title: Dose-normalization for exposure to mycophenolic acid and the early clinical outcome in patients taking tacrolimus after heart transplantation.
abstract: BACKGROUND
  The early phase of MPA exposure has rarely been investigated after solid organ transplantation, especially in heart transplantation patients. We evaluated the association between exposure to mycophenolic acid (MPA), a main metabolite of mycophenolate mofetil (MMF), and clinical events within 3 months after heart transplantation.
  
  
  METHODS
  Trough (C0) and area under the curve (AUC)0-12h levels of MPA and its metabolite, mycophenolic acid glucuronide (MPAG), were determined using high-performance liquid chromatography. Corresponding clinical endpoints included acute rejection or MMF-related adverse events (gastrointestinal symptoms, leucopenia, and anemia). AUC measurements (n=77) were collected from 21 patients. Dose-normalized C0 and AUC0-12h levels were used to evaluate the association between MPA or MPAG exposure and MMF-related adverse events.
  
  
  RESULTS
  No acute rejection or mortality occurred during the follow-up period. Twelve patients (57%) developed 13 MMF-related adverse events. The MMF dose was tapered from 2.50 g/day on D1 to 1.55±0.54 g/day on D90. Significantly higher levels of dose-normalized MPA C0 and AUC0-12h were associated with the events than with the absence of the events (C0: 1.04±0.42 vs. 0.84±0.85 µg/mL/g [p=0.047]; AUC0-12h: 20.37±3.21 vs. 14.97±1.13 µg × h/mL/g; [p=0.038]). Conclusions Dose-normalized MPA exposure may protect against MMF toxicity in the early stage after heart transplantation. The MMF dose can be decreased to near 1.5 g/day 3 months post-transplantation without jeopardizing patient safety; a well-planned, tapered MMF regimen should also be considered.
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan.
authors.forename: Jun-Neng
authors.initials: JN
authors.lastname: Roan
authors.forename: Chen-Hsi
authors.initials: CH
authors.lastname: Chou
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Hsu
authors.forename: Shuan-Yin
authors.initials: SY
authors.lastname: Wu
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Huang
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Yang
authors.forename: Chwan-Yau
authors.initials: CY
authors.lastname: Luo
mesh_terms: D000328:Adult; D019540:Area Under Curve; D005260:Female; D020719:Glucuronides / Q000097:blood; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood*; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; D009173:Mycophenolic Acid; D016559:Tacrolimus