title: High interpatient variability in response to mycophenolic acid maintenance therapy in patients with ANCA-associated vasculitis.
abstract: BACKGROUND
  Mycophenolic acid (MPA) is used in the maintenance therapy of antineutrophil cytoplasm antibody-associated systemic vasculitis (AASV). MPA exerts its immunosuppression by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), depleting activated lymphocytes of guanine nucleotides and retarding their proliferation. The purpose of our study was to examine the correlation between clinical outcome and pharmacokinetic-pharmacodynamic (PD) relationships of MPA in patients with AASV.
  
  
  METHODS
  We studied 358 Caucasian control patients without any MPA therapy to examine basal IMPDH activity. Thirty Caucasian patients with AASV under maintenance therapy with mycophenolate mofetil (MMF) underwent therapeutic drug monitoring.
  
  
  RESULTS
  We observed a high interindividual variability with regard to basal IMPDH activity in patients without any MPA treatment (0.8-35 nmol/mg protein/h). Patients were followed for a mean (±SD) period of 22 ± 8 months. During the observation period, seven patients had a relapse with an elevated Birmingham Vasculitis Activity Score of 9.2 ± 6. The basal IMPDH activity (Abasal) in patients who subsequently relapsed was raised at baseline, before receiving their first dose of MMF, and further increased at the time of relapse, when compared with stable patients. Patients with a relapse during the maintenance therapy had significantly higher levels of IMPDH activity [IMPDH enzyme activity curve (AEC) (0-12)] than stable patients (P = 0.001), indicating inadequate IMPDH suppression. MPA-AUC (0-12) was significantly decreased in relapse patients, in contrast to stable patients (P < 0.05).
  
  
  CONCLUSIONS
  Due to the highly variable response to maintenance therapy with MPA, PD drug monitoring is a new tool for detecting inadequate immunosuppression in AASV patients.
authors: Department of Nephrology, University of Heidelberg, University Hospital Heidelberg and Mannheim, Heidelberg, Germany.
authors: Matthias
authors: M
authors: Schaier
authors: Department of Nephrology, University of Heidelberg, University Hospital Heidelberg and Mannheim, Heidelberg, Germany.
authors: Christian
authors: C
authors: Scholl
authors: Department of Nephrology, University of Heidelberg, University Hospital Heidelberg and Mannheim, Heidelberg, Germany.
authors: Dominik
authors: D
authors: Scharpf
authors: Department of Nephrology, University of Heidelberg, University Hospital Heidelberg and Mannheim, Heidelberg, Germany.
authors: Wilhelm H
authors: WH
authors: Schmitt
authors: Department of Nephrology, University of Heidelberg, University Hospital Heidelberg and Mannheim, Heidelberg, Germany.
authors: Vedat
authors: V
authors: Schwenger
authors: Department of Nephrology, University of Heidelberg, University Hospital Heidelberg and Mannheim, Heidelberg, Germany.
authors: Martin
authors: M
authors: Zeier
authors: Department of Nephrology, University of Heidelberg, University Hospital Heidelberg and Mannheim, Heidelberg, Germany.
authors: Claudia
authors: C
authors: Sommerer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000188:drug therapy* / Q000201:enzymology; D015415:Biomarkers / Q000097:blood*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000097:blood*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D057285:Precision Medicine; D012008:Recurrence; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid
keywords: ANCA-associated vasculitis; maintenance therapy; mycophenolic acid; therapeutic drug monitoring