Pharmacokinetic, pharmacodynamic, and outcome investigations as the basis for mycophenolic acid therapeutic drug monitoring in renal and heart transplant patients

Mycophenolate mofetil is widely used in combination with either cyclosporin e or tacrolimus for rejection prophylaxis in renal and heart transplant pat ients. Although not monitored routinely nearly to the degree that other age nts such as cyclosporine or tacrolimus, there is an expanding body of exper imental evidence for the utility of monitoring mycophenolic acid, the prima ry active metabolite of mycophenolate mofetil, plasma concentration as an i ndex of risk for the development of acute rejection. The following are impo rtant experimentally-based reasons for recommending the incorporation of ta rget therapeutic concentration monitoring of mycophenolic acid: (1) the MPA dose-interval area-under-the-concentration-time curve, and less precisely, MPA predose concentrations predict the risk for development of acute rejec tion, (2) the strong correlation between mycophenolic acid plasma concentra tions and expression of important cell surface activation antigens, whole b lood pharmacodynamic assays of lymphocyte proliferation and median graft re jection scores in a heart transplant animal model: (3) the greater than IO- fold interindividual variation of MPA area under the concentration time cur ve values in heart and renal transplant patients receiving a fixed dose of the parent drug; (4) drug-drug interactions involving other immunosuppressi ves are such that when switching from one to another leg, from cyclosporine to (acrolimus or vice-versa) substantial changes in MPA concentrations can occur in patients receiving a fixed dose of the parent drug; (5) significa nt effects of liver and kidney diseases on the steady-state total and free mycophenolic acid area under the concentration time curve values; (6) the n eed to closely monitor mycophenolic acid when a major change in immunosuppr ession is planned such as steroid withdrawal. Current investigations are fo cused on determination of the most optimal sampling time and for mycophenol ic acid target therapeutic concentration monitoring. Further investigations are needed to evaluate the pharmacologic activity of the newly described a cyl glucuronide metabolite of mycophenolic acid which has been shown to inh ibit, in vitro, inosine monophosphate dehydrogenase. (C) 2001 The Canadian Society of Clinical Chemists. All rights reserved.