Top

Published in:

01-04-2015 | Original Research Article

Influence of Sex and Race on Mycophenolic Acid Pharmacokinetics in Stable African American and Caucasian Renal Transplant Recipients

Authors: Kathleen M. Tornatore, Calvin J. Meaney, Gregory E. Wilding, Shirley S. Chang, Aijaz Gundroo, Louise M. Cooper, Vanessa Gray, Karen Shin, Gerald J. Fetterly, Joshua Prey, Kimberly Clark, Rocco C. Venuto

Published in: Clinical Pharmacokinetics | Issue 4/2015

Abstract

Background and Objectives

No evaluation of sex and race influences on mycophenolic acid (MPA) pharmacokinetics and adverse effects (AEs) during enteric-coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. The primary objective of this study was to investigate the influence of sex and race on MPA and MPA glucuronide (MPAG) pharmacokinetics in stable renal transplant recipients receiving ECMPS and tacrolimus

Methods

The pharmacokinetics of MPA and MPAG and their associated gastrointestinal AEs were investigated in 67 stable renal transplant recipients: 22 African American males (AAMs), 13 African American females (AAFs), 16 Caucasian males (CMs), and 16 Caucasian females (CFs) receiving ECMPS and tacrolimus. A validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting, and acid-suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under the concentration–time curve from time zero to 12 h (AUC₁₂) and dose-normalized AUC₁₂ (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates.

Results

Males had more rapid apparent MPA clearance (CMs 13.8 ± 6.27 L/h vs. AAMs 10.2 ± 3.73 L/h) than females (CFs 8.70 ± 3.33 L/h and AAFs 9.71 ± 3.94 L/h; p = 0.014) with a race–sex interaction (p = 0.043). Sex differences were observed in MPA clearance/BMI (p = 0.033) and AUC* (p = 0.033). MPA AUC₁₂ was greater than 60 mg·h/L in 57 % of renal transplant recipients (RTR) with 71 % of patients demonstrating gastrointestinal AEs and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared with males (p = 0.024). Race (p = 0.044) and sex (p = 0.005) differences were evident with greater MPAG AUC₁₂ in AAFs and CFs.

Conclusion

Sex and race differences were evident, with females having slower MPA clearance, higher MPAG AUC₁₂, and more severe gastrointestinal AEs. These findings suggest sex and race should be considered during MPA immunosuppression.

Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007;46(1):13–58. doi:10.2165/00003088-200746010-00002.CrossRefPubMed

Budde K, Durr M, Liefeldt L, Neumayer HH, Glander P. Enteric-coated mycophenolate sodium. Expert Opin Drug Saf. 2010;9(6):981–94. doi:10.1517/14740338.2010.513379.CrossRefPubMed

Mycophenolate mofetil in renal transplantation: 3-year results from the placebo-controlled trial. European Mycophenolate Mofetil Cooperative Study Group. Transplantation. 1999;68(3):391–6.

Staatz CE, Tett SE. Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update. Arch Toxicol. 2014;88(7):1351–89. doi:10.1007/s00204-014-1247-1.CrossRefPubMed

Budde K, Bauer S, Hambach P, Hahn U, Roblitz H, Mai I, et al. Pharmacokinetic and pharmacodynamic comparison of enteric-coated mycophenolate sodium and mycophenolate mofetil in maintenance renal transplant patients. Am J Transplant. 2007;7(4):888–98. doi:10.1111/j.1600-6143.2006.01693.x.CrossRefPubMed

Budde K, Glander P, Kramer BK, Fischer W, Hoffmann U, Bauer S, et al. Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in maintenance renal transplant recipients receiving tacrolimus: clinical, pharmacokinetic, and pharmacodynamic outcomes. Transplantation. 2007;83(4):417–24. doi:10.1097/01.tp.0000251969.72691.ea.CrossRefPubMed

Cooper MSM, Budde K, Oppenheimer F, Sollinger H, Zeier M. Enteric coated mycophenolate sodium immunosuppression in renal transplant patients: efficacy and dosing. Transplant Rev. 2012;26:233–40.CrossRef

Ortega F, Sanchez-Fructuoso A, Cruzado JM, Gomez-Alamillo JC, Alarcon A, Pallardo L, et al. Gastrointestinal quality of life improvement of renal transplant recipients converted from mycophenolate mofetil to enteric-coated mycophenolate sodium drugs or agents: mycophenolate mofetil and enteric-coated mycophenolate sodium. Transplantation. 2011;92(4):426–32. doi:10.1097/TP.0b013e31822527ca.CrossRefPubMed

Machnicki G, Ricci JF, Brennan DC, Schnitzler MA. Economic impact and long-term graft outcomes of mycophenolate mofetil dosage modifications following gastrointestinal complications in renal transplant recipients. Pharmacoeconomics. 2008;26(11):951–67.CrossRefPubMed

10.

Langone A, Doria C, Greenstein S, Narayanan M, Ueda K, Sankari B, et al. Does reduction in mycophenolic acid dose compromise efficacy regardless of tacrolimus exposure level? An analysis of prospective data from the Mycophenolic Renal Transplant (MORE) Registry. Clin Transplant. 2013;27(1):15–24. doi:10.1111/j.1399-0012.2012.01694.x.CrossRefPubMedCentralPubMed

11.

Borrows R, Chusney G, Loucaidou M, James A, Lee J, Tromp JV, et al. Mycophenolic acid 12-h trough level monitoring in renal transplantation: association with acute rejection and toxicity. Am J Transplant. 2006;6(1):121–8. doi:10.1111/j.1600-6143.2005.01151.x.CrossRefPubMed

12.

Tett SE, St Marcoux F, Staatz CE, Brunet M, Vinks AA, Miura M, Kuypers DR, van Gelder T, Cattaneo D. Mycophenolate, clinical pharmacokinetics,formulations and methods for assessing drug exposure. Transplant Rev. 2011;25:47–57.CrossRef

13.

van Hest RM, Mathot RA, Pescovitz MD, Gordon R, Mamelok RD, van Gelder T. Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: a population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients. J Am Soc Nephrol. 2006;17(3):871–80. doi:10.1681/asn.2005101070.CrossRefPubMed

14.

Kuypers DRJLY, Cantarovich M, Tredger MJ, Tett SE, Cattaneo D, Tonshoff B, Holt DW, Chapman J, van Gelder T. Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol. 2010;5:341–58.CrossRefPubMed

15.

Shaw LM, Korecka M, Venkataramanan R, Goldberg L, Bloom R, Brayman KL. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant. 2003;3(5):534–42.CrossRefPubMed

16.

Tornatore KM, Sudchada P, Dole K, DiFrancesco R, Leca N, Gundroo AC, et al. Mycophenolic acid pharmacokinetics during maintenance immunosuppression in African American and Caucasian renal transplant recipients. J Clin Pharmacol. 2011;51(8):1213–22. doi:10.1177/0091270010382909.CrossRefPubMed

17.

Tornatore KM, Sudchada P, Attwood K, Wilding GE, Gundroo AC, DiFrancesco R, et al. Race and drug formulation influence on mycophenolic acid pharmacokinetics in stable renal transplant recipients. J Clin Pharmacol. 2013;53(3):285–93. doi:10.1177/0091270012447814.CrossRefPubMed

18.

Shaw LM, Korecka M, Aradhye S, Grossman R, Bayer L, Innes C, et al. Mycophenolic acid area under the curve values in African American and Caucasian renal transplant patients are comparable. J Clin Pharmacol. 2000;40(6):624–33.CrossRefPubMed

19.

Pescovitz MD, Guasch A, Gaston R, Rajagopalan P, Tomlanovich S, Weinstein S, et al. Equivalent pharmacokinetics of mycophenolate mofetil in African-American and Caucasian male and female stable renal allograft recipients. Am J Transplant. 2003;3(12):1581–6.CrossRefPubMed

20.

Huang SM, Temple R. Is this the drug or dose for you? Impact and consideration of ethnic factors in global drug development, regulatory review, and clinical practice. Clin Pharmacol Ther. 2008;84(3):287–94. doi:10.1038/clpt.2008.144.CrossRefPubMed

21.

Chen ML. Ethnic or racial differences revisited: impact of dosage regimen and dosage form on pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2006;45(10):957–64. doi:10.2165/00003088-200645100-00001.CrossRefPubMed

22.

Food and Drug Administration 21 CFR Parts 312 and 314. 1998. http://www.gpo.gov/fdsys/pkg/FR-1998-02-11/html/98-3422.htm. Accessed 23 June 2014.

23.

Coakley M, Fadiran EO, Parrish LJ, Griffith RA, Weiss E, Carter C. Dialogues on diversifying clinical trials: successful strategies for engaging women and minorities in clinical trials. J Women’s Health (2002). 2012;21(7):713–6.CrossRef

24.

Hesselink DA, van Hest RM, Mathot RA, Bonthuis F, Weimar W, de Bruin RW, et al. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant. 2005;5(5):987–94. doi:10.1046/j.1600-6143.2005.00779.x.CrossRefPubMed

25.

Grinyo JM, Ekberg H, Mamelok RD, Oppenheimer F, Sanchez-Plumed J, Gentil MA, et al. The pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standard-dose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony pharmacokinetic substudy. Nephrol Dial Transplant. 2009;24(7):2269–76. doi:10.1093/ndt/gfp162.CrossRefPubMed

26.

Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y. Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation. 2006;82(8):1074–84. doi:10.1097/01.tp.0000235533.29300.e7.CrossRefPubMed

27.

Zucker KTA, Olson L, Esquenazi V, Tzakis A, Miller J. Evidence that tacrolimus augments the bioavailability of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit. 1999;21(1):35–43.CrossRefPubMed

28.

Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients 2010 data report. Am J Transplant. 2012;12 Suppl 1:1–156. doi:10.1111/j.1600-6143.2011.03886.x.

29.

Meaney CJ, Arabi Z, Venuto RC, Consiglio JD, Wilding GE, Tornatore KM. Validity and reliability of a novel immunosuppressive adverse effects scoring system in renal transplant recipients. BMC Nephrol. 2014;15:88. doi:10.1186/1471-2369-15-88.CrossRefPubMedCentralPubMed

30.

Difrancesco R, Frerichs V, Donnelly J, Hagler C, Hochreiter J, Tornatore KM. Simultaneous determination of cortisol, dexamethasone, methylprednisolone, prednisone, prednisolone, mycophenolic acid and mycophenolic acid glucuronide in human plasma utilizing liquid chromatography-tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2007;859(1):42–51. doi:10.1016/j.jchromb.2007.09.003.CrossRef

31.

Sollinger HW, Deierhoi MH, Belzer FO, Diethelm AG, Kauffman RS. RS-61443–a phase I clinical trial and pilot rescue study. Transplantation. 1992;53(2):428–32.CrossRefPubMed

32.

Roberts MS, Magnusson BM, Burczynski FJ, Weiss M. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet. 2002;41(10):751–90. doi:10.2165/00003088-200241100-00005.CrossRefPubMed

33.

Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–70.CrossRefPubMed

34.

Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther. 2004;75(5):434–47. doi:10.1016/j.clpt.2003.12.009.CrossRefPubMed

35.

de Jonge H, Naesens M, Kuypers DR. New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation. Ther Drug Monit. 2009;31(4):416–35. doi:10.1097/FTD.0b013e3181aa36cd.CrossRefPubMed

36.

Johnston A, He X, Holt DW. Bioequivalence of enteric-coated mycophenolate sodium and mycophenolate mofetil: a meta-analysis of three studies in stable renal transplant recipients. Transplantation. 2006;82(11):1413–8. doi:10.1097/01.tp.0000242137.68863.89.CrossRefPubMed

37.

Johnson HJ, Swan SK, Heim-Duthoy KL, Nicholls AJ, Tsina I, Tarnowski T. The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function. Clin Pharmacol Ther. 1998;63(5):512–8. doi:10.1016/s0009-9236(98)90102-3.CrossRefPubMed

38.

Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet. 2003;42(2):107–21. doi:10.2165/00003088-200342020-00001.CrossRefPubMed

39.

Mulder GJ. Sex differences in drug conjugation and their consequences for drug toxicity. Sulfation, glucuronidation and glutathione conjugation. Chem Biol Interact. 1986;57(1):1–15.CrossRefPubMed

40.

Morissette P, Albert C, Busque S, St-Louis G, Vinet B. In vivo higher glucuronidation of mycophenolic acid in male than in female recipients of a cadaveric kidney allograft and under immunosuppressive therapy with mycophenolate mofetil. Ther Drug Monit. 2001;23(5):520–5.CrossRefPubMed

41.

Staatz CE, Duffull SB, Kiberd B, Fraser AD, Tett SE. Population pharmacokinetics of mycophenolic acid during the first week after renal transplantation. Eur J Clin Pharmacol. 2005;61(7):507–16. doi:10.1007/s00228-005-0927-4.CrossRefPubMed

42.

Le Guellec C, Bourgoin H, Buchler M, Le Meur Y, Lebranchu Y, Marquet P, et al. Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in stable renal transplant patients. Clin Pharmacokinet. 2004;43(4):253–66. doi:10.2165/00003088-200443040-00004.CrossRefPubMed

43.

Kobayashi M, Saitoh H, Tadano K, Takahashi Y, Hirano T. Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats. J Pharmacol Exp Ther. 2004;309(3):1029–35. doi:10.1124/jpet.103.063073.CrossRefPubMed

44.

Cattaneo D, Merlini S, Zenoni S, Baldelli S, Gotti E, Remuzzi G, et al. Influence of co-medication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J Transplant. 2005;5(12):2937–44. doi:10.1111/j.1600-6143.2005.01107.x.CrossRefPubMed

45.

Hohage H, Zeh M, Heck M, Gerhardt UW, Welling U, Suwelack BM. Differential effects of cyclosporine and tacrolimus on mycophenolate pharmacokinetics in patients with impaired kidney function. Transpl Proc. 2005;37(4):1748–50. doi:10.1016/j.transproceed.2005.03.078.CrossRef

46.

Hesselink DA, van Gelder T. Genetic and nongenetic determinants of between-patient variability in the pharmacokinetics of mycophenolic acid. Clin Pharmacol Ther. 2005;78(4):317–21. doi:10.1016/j.clpt.2005.06.008.CrossRefPubMed

47.

Hoffmann U, Kroemer HK. The ABC transporters MDR1 and MRP2: multiple functions in disposition of xenobiotics and drug resistance. Drug Metab Rev. 2004;36(3–4):669–701. doi:10.1081/dmr-200033473.CrossRefPubMed

48.

van Gelder T, Klupp J, Barten MJ, Christians U, Morris RE. Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid. Ther Drug Monit. 2001;23(2):119–28.CrossRefPubMed

49.

Sherwin CM, Fukuda T, Brunner HI, Goebel J, Vinks AA. The evolution of population pharmacokinetic models to describe the enterohepatic recycling of mycophenolic acid in solid organ transplantation and autoimmune disease. Clin Pharmacokinet. 2011;50(1):1–24. doi:10.2165/11536640-000000000-00000.CrossRefPubMed

50.

Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562–75. doi:10.1056/NEJMoa067411.CrossRefPubMed

51.

Le Meur Y, Buchler M, Thierry A, Caillard S, Villemain F, Lavaud S, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. 2007;7(11):2496–503. doi:10.1111/j.1600-6143.2007.01983.x.CrossRefPubMed

52.

Gaston RS, Kaplan B, Shah T, Cibrik D, Shaw LM, Angelis M, et al. Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: the Opticept trial. Am J Transplant. 2009;9(7):1607–19. doi:10.1111/j.1600-6143.2009.02668.x.CrossRefPubMed

53.

van Gelder T, Silva HT, de Fijter JW, Budde K, Kuypers D, Tyden G, et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation. 2008;86(8):1043–51. doi:10.1097/TP.0b013e318186f98a.CrossRefPubMed

54.

Bunnapradist S, Ambuhl PM. Impact of gastrointestinal-related side effects on mycophenolate mofetil dosing and potential therapeutic strategies. Clin Transplant. 2008;22(6):815–21. doi:10.1111/j.1399-0012.2008.00892.x.CrossRefPubMed

55.

Arns W. Noninfectious gastrointestinal (GI) complications of mycophenolic acid therapy: a consequence of local GI toxicity? Transpl Proc. 2007;39(1):88–93. doi:10.1016/j.transproceed.2006.10.189.CrossRef

56.

Franconi F Campesi I, Occhioni S, Antonini P, Murphy MF. Sex and gender in adverse drug events, addiction, and placebo. Handb Exp Pharmacol. 2012;(214):107–26.

57.

Drug safety: most drugs withdrawn in recent years had greater health risks for women. U.S. Government Accountability Office. 2001 Jan 19. http://www.gao.gov/assets/100/90642.pdf. Accessed 23 June 2014.

Title: Influence of Sex and Race on Mycophenolic Acid Pharmacokinetics in Stable African American and Caucasian Renal Transplant Recipients
Authors: Kathleen M. Tornatore
Calvin J. Meaney
Gregory E. Wilding
Shirley S. Chang
Aijaz Gundroo
Louise M. Cooper
Vanessa Gray
Karen Shin
Gerald J. Fetterly
Joshua Prey
Kimberly Clark
Rocco C. Venuto
Publication date: 01-04-2015
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 4/2015
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-014-0213-7

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Influence of Sex and Race on Mycophenolic Acid Pharmacokinetics in Stable African American and Caucasian Renal Transplant Recipients

Abstract

Background and Objectives

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background and Objectives

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 4/2015

Population Pharmacokinetic-Pharmacodynamic Modelling of 24-h Diastolic Ambulatory Blood Pressure Changes Mediated by Axitinib in Patients with Metastatic Renal Cell Carcinoma

A Review of Pharmacokinetic Drug–Drug Interactions with the Anthelmintic Medications Albendazole and Mebendazole

Comment on: “Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus”

Evaluating Plasma Pharmacokinetics of Intravenous Iron Formulations: Judging Books by Their Covers?

Comparing Dosage Adjustment Methods for Once-Daily Tobramycin in Paediatric and Adolescent Patients with Cystic Fibrosis

Erratum to: Application of Modeling and Simulation to a Long-Term Clinical Trial: A Direct Comparison of Simulated Data and Data Actually Observed in Japanese Osteoporosis Patients Following 3-Year Ibandronate Treatment