Therapeutic Drug Monitoring of Mycophenolic Acid

Abstract

Mycophenolic acid (MPA)-based therapies are widely used in combination with calcineurin inhibitors as maintenance immunosuppression for kidney transplant recipients (1). The two MPA therapies used in clinical transplantation are mycophenolate mofetil (MMF [brand name CellCept, Roche Pharmaceuticals, Nutley, NJ]) and mycophenolate sodium (MPS [brand name Myfortic, Norvartis Pharmaceuticals, Nutley, NJ]). MMF has been used for more than a decade and is a prodrug of MPA. The standard dosage of MMF in combination with cyclosporine (CsA) is 1 g given twice daily, although the dosage may be somewhat lower when co-administered with tacrolimus. MPS is an enteric coated form of MPA that was more recently introduced into the clinical arena. A dosage of 720 mg of MPS provides bioequivalence to a dosage of 1000 mg of MMF in kidney transplant patients (2). Immunosuppression afforded by MPA is achieved via reversible and uncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH), resulting in inhibition of guanine nucleotide biosynthesis (3,4). This consequently leads to suppression of both new DNA synthesis and other pathways that depend on a continuous supply of guanine nucleotide pool, such as T cell surface antigens and other glycosylated membrane proteins (4). Although there has been increased interest to incorporate MPA therapeutic drug monitoring into routine clinical practice (5–9), this has not yet become widespread in the United States for several possible reasons, including ( 1 ) lack of availability of US Food and Drug Administration–approved automated simple assays, ( 2 ) attainment of low rejection rates using empiric dosing of MMF in many maintenance immunosuppression regimens, ( 3 ) the complex pharmacokinetics (PK) of MPA, and ( 4 ) absence of overt organ toxicity. Here we discuss and review the pertinent information and study data regarding ( 1 ) our current understanding of MPA PK and major factors that can influence MPA clearance, ( 2 ) the performance …