Monitoring of Inosine Monophosphate Dehydrogenase Activity as a Biomarker for Mycophenolic Acid Effect: Potential Clinical Implications

Abstract

Mycophenolic acid (MPA) is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) and, in combination with other immunosuppressive drugs, effectively inhibits rejection in solid organ transplant recipients. MPA has a relatively narrow therapeutic window and exhibits wide inter- and intrapatient pharmacokinetic (PK) variability. This has stimulated the use of therapeutic drug monitoring as a strategy to tailor the MPA exposure to each patient's individual needs. Despite increasing therapeutic drug monitoring use, PK-assisted dosing is not universally adopted in part because of MPA's complex PK behavior. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic (PD) marker of MPA-induced immunosuppression may allow for increased precision when used in an integrated PK-PD fashion, providing a more accurate assessment of efficacy and aid in limiting toxicity. IMPDH activity displays wide interpatient variability but relatively small intrapatient variability even after long-term administration of MPA. The advent of calcineurin and corticosteroid-sparing regimens necessitates more patient-specific PK-PD parameters, which can be used throughout the posttransplant period to optimize MPA exposure and immediate and long-term graft and patient outcomes. Quantification of IMPDH posttransplant may serve as a stable, surrogate PD marker of MPA-induced immunosuppression when combined with current PK and monitoring strategies.