Inosine Monophosphate Dehydrogenase (IMPDH) Activity as a Pharmacodynamic Biomarker of Mycophenolic Acid Effects in Pediatric Kidney Transplant Recipients

There exists a clinical need to better understand intra-and interpatient variability inthe dose- concentration response to mycophenolate mofetil (MMF, CellCept) and in the susceptibility to adverse events related to this drug in pediatric kidney transplant recipients.1–3 MMF is a prodrug that is rapidly converted presystemically to its active immunosup-pressive moiety, mycophenolic acid (MPA). MPA exhibits its immunosuppressive effect through reversible noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides in T and B lymphocytes.4,5 According to the Scientific Registry for Transplant Recipients (SRTR) in 2007, approximately 70% of pediatric renal transplant recipients with functioning grafts 30 days posttrans-plant were treated with some form of MPA.6 The recommended MMF dose in children is 600 to 1200 mg/m2 divided in 2 doses, depending on comedication.1,7,8 Earlier clinical studies in pediatric patients showed large intra- and interpatient variability in MPA pharmacokinetics (PK) and exposure, despite dosing normalization to body surface area. Accordingly, possible benefits of therapeutic drug monitoring of MMF therapy have been outlined by several groups.9–11 In addition, data from adult populations indicate that concentration-controlled dosing strategies with an exposure target of 30 to 60 mg·h/L are associated with improved clinical outcomes and reduced drug-related toxicity.12–15 However, MPA PK are quite complex both in adult and pediatric transplant recipients because of variable absorption profiles, enterohepatic recycling, and changing drug clearance over time.3,16,17 Drug exposure in plasma may also not be directly reflective of intracellular pharmacodynamics (PD) in the immune system. Therefore, plasma drug concentrations alone may not fully predict freedom from rejection or side effects or long-term graft function.18,19 Recently, assays for measuring the pharmacodynamic effect of MPA by evaluating the level of IMPDH inhibition in mononuclear cells during MPA therapy have been introduced,20–22 adding a potential new dimension to the optimization of individual MPA therapy. To date, only few data on the PK-IMPDH relationship are available in MPA-treated adult kidney transplant patients,23,24 and no data have been reported in children. In adults, IMPDH activity displays wide interpatient but relatively small intrapatient variability even after long-term administration of MPA.25 Targeting IMPDH activity as a surrogate pharmacodynamic marker of MPA-induced immunosuppression may thus allow increased precision when used in an integrated PK/PD fashion, providing a more accurate assessment of efficacy and aid in limiting toxicity.25,26 In adult transplant patients, an association between pretransplant IMPDH activity and outcome of therapy has in fact been documented,24 but the impact of MPA PK on IMPDH activity variations posttrans-plant and the relationship between the level of post-transplant IMPDH inhibition and clinical outcomes have not been well established. In addition, the advent of calcineurin inhibitor- and corticosteroid-sparing immunosuppressive regimens may necessitate more patient- and protocol-specific PK/PD targets.27 Assessment of posttransplant IMPDH inhibition may thus serve as a useful pharmacodynamic marker of MPA-induced immunosuppression when combined with current PK monitoring strategies. The objective of this investigation was to study for the first time the PK and PD of MPA using IMPDH inhibition as a PD marker in pediatric renal transplant recipients early posttransplant and during maintenance treatment.