Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic haematopoietic cell transplantation: Effect of pharmacogenetic factors

British Journal of Clinical Pharmacology

Volumn 75, Issue 2, 2013, Pages 463-475

  Frymoyer, Adam ^a   Verotta, Davide ^a   Jacobson, Pamala ^b   Long Boyle, Janel ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF MINNESOTA   (United States)

Author keywords

Acute graft vs. host disease; Haematopoietic cell transplantation; Mycophenolate; Mycophenolic acid; Pharmacogenomics; Pharmacokinetics

Indexed keywords

CYCLOSPORIN A; GLUCURONOSYLTRANSFERASE 1A8; GLUCURONOSYLTRANSFERASE 1A9; GLUCURONOSYLTRANSFERASE 2B7; MULTIDRUG RESISTANCE PROTEIN 2; MYCOPHENOLIC ACID; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER;

ACUTE GRAFT VERSUS HOST DISEASE; ADULT; AGED; ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION; AREA UNDER THE CURVE; ARTICLE; CREATININE CLEARANCE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG ELIMINATION; DRUG EXPOSURE; FEMALE; GENETIC POLYMORPHISM; GENETIC VARIABILITY; GRAFT RECIPIENT; HUMAN; MAJOR CLINICAL STUDY; MALE; PHARMACOGENETICS; POPULATION RESEARCH; PREDICTOR VARIABLE; PRIORITY JOURNAL; RETROSPECTIVE STUDY;

ADMINISTRATION, ORAL; ADULT; AGED; AREA UNDER CURVE; BIOLOGICAL AVAILABILITY; ENZYME INHIBITORS; FEMALE; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMANS; IMMUNOSUPPRESSIVE AGENTS; INJECTIONS, INTRAVENOUS; MALE; MIDDLE AGED; MYCOPHENOLIC ACID; NONLINEAR DYNAMICS; PHARMACOGENETICS; POLYMORPHISM, GENETIC; RETROSPECTIVE STUDIES; TRANSPLANTATION, HOMOLOGOUS; YOUNG ADULT;

EID: 84872249602     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/j.1365-2125.2012.04372.x     Document Type: Article

References (56)

1. Soiffer RJ. Hematopoietic Stem Cell Transplantation, 2nd Editon. Totowa, NJ and London: Humana and Springer Distributor, 2008.
2. Majhail NS, Weisdorf DJ, Wagner JE, Defor TE, Brunstein CG, Burns LJ. Comparable results of umbilical cord blood and HLA-matched sibling donor hematopoietic stem cell transplantation after reduced-intensity preparative regimen for advanced Hodgkin lymphoma. Blood 2006; 107: 3804-3807.
3. Anonymous. Product Information: CellCept (R) (Mycophenolate Mofetil) Oral and Injectable. South San Francisco, CA: Genetech, 2010.
4. Jacobson P, Rogosheske J, Barker JN, Green K, Ng J, Weisdorf D, Tan Y, Long J, Remmel R, Sawchuk R, McGlave P. Relationship of mycophenolic acid exposure to clinical outcome after hematopoietic cell transplantation. Clin Pharmacol Ther 2005; 78: 486-500.
5. Jenke A, Renner U, Richte M, Freiberg-Richter J, Platzbecker U, Helwig A, Thiede HM, Schafer-Eckart K, Ehninger G, Bornhauser M. Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation. Clin Transplant 2001; 15: 176-184.
6. Kiehl MG, Shipkova M, Basara N, Blau IW, Schutz E, Armstrong VW, Oellerich M, Fauser AA. Mycophenolate mofetil in stem cell transplant patients in relation to plasma level of active metabolite. Clin Biochem 2000; 33: 203-208.
7. Nash RA, Johnston L, Parker P, McCune JS, Storer B, Slattery JT, Furlong T, Anasetti C, Appelbaum FR, Lloid ME, Deeg HJ, Kiem HP, Martin PJ, Schubert MM, Witherspoon RP, Forman SJ, Blume KG, Storb R. A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2005; 11: 495-505.
8. Basara N, Blau WI, Kiehl MG, Schmetzer B, Bischoff M, Kirsten D, Gunzelmann S, Fauser AA. Mycophenolate mofetil for the prophylaxis of acute GVHD in HLA-mismatched bone marrow transplant patients. Clin Transplant 2000; 14: 121-126.
9. Bornhauser M, Schuler U, Porksen G, Naumann R, Geissler G, Thiede C, Schwerdtfeger R, Ehninger G, Thiede HM. Mycophenolate mofetil and cyclosporine as graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation. Transplantation 1999; 67: 499-504.
10. Giaccone L, McCune JS, Maris MB, Gooley TA, Sandmaier BM, Slattery JT, Cole S, Nash RA, Storb RF, Georges GE. Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation. Blood 2005; 106: 4381-4388.
11. Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D, Petersdorf E, McSweeney P, Pulsipher M, Woolfrey A, Chauncey T, Agura E, Heimfeld S, Slattery J, Hegenbart U, Anasetti C, Blume K, Storb R. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 2003; 102: 2021-2030.
12. Kim H, Long-Boyle J, Rydholm N, Orchard PJ, Tolar J, Smith AR, Jacobson P, Brundage R. Population pharmacokinetics of unbound mycophenolic acid in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplantation. J Clin Pharmacol 2011; Nov 22 [Epub ahead of print].
13. Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P. Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos 2005; 33: 139-146.
14. Bullingham RE, Nicholls A, Hale M. Pharmacokinetics of mycophenolate mofetil (RS61443): a short review. Transplant Proc 1996; 28: 925-929.
15. Miles KK, Stern ST, Smith PC, Kessler FK, Ali S, Ritter JK. An investigation of human and rat liver microsomal mycophenolic acid glucuronidation: evidence for a principal role of UGT1A enzymes and species differences in UGT1A specificity. Drug Metab Dispos 2005; 33: 1513-1520.
16. Bernard O, Guillemette C. The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants. Drug Metab Dispos 2004; 32: 775-778.
17. Hesselink DA, van Hest RM, Mathot RA, Bonthuis F, Weimar W, de Bruin RW, van Gelder T. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant 2005; 5: 987-994.
18. Kobayashi M, Saitoh H, Kobayashi M, 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: 1029-1035.
19. 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: 119-128.
20. Levesque E, Delage R, Benoit-Biancamano MO, Caron P, Bernard O, Couture F, Guillemette C. The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single oral dose in healthy volunteers. Clin Pharmacol Ther 2007; 81: 392-400.
21. Girard H, Court MH, Bernard O, Fortier LC, Villeneuve L, Hao Q, Greenblatt DJ, von Moltke LL, Perussed L, Guillemette C. Identification of common polymorphisms in the promoter of the UGT1A9 gene: evidence that UGT1A9 protein and activity levels are strongly genetically controlled in the liver. Pharmacogenetics 2004; 14: 501-515.
22. Villeneuve L, Girard H, Fortier LC, Gagne JF, Guillemette C. Novel functional polymorphisms in the UGT1A7 and UGT1A9 glucuronidating enzymes in Caucasian and African-American subjects and their impact on the metabolism of 7-ethyl-10-hydroxycamptothecin and flavopiridol anticancer drugs. J Pharmacol Exp Ther 2003; 307: 117-128.
23. Kuypers DR, Naesens M, Vermeire S, Vanrenterghem Y. The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin Pharmacol Ther 2005; 78: 351-361.
24. Huang YH, Galijatovic A, Nguyen N, Geske D, Beaton D, Green J, Green M, Peters WH, Tukey RH. Identification and functional characterization of UDP-glucuronosyltransferases UGT1A8*1, UGT1A8*2 and UGT1A8*3. Pharmacogenetics 2002; 12: 287-297.
25. Barraclough KA, Lee KJ, Staatz CE. Pharmacogenetic influences on mycophenolate therapy. Pharmacogenomics 2010; 11: 369-390.
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: 1074-1084.
27. Miura M, Kagaya H, Satoh S, Inoue K, Saito M, Habuchi T, Suzuki T. Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients. Ther Drug Monit 2008; 30: 559-564.
28. Zhang WX, Chen B, Jin Z, Yu Z, Wang X, Chen H, Mao A, Cai W. Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients. Xenobiotica 2008; 38: 1422-1436.
29. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet 2007; 46: 13-58.
30. Jacobson P, El-Massah SF, Rogosheske J, Kerr A, Long-Boyle J, Defor T, Jennissen C, Brunstein C, Wagner J, Tomblyn M, Weisdorf D. Comparison of two mycophenolate mofetil dosing regimens after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44: 113-120.
31. Jacobson P, Green K, Rogosheske J, Brunstein C, Ebeling B, DeFor T, McGlave P, Weisdorf D. Highly variable mycophenolate mofetil bioavailability following nonmyeloablative hematopoietic cell transplantation. J Clin Pharmacol 2007; 47: 6-12.
32. Weisdorf DJ, Snover DC, Haake R, Miller WJ, McGlave PB, Blazar B, Ramsay NK, Kersey JH, Filipovich A. Acute upper gastrointestinal graft-versus-host disease: clinical significance and response to immunosuppressive therapy. Blood 1990; 76: 624-629.
33. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825-828.
34. Anonymous. Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function-Study Design, Data Analysis, and Impact on Dosing and Labeling. Rockville, MD: Center for Drug Evaluation and Research, 1998.
35. Uchaipichat V, Winner LK, Mackenzie PI, Elliot DJ, Williams JA, Miners JO. Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data: the effect of fluconazole on zidovudine glucuronidation. Br J Clin Pharmacol 2006; 61: 427-439.
36. Naderer OJ, Dupuis RE, Heinzen EL, Wiwattanawongsa K, Johnson MW, Smith PC. The influence of norfloxacin and metronidazole on the disposition of mycophenolate mofetil. J Clin Pharmacol 2005; 45: 219-226.
37. Guillet BA, Simon NS, Purgus R, Botta C, Morange S, Berland Y, Pisano PS. Population pharmacokinetics analysis of mycophenolic acid in adult kidney transplant patients with chronic graft dysfunction. Ther Drug Monit 2010; 32: 427-432.
38. van Hest RM, van Gelder T, Vulto AG, Shaw LM, Mathot RA. Pharmacokinetic modelling of the plasma protein binding of mycophenolic acid in renal transplant recipients. Clin Pharmacokinet 2009; 48: 463-476.
39. Ozdemir V, Kalow W, Tang BK, Paterson AD, Walker SE, Endrenyi L, Kashuba AD. Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics 2000; 10: 373-388.
40. Shaw LM, Mick R, Nowak I, Korecka M, Brayman KL. Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed graft function. J Clin Pharmacol 1998; 38: 268-275.
41. Kaplan B, Meier-Kriesche HU, Friedman G, Mulgaonkar S, Gruber S, Korecka M, Brayman KL, Shaw LM. The effect of renal insufficiency on mycophenolic acid protein binding. J Clin Pharmacol 1999; 39: 715-720.
42. de Winter BC, van Gelder T, Sombogaard F, Shaw LM, van Hest RM, Mathot RA. Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients. J Pharmacokinet Pharmacodyn 2009; 36: 541-564.
43. 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: 871-880.
44. Weber LT, Shipkova M, Armstrong VW, Wagner N, Schutz E, Mehls O, Zimmerhackl LB, Oellerich M, Tonshoff B. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: a report of the german study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002; 13: 759-768.
45. Jacobson P, Long J, Rogosheske J, Brunstein C, Weisdorf D. High unbound mycophenolic acid concentrations in a hematopoietic cell transplantation patient with sepsis and renal and hepatic dysfunction. Biol Blood Marrow Transplant 2005; 11: 977-978.
46. Mudge DW, Atcheson BA, Taylor PJ, Pillans PI, Johnson DW. Severe toxicity associated with a markedly elevated mycophenolic acid free fraction in a renal transplant recipient. Ther Drug Monit 2004; 26: 453-455.
47. Kaplan B, Gruber SA, Nallamathou R, Katz SM, Shaw LM. Decreased protein binding of mycophenolic acid associated with leukopenia in a pancreas transplant recipient with renal failure. Transplantation 1998; 65: 1127-1129.
48. Jacobson PA, Rydhom N, Huang J, Baker KS, Verneris MR. High-unbound mycophenolic acid concentrations in an infant on peritoneal dialysis following hematopoietic cell transplant. Bone Marrow Transplant 2007; 40: 911-912.
49. Bullingham R, Monroe S, Nicholls A, Hale M. Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration. J Clin Pharmacol 1996; 36: 315-324.
50. Rupprecht K, Schmidt C, Raspe A, Schweda F, Shipkova M, Fischer W, Bucher M, Kees F, Faerber L. Bioavailability of mycophenolate mofetil and enteric-coated mycophenolate sodium is differentially affected by pantoprazole in healthy volunteers. J Clin Pharmacol 2009; 49: 1196-1201.
51. Bullingham R, Shah J, Goldblum R, Schiff M. Effects of food and antacid on the pharmacokinetics of single doses of mycophenolate mofetil in rheumatoid arthritis patients. Br J Clin Pharmacol 1996; 41: 513-516.
52. Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Suzuki T, Habuchi T. Influence of lansoprazole and rabeprazole on mycophenolic acid pharmacokinetics one year after renal transplantation. Ther Drug Monit 2008; 30: 46-51.
53. van Hest RM, Doorduijn JK, de Winter BC, Cornelissen JJ, Vulto AG, Oellerich M, Lowenberg B, Mathot RA, Armstrong VW, van Gelder T. Pharmacokinetics of mycophenolate mofetil in hematopoietic stem cell transplant recipients. Ther Drug Monit 2007; 29: 353-360.
54. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34: 429-455.
55. Osunkwo I, Bessmertny O, Harrison L, Cheung YK, Van de Ven C, del Toro G, Garvin J, George D, Bradley MB, Wolownik K, Wischhover C, Levy J, Skerrett D, Cairo MS. A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients. Biol Blood Marrow Transplant 2004; 10: 246-258.
56. Haentzschel I, Freiberg-Richter J, Platzbecker U, Kiani A, Schetelig J, Illmer T, Ehninger G, Schleyer E, Bornhauser M. Targeting mycophenolate mofetil for graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation. Bone Marrow Transplant 2008; 42: 113-120.