The influence of cyclosporine on mycophenolic acid plasma concentrations: A review

If mycophenolate mofetil (MMF) treatment is combined with cyclosporine, mycophenolic acid (MPA) plasma concentrations decrease, mycophenolic acid glucuronide (MPAG) increases, and the second peak in the MPA pharmacokinetic profile disappears. This is presumed to be caused by a cyclosporine-induced inhibition of the biliary excretion of MPAG, probably at the level of one of the drug transporters in the apical (canalicular) membrane of the hepatocyte. The most likely candidate for this inhibitory effect is canalicular multiple organic anion transporter. In patients switched from cyclosporine therapy to tacrolimus, as a result of this switch with unchanged MMF dose, the MPA concentrations will increase. It is not impossible that, after patients are switched from cyclosporine to tacrolimus, suddenly patients will have MMF-related side effects, although they may have been fine with that same dose before discontinuation of cyclosporine. Clinically, the difference in MPA levels between cyclosporine-and non-cyclosporine-containing regimens is also important in view of the accumulating evidence relating drug concentrations to efficacy. A potential strategy of increasing the MMF dose early after transplantation to reach the target concentration and tapering the dose at later points could reduce the incidence of acute rejection and avoid toxicity. In March 2003, the so-called Fixed Dose vs Concentration Controlled trial (FDCC) was started. In the FDCC trial, 900 patients will be randomized for either standard-dose therapy or concentration-controlled MMF therapy. The final results of this trial are expected in early 2006.

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