling strategies or single concentration, especially trough concentrations, is used, as the concentration-time profiles of MPA from the 2 formulations are quite different. The 2 MPA formulations cannot be considered as bioequivalent. • The area under the concentration-time curve (AUC0–12 ) is considered the criterion standard for monitoring of MPA, which is a reflection of exposure to the drug over the entire dosing period. If a limited sampling protocol coupled with multilinear regression or Bayesian estimation is used to estimate this parameter, it should be used only for the population in which the model has been developed and should preferably include at least one time point after 4 hours (preferably around 8 or 9 hours after MMF dosing). If a single time point is to be used as a surrogate for an AUC0–12 , trough concentration of MPA may be the most practical but, from a pharmacokinetic standpoint, is not the most informative time point to choose. • Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC0–12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS. • Lower (or higher) than expected total MPA exposure in patients with severe renal impairment may still indicate sufficient free MPA exposure. Mycophenolate free exposure measurement/estimation is likely to be beneficial in patients with severe renal im