title: Limits to intensified mycophenolate mofetil dosing in kidney transplantation.
abstract: BACKGROUND
  Studies have shown that achieving adequate exposure of mycophenolic acid (MPA) early post transplant is associated with less acute rejection in kidney recipients. Intensified dosing with the equivalent of mycophenolate mofetil (MMF) 3 g daily in tacrolimus-treated patients has been shown to increase exposure however about 15% remain below the lower therapeutic threshold of MPA area under the curve (AUC) of 30 mg · hr⁻¹ · L⁻¹ early post transplant. A post hoc analysis of this study showed that a target MPA AUC >40 mg · hr⁻¹ · L⁻¹ was most effective. The primary objective of this study was to determine whether 4 g daily of MMF would result in a greater proportion achieving adequate MPA exposure.
  
  
  METHODS
  MMF 4 g daily was used in tacrolimus treated de novo kidney transplant recipients. A 3-point limited sample strategy was used to measure MPA AUC on days 5 and 14. Doses were adjusted at day 5 if exposure was high.
  
  
  RESULTS
  In 30 patients, the mean AUC was 63 ± 28 mg · hr⁻¹ · L⁻¹ on day 5, with 13% (4/30) ≤ 30 mg · hr⁻¹ · L⁻¹ and 57% (17/30) >60 mg · hr⁻¹ · L⁻¹. The target MPA AUC was <40 mg · hr⁻¹ · L⁻¹ in 23% (7/30). Three patients developed gastrointestinal toxicity and required dose changes. Acute rejection occurred in only 2 patients (grade 1A and 2B) within 3 months (day 5 MPA AUCs were 29.9 and 33 mg · hr⁻¹ · L⁻¹. On day 14 the mean AUC was 46 ± 17 mg · hr⁻¹ · L⁻¹. Many were on MMF doses >2 g daily (8 on 3 g and 9 on 4 g daily).
  
  
  CONCLUSIONS
  Compared to MMF 3 g daily, 4 g daily dose not result in a greater proportion adequately exposed. Rejections were few and occurred in the lower MPA exposed recipients. More than 50% of patients needed doses of MMF >2 g daily for 2 weeks to avoid underexposure. If intensified MPA dosing is considered, exceeding 3 g daily in tacrolimus-treated patients provides no added benefit.
authors.affiliation: Department of Medicine, Dalhousie University, Halifax, Canada. bryce.kiberd@dal.ca
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Kiberd
authors.forename: Joseph
authors.initials: J
authors.lastname: Lawen
authors.forename: Christopher
authors.initials: C
authors.lastname: Daley
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010865:Pilot Projects; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D011355:Prodrugs; D009173:Mycophenolic Acid; D016559:Tacrolimus