title: Effect of cyclosporine on steady-state pharmacokinetics of MPA in renal transplant recipients is not affected by the MPA formulation: analysis based on therapeutic drug monitoring data.
abstract: BACKGROUND
  Two oral mycophenolic acid (MPA) formulations, immediate-release mycophenolate mofetil and enteric-coated mycophenolate sodium, have been shown to differ regarding some drug-drug interactions. The aim was to assess whether the effects of cyclosporine (CsA) on steady-state pharmacokinetics (PK) of MPA in renal transplant patients were affected by MPA formulation.
  
  
  METHODS
  A prospective, stratified observational study based on therapeutic drug monitoring of MPA (6 total plasma concentrations over a 12-hour dosing interval, τ) in consecutive stable adult renal transplant recipients (n = 68).
  
  
  RESULTS
  Patients treated with enteric-coated mycophenolate sodium (n = 45) or mycophenolate mofetil (n = 23) and with either CsA (microemulsion, n = 43) or tacrolimus (Tac) (immediate release, n = 25) were comparable regarding demographics, comorbidity, renal and liver functions, comedication, corticosteroid dose, CsA or Tac dose, and trough concentrations. Based on dose-normalized MPA concentrations and with adjustment for age, sex, body mass index, estimated glomerular filtration rate, and corticosteroid dose, CsA (as compared with Tac) consistently reduced MPA area under the concentration-time curve during the dosing interval at steady state overall [geometric mean ratio (GMR), 0.78; 95% confidence interval, 0.62-0.99] and by MPA formulation (by 22% and 21%, respectively), increased CLT/F,ss overall (1.31; 1.00-1.70) and by formulation (by 25% and 36%, respectively), reduced morning predose MPA concentration overall (0.59; 0.38-0.92) and by formulation (by 34% and 47%, respectively), increased peak-trough fluctuation overall (1.51; 1.06-2.17) and by formulation (by 58% and 45%, respectively), and prolonged tmax,ss overall (adjusted median difference 0.58, 0.04-1.12 hours) and by formulation (by 0.6 and 0.5 hours, respectively).
  
  
  CONCLUSIONS
  Qualitatively and quantitatively, the effect of CsA on steady-state PK of MPA is not conditional on MPA formulation.
authors: *Department of Pharmacology, Zagreb University School of Medicine; Departments of †Laboratory Diagnostics; and ‡Urology, University Hospital Center Zagreb; and §Teva Pharmaceuticals Europa-Pliva Croatia Ltd, Zagreb, Croatia.
authors: Vladimir
authors: V
authors: Trkulja
authors: Zdenka
authors: Z
authors: Lalić
authors: Sandra
authors: S
authors: Nađ-Škegro
authors: Ana
authors: A
authors: Lebo
authors: Paula
authors: P
authors: Granić
authors: Mila
authors: M
authors: Lovrić
authors: Josip
authors: J
authors: Pasini
authors: Nada
authors: N
authors: Božina
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016572:Cyclosporine / Q000627:therapeutic use*; D016903:Drug Monitoring / Q000379:methods; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011446:Prospective Studies; D016559:Tacrolimus / Q000627:therapeutic use; D066027:Transplant Recipients; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D016559:Tacrolimus