title: Pharmacokinetics of mycophenolic acid and determination of area under the curve by abbreviated sampling strategy in Chinese liver transplant recipients.
abstract: OBJECTIVE
  This study aimed to: (i) define the clinical pharmacokinetics of mycophenolic acid (MPA) in Chinese liver transplant recipients; and (ii) develop a regression model best fitted for the prediction of MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) by abbreviated sampling strategy.
  
  
  METHODS
  Forty liver transplant patients received mycophenolate mofetil 1g as a single dose twice daily in combination with tacrolimus. MPA concentrations were determined by high-performance liquid chromatography before dose (C(0)) and at 0.5 (C(0.5)), 1 (C(1)), 1.5 (C(1.5)), 2 (C(2)), 4 (C(4)), 6 (C(6)), 8 (C(8)), 10 (C(10)) and 12 (C(12)) hours after administration on days 7 and 14. A total of 72 pharmacokinetic profiles were obtained. MPA AUC(12) was calculated with 3P97 software. The trough concentrations (C(0)) of tacrolimus and hepatic function were also measured simultaneously. Multiple linear regression analysis was used to establish the models for estimated MPA AUC(12). The agreement between predicted MPA AUC(12) and observed MPA AUC(12) was investigated by Bland-Altman analysis.
  
  
  RESULTS
  The pattern of MPA concentrations during the 12-hour interval on day 7 was very similar to that on day 14. In the total of 72 profiles, the mean maximum plasma concentration (C(max)) and time to reach C(max) (t(max)) were 9.79 +/- 5.26 mg/L and 1.43 +/- 0.78 hours, respectively. The mean MPA AUC(12) was 46.50 +/- 17.42 mg . h/L (range 17.99-98.73 mg . h/L). Correlation between MPA C(0) and MPA AUC(12) was poor (r(2) = 0.300, p = 0.0001). The best model for prediction of MPA AUC(12) was by using 1, 2, 6 and 8 hour timepoint MPA concentrations (r(2) = 0.921, p = 0.0001). The regression equation for estimated MPA AUC(12) was 5.503 + 0.919 . C(1) + 1.871 . C(2) + 3.176 . C(6) + 3.664 . C(8). This model had minimal mean prediction error (1.24 +/- 11.19%) and minimal mean absolute prediction error (8.24 +/- 7.61%). Sixty-three of 72 (88%) estimated MPA AUC(12) were within 15% of MPA AUC(12). Bland-Altman analysis also revealed the best agreement of this model compared with the others and a mean error of +/-9.89 mg . h/mL.
  
  
  CONCLUSIONS
  This study showed the wide variability in MPA AUC(12) in Chinese liver transplant recipients. Single timepoint MPA concentration during the 12-hour dosing interval cannot reflect MPA AUC(12). MPA AUC(12) could be predicted accurately using 1, 2, 6 and 8 hour timepoint MPA concentrations by abbreviated sampling strategy.
authors.affiliation: Center of Organ Transplantation, Ruijin Hospital, Medical School of Shanghai Jiaoton University, Shanghai, P.R. China. haochendr@yahoo.com.cn
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Chenghong
authors.initials: C
authors.lastname: Peng
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Yu
authors.forename: Baiyong
authors.initials: B
authors.lastname: Shen
authors.forename: Xiaxing
authors.initials: X
authors.lastname: Deng
authors.forename: Weihua
authors.initials: W
authors.lastname: Qiu
authors.forename: Yue
authors.initials: Y
authors.lastname: Fei
authors.forename: Chuan
authors.initials: C
authors.lastname: Shen
authors.forename: Guangwen
authors.initials: G
authors.lastname: Zhou
authors.forename: Weiping
authors.initials: W
authors.lastname: Yang
authors.forename: Hongwei
authors.initials: H
authors.lastname: Li
mesh_terms: D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D002681:China / Q000453:epidemiology; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016014:Linear Models; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D011237:Predictive Value of Tests; D016559:Tacrolimus / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus