**6.6. Mycophenolate mofetil**

Mycophenolate mofetil (MMF) is a maintenance immunosuppressant used often in combina‐ tion with CNIs and steroids. MMF was introduced in 1995 and has largely replaced azathio‐ prine in transplantation, as clinical trials showed superiority of MMF when compared to azathioprine. [29] Based on a recent SRTR report in 2009, MMF was part of the initial mainte‐ nance regimen in 89.9% of kidney transplant recipients.

#### **6.7. Mechanism of action**

Mycophenolate mofetil is an inactive prodrug with mycophenolic acid (MPA) being its active component. The mofetil entity significantly increases bioavailability of MPA. There is an enteric coated form of MPA also available for use that may be better tolerated in some patients. MPA is a selective, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) which is the rate-limiting enzyme in the denovo synthesis of purines. T- and B-lymphocytes are more dependent on this pathway than other cell types for proliferation since they do not have a salvage pathway for purine synthesis. Moreover, MPA is a more potent inhibitor of the type II isoform of IMPDH, which is predominatly expressed in activated lymphocytes.

#### **6.8. Clinical use**

MMF was initially approved for standard dose administration of 1 gram twice daily in adult kidney transplant recipients. Therapeutic drug monitoring for MMF/MPA is not performed routinely since several factors can impact the MPA AUC (detailed in the section below). Recent studies however have shown an association between MPA exposure and clinical outcomes (rejection and toxicity) and therapeutic drug monitoring (TDM) in certain circumstances may be warranted. [30] [31] The APOMYGRE study has shown decreased incidence of acute rejection with individualized MMF dosing based on drug exposure. [32]

When a serious infection develops, MMF or MPA is typically held since the drug's impact on lymphocyte proliferation is reversible and the immunosuppressive effects disappear within a few days. Intravenous formulations are available for MMF and intravenous dosing is the same as oral dosing with 1:1 conversion. Dose adjustment is not necessary in renal insufficiency. These drugs are not dialyzable. Use of MMF in pregnancy is contraindicated since it is associated with congenital malformations in the fetus especially facial abnormalities.[33] Mycophenolate should be discontinued before planned pregnancy in both male and female transplant recipients.
