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Pharmacokinetics of Mycophenolic Acid and Determination of Area Under the Curve by Abbreviated Sampling Strategy in Chinese Liver Transplant Recipients

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Abstract

Objectives

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 (AUC12) 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 (C0) and at 0.5 (C0.5), 1 (C1), 1.5 (C1.5), 2 (C2), 4 (C4), 6 (C6), 8 (C8), 10 (C10) and 12 (C12) hours after administration on days 7 and 14. A total of 72 pharmacokinetic profiles were obtained. MPA AUC12 was calculated with 3P97 software. The trough concentrations (C0) of tacrolimus and hepatic function were also measured simultaneously. Multiple linear regression analysis was used to establish the models for estimated MPA AUC12. The agreement between predicted MPA AUC12 and observed MPA AUC12 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 (Cmax) and time to reach Cmax (tmax) were 9.79 ± 5.26 mg/L and 1.43 ± 0.78 hours, respectively. The mean MPA AUC12 was 46.50 ± 17.42 mg · h/L (range 17.99–98.73 mg · h/L). Correlation between MPA C0 and MPA AUC12 was poor (r2 = 0.300, p = 0.0001). The best model for prediction of MPA AUC12 was by using 1, 2, 6 and 8 hour timepoint MPA concentrations (r2 = 0.921, p = 0.0001). The regression equation for estimated MPA AUC12 was 5.503 + 0.919 · C1 + 1.871 · C2 + 3.176 · C6 + 3.664 · C8. 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 AUC12 were within 15% of MPA AUC12. 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.

Conclusion

This study showed the wide variability in MPA AUC12 in Chinese liver transplant recipients. Single timepoint MPA concentration during the 12-hour dosing interval cannot reflect MPA AUC12. MPA AUC12 could be predicted accurately using 1, 2, 6 and 8 hour timepoint MPA concentrations by abbreviated sampling strategy.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Bullingham RES, Nicholls A, Hale M. Pharmacokinetics of mycophenolate mofetil (RS61443): a short review. Transplant Proc 1996; 28: 925–9

    PubMed  CAS  Google Scholar 

  2. Johnston A, Holt DW. Immunosuppressant drugs: role of therapeutic drug monitoring. Br J Clin Pharmacol 2001; 52: 61S–73S

    Article  PubMed  CAS  Google Scholar 

  3. Titte RS, Bruce K, Herwig-Ulf MK. Mycophenolate mofetil in solid-organ transplantation. Expert Opin Pharmacother 2003; 4: 2325–45

    Article  Google Scholar 

  4. McDiarmid SV. Mycophenolate mofetil in liver transplantation. Clin Transplant 1996; 10: 140–5

    PubMed  CAS  Google Scholar 

  5. Beckebaum S, Cicinnati VR, Klein CG, et al. Impact of combined mycophenolate mofetil and low-dose calcineurin inhibitor therapy on renal function, cardiovascular risk factors, and graft function in liver transplant patients: preliminary results of an open prospective study. Transplant Proc 2004; 36: 2671–4

    Article  PubMed  CAS  Google Scholar 

  6. Cantarovich M, Tzimas GN, Barkun J, et al. Efficacy of mycophenolate mofetil combined with very low-dose cyclosporine microemulsion in long-term liver-transplant patients with renal dysfunction. Transplantation 2003; 76: 98–102

    Article  PubMed  CAS  Google Scholar 

  7. van Gelder T, Hilbrands LB, Vanrenterghem Y, et al. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation 1999; 68: 261–6

    Article  PubMed  Google Scholar 

  8. Mourad M, Malaise J, Chaib Eddour D, et al. Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil. Clin Chem 2001; 47: 88–94

    PubMed  CAS  Google Scholar 

  9. Johnson AG, Rigby RJ, Taylor PJ, et al. The kinetics of mycophenolic acid and its glucuronide metabolite in adult kidney transplant recipients. Clin Pharmacol Ther 1999; 66: 492–500

    Article  PubMed  CAS  Google Scholar 

  10. Filler G, Mai I. Limited sampling strategy for mycophenolic acid area under the curve. Ther Drug Monit 2000; 22: 169–73

    Article  PubMed  CAS  Google Scholar 

  11. Yu Z, Cai WM, Xu D, et al. HPLC determination of mycophenolate mofetil and its active metabolite mycophenolic acid in human plasma. Chin J Pharm Anal 2005; 25: 381–4

    CAS  Google Scholar 

  12. Sheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 1981; 9: 503–12

    Article  PubMed  CAS  Google Scholar 

  13. Shaw LM, Korecka M, DeNofrio D, et al. Pharmacokinetic, pharmacodynamic, and outcome investigations as the basis for mycophenolic acid therapeutic drug monitoring in renal transplant patients. Clin Biochem 2001; 34: 17–22

    Article  PubMed  CAS  Google Scholar 

  14. Shaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion. Ther Drug Monit 2001; 23: 305–15

    Article  PubMed  CAS  Google Scholar 

  15. Brunet M, Cirera I, Martorell J, et al. Sequential determination of pharmacokinetics and pharmacodynamics of mycophenolic acid in liver transplant patients treated with mycophenolate mofetil. Transplantation 2006; 81: 541–6

    Article  PubMed  CAS  Google Scholar 

  16. Venkataramanan R, Shaw LW. Therapeutic monitoring of mycophenolic acid in liver transplant patients. Liver Transpl 2004; 10: 503–5

    Article  PubMed  Google Scholar 

  17. Sollinger HW. Mycophenolates in transplantation. Clin Transplant 2004; 18: 485–92

    Article  PubMed  Google Scholar 

  18. CellCept [package insert]. Nutley (NJ): Roche Laboratories Inc, 2004

  19. Jain A, Venkataramanan R, Hamad IS, et al. Pharmacokinetics of mycophenolic acid after mycophenolate mofetil administration in liver transplant patients treated with tacrolimus. J Clin Pharmacol 2001; 41: 268–76

    Article  PubMed  CAS  Google Scholar 

  20. Shaw LM, Korecka M, Venkataramanan R, et al. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 2003; 3: 534–42

    Article  PubMed  CAS  Google Scholar 

  21. Hebert MF, Chang T, Linna TJ, et al. Pharmacokinetics of intravenous mycophenolate mofetil (MMF) in liver transplant patients [abstract]. Clin Pharmacol Ther 1996; 59: 184

    Article  Google Scholar 

  22. Mardigyan V, Tchervenkov J, Metrakos P, et al. Best single time points as surrogates to the tacrolimus and mycophenolate acid area under the curve in adult liver transplant patients beyond 12 months of transplantation. Clin Ther 2005; 27: 463–9

    Article  PubMed  CAS  Google Scholar 

  23. Pisupati J, Jain A, Burckart G, et al. Intraindividual and Interindividual variations in the pharmacokinetics of mycophenolic acid in liver transplant patients. J Clin Pharmacol 2005; 45: 34–41

    Article  PubMed  CAS  Google Scholar 

  24. Oellerich M, Shipkova M, Schutz E, et al. Pharmacokinetic and metabolic investigations of mycophenolic acid in pediatric renal transplant recipients: implications for therapeutic drug monitoring. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients. Ther Drug Monit 2000; 22: 20–6

    Article  PubMed  CAS  Google Scholar 

  25. Tredger JM, Brown NW, Adams J, et al. Monitoring mycophenolate in liver transplant recipients: toward a therapeutic range. Liver Transpl 2004; 10: 492–502

    Article  PubMed  Google Scholar 

  26. Macchi-Andanson M, Charpiat B, Jelliffe RW, et al. Failure of traditional trough levels to predict tacrolimus concentrations. Ther Drug Monit 2001; 23: 129–33

    Article  PubMed  CAS  Google Scholar 

  27. Pawinski T, Hale M, Korecka M, et al. Limited sampling strategy for the estimation of mycophenolic acid area under the curve in adult renal transplant patients treated with concomitant tacrolimus. Clin Chem 2002; 48: 1497–504

    PubMed  CAS  Google Scholar 

  28. Yeung S, Tong KL, Tsang HL, et al. Determination of mycophenolate area under the curve by limited sampling strategy. Transplant Proc 2001; 33: 1052–3

    Article  PubMed  CAS  Google Scholar 

  29. Willis C, Taylor P, Salm P, et al. Evaluation of limited sampling strategies for estimation of 12-hour mycophenolic acid area under the plasma concentration-time curve in adult renal transplant patients. Ther Drug Monit 2000; 22: 549–54

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Dr Peijun Zhou for his help in reviewing the manuscript and Dr Tao Ma for statistical analysis.

The authors did not receive any funding for this study. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Center of Organ Transplantation, Ruijin Hospital, Medical School of Shanghai Jiaoton University, 197 Ruijin Er Road, Shanghai, 200025, P.R. China

    Hao Chen,  Chenghong Peng, Baiyong Shen, Xiaxing Deng, Weihua Qiu, Yue Fei, Chuan Shen, Guangwen Zhou, Weiping Yang & Hongwei Li

  2. Institute of Clinical Pharmacology, Ruijin Hospital, Medical School of Shanghai Jiaoton University, Shanghai, P.R. China

    Zhicheng Yu

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  1. Hao Chen
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Correspondence to Hao Chen or Chenghong Peng.

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Chen, H., Peng, C., Yu, Z. et al. Pharmacokinetics of Mycophenolic Acid and Determination of Area Under the Curve by Abbreviated Sampling Strategy in Chinese Liver Transplant Recipients. Clin Pharmacokinet 46, 175–185 (2007). https://doi.org/10.2165/00003088-200746020-00005

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