title: Development and validation of limited sampling strategies for the estimation of mycophenolic acid area under the curve in adult kidney and liver transplant recipients receiving concomitant enteric-coated mycophenolate sodium and tacrolimus.
abstract: BACKGROUND
  Mycophenolic acid (MPA) is widely used in solid organ transplantation. MPA absorption from enteric-coated mycophenolate sodium (EC-MPS) is delayed, which results in a delayed enterohepatic recirculation and subsequently higher and more variable MPA 12-hour trough concentration and tmax values. Therefore, MPA trough level monitoring cannot be used to monitor MPA exposure in patients who are given EC-MPS. The aim of the study was to develop and validate a limited sampling strategy (LSS) for accurate prediction of the 12-hour area under the concentration-time curve (AUC0-12h) for MPA in patients who receive concomitant EC-MPS and Tacrolimus (Prograf or Advagraf) within 196 months posttransplantation. According to our knowledge, the LSS for MPA AUC estimation using high-performance liquid chromatography to determine MPA concentrations in plasma samples of kidney and liver transplant patients receiving EC-MPS and Tacrolimus (Advagraf) has not been previously evaluated.
  
  
  METHODS
  Seventy-four renal and liver transplant patients receiving EC-MPS and concomitant tacrolimus (either Prograf or Advagraf) provided a total of 74 pharmacokinetic profiles. MPA concentrations were measured using a validated high-performance liquid chromatography method for 9 plasma samples collected at predose and at 0.5, 1, 2, 3, 4, 6, 9, and 12 hours after the morning dose of EC-MPS after an overnight fast. LSS were developed and validated by stepwise multiple regression analysis with the use of a 2-group method (test, n = 37; and validation, n = 37).
  
  
  RESULTS
  The 3 and 4 time point equations using C1h, C3h, C9h and C1h, C2h, C3h, C6h, respectively, were found to be superior to all other models tested. When these LSS models were tested in the validation group, the results were acceptable [for 3 time points equation: r = 0.824, percentage of prediction error: 6.32 ± 25.75, 95% confidence interval (CI): -40.71 to 79.76; percentage of absolute prediction error: 27.45 ± 29.89, 95% CI: 0.04-199.92, predictive performance, 71% of estimated AUCs comprised within 85%-115% of the measured full MPA AUC, natural logarithmic residuals (ln) mean ± SD: -0.03 ± 0.24; for 4 time points equation: r = 0.898, percentage of prediction error: 3.32 ± 18.26, 95% CI: -49.35 to 51.06; percentage of absolute prediction error: 14.05 ± 11.89, 95% CI 0.13-49.86, percentage of predictive performance, 83% of estimated AUCs comprised within 85%-115% of the measured full MPA AUC, natural logarithmic residuals (ln) mean ± SD: -0.01 ± 0.19].
  
  
  CONCLUSIONS
  LSS equations using concentrations at 1, 3, and 9 hours or 1, 2, 3, and 6 hours time points provided the most reliable and accurate estimations of the MPA AUC in stable renal and liver transplant recipients treated with EC-MPS and tacrolimus. Further studies on independent groups of patients are required to confirm clinical utility of the presented LSS models.
authors.affiliation: *Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warsaw; †Department of Transplantation Medicine and Nephrology, Transplantation Institute, Warsaw; ‡Department of Physical Pharmacy and Pharmacokinetics, University of Medical Sciences, Poznan; §Department of Transplantation and General Surgery, District Hospital, Poznan; and ¶Department of Nephrology and Transplantation Medicine, Medical University, Wroclaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Pawinski
authors.forename: Paulina
authors.initials: P
authors.lastname: Luszczynska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Durlik
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Majchrzak
authors.forename: Teresa
authors.initials: T
authors.lastname: Baczkowska
authors.forename: Maria
authors.initials: M
authors.lastname: Chrzanowska
authors.forename: Joanna
authors.initials: J
authors.lastname: Sobiak
authors.forename: Maciej
authors.initials: M
authors.lastname: Glyda
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kuriata-Kordek
authors.forename: Dorota
authors.initials: D
authors.lastname: Kamińska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Krajewska
authors.forename: Marian
authors.initials: M
authors.lastname: Klinger
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012044:Regression Analysis; D015203:Reproducibility of Results; D013608:Tablets, Enteric-Coated; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time Factors; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D013608:Tablets, Enteric-Coated; D009173:Mycophenolic Acid; D016559:Tacrolimus