Individualized MMF Dosing
Individualized MMF Dosing
Le Meur Y, Büchler M, Thierry A, et al
Am J Transplant. 2007;7:2496-2503
This trial of kidney transplantation conducted in France randomized patients to fixed-dose mycophenolate mofetil (MMF) vs concentration-controlled MMF. All patients received basiliximab induction, cyclosporine, and corticosteroids, which were withdrawn by 4-6 months after transplantation. Concentration-controlled dosing was targeted to an area under the plasma concentration time curve (AUC) of 30 to 60 mg*h/L, using a Bayesian estimator of mycophenolic acid AUC that used 3-point sampling at various points after transplantation, as previously described by these authors.
The incidence of acute rejection (clinical and biopsy-proven) was significantly lower in the concentration-controlled group. The MMF dosage was significantly higher in the concentration-controlled group at 2 weeks, 1 month, and 3 months after transplantation. Patient and graft survival rates were identical. The complication rate was otherwise similar, except for a higher incidence of herpes virus infection in the concentration-controlled group.
It is ironic that the most commonly used immunosuppressive agent in the field of transplantation, MMF, has generally been dosed without regard to therapeutic drug monitoring. The lack of need for monitoring was proffered to and generally accepted by the transplant community from the outset, after Food and Drug Administration (FDA) approval of MMF in 1995 (parenthetically, there was no FDA-approved assay). This study suggests that this approach may not have been optimal. With the exception of corticosteroids, the dosing of all other immunosuppressive agents has been based on therapeutic drug monitoring. Unfortunately, according to the authors, single determinations of MPA levels are less useful than AUC estimations, a fact that makes it difficult to routinely monitor patients. The benefit of monitoring in this study is that it identified patients with low AUCs and allowed for significant early dosage increases in the concentration-controlled group.
If we are to believe the conclusions from this study, it is time to abandon fixed-dose MMF and use therapeutic drug monitoring to ensure optimal dosing. This will require a significant (and somewhat painful) change in the behavior of transplant programs that use MMF.
Le Meur Y, Büchler M, Thierry A, et al
Am J Transplant. 2007;7:2496-2503
This trial of kidney transplantation conducted in France randomized patients to fixed-dose mycophenolate mofetil (MMF) vs concentration-controlled MMF. All patients received basiliximab induction, cyclosporine, and corticosteroids, which were withdrawn by 4-6 months after transplantation. Concentration-controlled dosing was targeted to an area under the plasma concentration time curve (AUC) of 30 to 60 mg*h/L, using a Bayesian estimator of mycophenolic acid AUC that used 3-point sampling at various points after transplantation, as previously described by these authors.
The incidence of acute rejection (clinical and biopsy-proven) was significantly lower in the concentration-controlled group. The MMF dosage was significantly higher in the concentration-controlled group at 2 weeks, 1 month, and 3 months after transplantation. Patient and graft survival rates were identical. The complication rate was otherwise similar, except for a higher incidence of herpes virus infection in the concentration-controlled group.
It is ironic that the most commonly used immunosuppressive agent in the field of transplantation, MMF, has generally been dosed without regard to therapeutic drug monitoring. The lack of need for monitoring was proffered to and generally accepted by the transplant community from the outset, after Food and Drug Administration (FDA) approval of MMF in 1995 (parenthetically, there was no FDA-approved assay). This study suggests that this approach may not have been optimal. With the exception of corticosteroids, the dosing of all other immunosuppressive agents has been based on therapeutic drug monitoring. Unfortunately, according to the authors, single determinations of MPA levels are less useful than AUC estimations, a fact that makes it difficult to routinely monitor patients. The benefit of monitoring in this study is that it identified patients with low AUCs and allowed for significant early dosage increases in the concentration-controlled group.
If we are to believe the conclusions from this study, it is time to abandon fixed-dose MMF and use therapeutic drug monitoring to ensure optimal dosing. This will require a significant (and somewhat painful) change in the behavior of transplant programs that use MMF.
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