Ann Hepatobiliary Pancreat Surg.  2017 Feb;21(1):11-16. 10.14701/ahbps.2017.21.1.11.

Intra-individual variability of mycophenolic acid concentration according to renal function in liver transplant recipients receiving mycophenolate monotherapy

• Hwang S
• Song GW
• Jung DH
• Park GC
• Ahn CS
• Moon DB
• Ha TY
• Kim KH
• Lee SG

• KMID: 2371562
• DOI: http://doi.org/10.14701/ahbps.2017.21.1.11

Abstract

BACKGROUNDS/AIMS
Mycophenolate mofetil (MMF) has wide inter- and intra-individual variability of mycophenolic acid (MPA) after liver transplantation (LT). On this study, we aimed to analyse the intra-individual variability of MPA concentration in stable adult LT recipients receiving MMF monotherapy and develop a method to determine the target level in the situation of wide intra-individual variability.
METHODS
This retrospective cross-sectional study included 30 LT recipients. All patients received MMF monotherapy at a dose of 500 mg twice daily for ≥2 years and were divided into two groups based on renal function. MPA concentration-associated values were presented as mean with standard deviation and coefficient of variation (CV).
RESULTS
The normal renal function group (n=15) showed a mean 12-hour MPA concentration of 2.5±0.5 µg/ml (range, 1.8±0.5 to 3.6±0.7 µg/ml) and a mean CV of 20.4±7.7% (range, 8.7% to 39.4%). In the renal dysfunction group (n=15), the 12-hour MPA concentration fluctuated more widely with a mean value of 3.7±0.9 µg/ml (range, 2.8±0.8 to 5.1±1.2 µg/ml) and a mean CV of 24.5±4.9% (range, 17.1% to 37.5%). The 12-hour MPA concentration was significantly higher in the renal dysfunction group, as compared to the normal renal function group (p=0.001); whereas, the CV was not significantly different between the two groups (p=0.093).
CONCLUSIONS
We determined the inter- and intra-individual variability of 12-hour MPA concentration after LT. The results suggested that therapeutic drug monitoring of MPA is necessary due to the inter-individual and intra-individual variability of MMF pharmacokinetics, especially in LT recipients with renal dysfunction.

Keyword

Renal function; Mycophenolate mofetil; Mycophenolic acid; Variability; Liver transplantation

MeSH Terms

Adult
Cross-Sectional Studies
Drug Monitoring
Humans
Liver Transplantation
Liver*
Methods
Mycophenolic Acid*
Pharmacokinetics
Retrospective Studies
Transplant Recipients*
Mycophenolic Acid

Figure

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  Fig. 1 Serial measurement of 12-hour mycophenolic acid (MPA) concentration in liver transplant recipients with normal renal function after administration of mycophenolate mofetil 500 mg twice per day.

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  Fig. 2 Serial measurement of 12-hour mycophenolic acid (MPA) concentration in liver transplant recipients with renal dysfunction after administration of mycophenolate mofetil 500 mg twice per day.

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  Fig. 3 Scatter plot of mean 12-hour mycophenolic acid (MPA) concentration and coefficient of variation (CV) in liver transplant recipients with normal renal function (blank circle) and renal dysfunction (solid triangle) after administration of mycophenolate mofetil 500 mg twice per day.

Reference

1. Jain A, Vekatramanan R, Eghtesad B, Gadomski M, Mohanka R, Marcos A, et al. Long-term outcome of adding mycophenolate mofetil to tacrolimus for nephrotoxicity following liver transplantation. Transplantation. 2005; 80:859–864. PMID: 16210976.

2. Jain A, Kashyap R, Dodson F, Kramer D, Hamad I, Khan A, et al. A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone and mycophenolate mofetil in primary adult liver transplantation: a single center report. Transplantation. 2001; 72:1091–1097. PMID: 11579306.

3. Perry I, Neuberger J. Immunosuppression: towards a logical approach in liver transplantation. Clin Exp Immunol. 2005; 139:2–10. PMID: 15606606.

4. Sintchak MD, Fleming MA, Futer O, Raybuck SA, Chambers SP, Caron PR, et al. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell. 1996; 85:921–930. PMID: 8681386.

5. Brunet M, Cirera I, Martorell J, Vidal E, Millán O, Jiménez O, et al. Sequential determination of pharmacokinetics and pharmacodynamics of mycophenolic acid in liver transplant patients treated with mycophenolate mofetil. Transplantation. 2006; 81:541–546. PMID: 16495801.

6. Hwang S, Lee SG, Ahn CS, Kim KH, Moon DB, Ha TY, et al. A clinical assessment of mycophenolate drug monitoring after liver transplantation. Clin Transplant. 2010; 24:E35–E42. PMID: 20070319.

7. Jain A, Venkataramanan R, Hamad IS, Zuckerman S, Zhang S, Lever J, et al. Pharmacokinetics of mycophenolic acid after mycophenolate mofetil administration in liver transplant patients treated with tacrolimus. J Clin Pharmacol. 2001; 41:268–276. PMID: 11269567.

8. Park YH, Hwang S, Song GW, Jung DH, Ahn CS, Kim KH, et al. Correlation between mycophenolic acid blood level and renal dysfunction in stable liver transplant recipients receiving mycophenolate monotherapy. Transplant Proc. 2014; 46:811–815. PMID: 24767354.

9. Borra LC, Roodnat JI, Kal JA, Mathot RA, Weimar W, van Gelder T. High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant. 2010; 25:2757–2763. PMID: 20190242.

10. Shuker N, van Gelder T, Hesselink DA. Intra-patient variability in tacrolimus exposure: causes, consequences for clinical management. Transplant Rev (Orlando). 2015; 29:78–84. PMID: 25687818.

11. Tredger JM, Brown NW, Adams J, Gonde CE, Dhawan A, Rela M, et al. Monitoring mycophenolate in liver transplant recipients: toward a therapeutic range. Liver Transpl. 2004; 10:492–502. PMID: 15048791.

12. Glover TE, Watson CJ, Gibbs P, Bradley JA, Ntzani EE, Kosmoliaptsis V. Conversion from calcineurin to mammalian target of rapamycin inhibitors in liver transplantation: a meta-analysis of randomized controlled trials. Transplantation. 2016; 100:621–629. PMID: 26636736.

13. Hüsing A, Schmidt M, Beckebaum S, Cicinnati VR, Koch R, Thölking G, et al. Long-term renal function in liver transplant recipients after conversion from calcineurin inhibitors to mTOR inhibitors. Ann Transplant. 2015; 20:707–713. PMID: 26608590.

14. Bilbao I, Castells L, Rojas L, Cancino J, Dopazo C, Castro E, et al. Immunosuppression based on mycophenolate mofetil in stable liver transplanted patients. Int Immunopharmacol. 2006; 6:1977–1983. PMID: 17161351.

15. Orlando G, Baiocchi L, Cardillo A, Iaria G, De Liguori Carino N, De Luca L, et al. Switch to 1.5 grams MMF monotherapy for CNI-related toxicity in liver transplantation is safe and improves renal function, dyslipidemia, and hypertension. Liver Transpl. 2007; 13:46–54. PMID: 17154392.

16. Schmeding M, Neumann UP, Neuhaus R, Neuhaus P. Mycophenolate mofetil in liver transplantation--is monotherapy safe? Clin Transplant. 2006; 20(Suppl 17):75–79. PMID: 17100705.

17. Fairbanks KD, Thuluvath PJ. Mycophenolate mofetil monotherapy in liver transplant recipients: a single center experience. Liver Transpl. 2004; 10:1189–1194. PMID: 15350013.

18. Reich DJ, Clavien PA, Hodge EE. MMF Renal Dysfunction after Liver Transplantation Working Group. Mycophenolate mofetil for renal dysfunction in liver transplant recipients on cyclosporine or tacrolimus: randomized, prospective, multicenter pilot study results. Transplantation. 2005; 80:18–25. PMID: 16003228.

19. Schmeding M, Kiessling A, Neuhaus R, Heidenhain C, Bahra M, Neuhaus P, et al. Mycophenolate mofetil monotherapy in liver transplantation: 5-year follow-up of a prospective randomized trial. Transplantation. 2011; 92:923–929. PMID: 21832958.