title: 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.
authors.affiliation: Department of Pharmacy Services, Medical University of South Carolina, Charleston, South Carolina, USA. weimert@musc.edu
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Weimert
authors.forename: Maurits
authors.initials: M
authors.lastname: Derotte
authors.forename: Rita R
authors.initials: RR
authors.lastname: Alloway
authors.forename: E Steve
authors.initials: ES
authors.lastname: Woodle
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002986:Clinical Trials as Topic; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016377:Organ Transplantation
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid