title: Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patients.
abstract: OBJECTIVE
  To compare the pharmacokinetics of mycophenolic acid (MPA) and its metabolite (MPAG) when mycophenolate mofetil (MMF) is administered in combination with sirolimus or ciclosporin (CsA) in renal allograft recipients. Safety and efficacy (biopsy-proven acute rejection (BPAR)) were also assessed.
  
  
  METHODS
  Patients (n = 45) were randomized 2 : 1 to receive treatment with sirolimus (n = 30; dosed to maintain trough concentrations of 10-25 ng ml(-1) until week 8, and then 8-15 ng ml(-1) thereafter) or CsA (n = 15; administered as per centre practice) both in combination with daclizumab, oral MMF and corticosteroids. Pharmacokinetic assessments were performed at day 7, week 4, and months 3 and 6 post-transplant. The primary endpoint was the AUC(0,12 h) for MPA and MPAG. The pharmacokinetics of sirolimus were also assessed.
  
  
  RESULTS
  MPA exposure was 39-50% lower (month 6 mean AUC(0,12 h) (95%CI): 40.4 (33.8, 47.0) vs. 68.5 (54.9, 82.0) microg ml(-1) h) and MPAG exposure was 25-52% higher (722 (607, 838) vs. 485 (402, 569) microg ml(-1) h at month 6) in the presence of CsA compared with sirolimus across visits. BPAR was 40.0% with sirolimus and 13.3% with CsA. The incidence of hypertension, tremors and hirsutism was higher with CsA than with sirolimus, while the incidence of diarrhoea, hyperlipidaemia and impaired wound closure was higher with sirolimus. No deaths, malignancies or graft losses were reported.
  
  
  CONCLUSIONS
  Co-administration of sirolimus with MMF led to greater MPA exposure, but lower MPAG exposure, than co-administration with CsA. As rejection rates were higher in the absence of CsA, further study of calcineurin inhibitor-free regimens is required before general recommendations can be made.
authors.affiliation: Department of Surgery, Indiana University, Indianapolis, Indiana 46202, USA. mpescov@iupui.edu
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pescovitz
authors.forename: Flavio
authors.initials: F
authors.lastname: Vincenti
authors.forename: Marquis
authors.initials: M
authors.lastname: Hart
authors.forename: Larry
authors.initials: L
authors.lastname: Melton
authors.forename: John
authors.initials: J
authors.lastname: Whelchel
authors.forename: Shamkant
authors.initials: S
authors.lastname: Mulgaonkar
authors.forename: Diane
authors.initials: D
authors.lastname: McKay
authors.forename: Mimi
authors.initials: M
authors.lastname: Leung
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Calleja
authors.forename: M René
authors.initials: MR
authors.lastname: Bouw
mesh_terms: D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control*; D006801:Humans; D016030:Kidney Transplantation; D007970:Leukopenia / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus