Abstract
Mycophenolate mofetil (MMF) has been used successfully in solid organ transplantation (SOT) and more recently in nonmyeloablative hematopoietic stem cell transplantation (HSCT) for prophylaxis of graft rejection and acute graft-versus-host disease. However, the pharmacokinetics of MMF seem to differ when applied in HSCT compared to SOT. Here, we analyzed pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF, in a nonmyeloablative canine HSCT model. Dogs received nonmyeloablative TBI for conditioning followed by leukocyte antigen-identical littermate HSCT and immunosuppression containing cyclosporin A (CsA) and different doses of MMF. Pharmacokinetics were performed on days 2, 14 and 27. Dose escalation of MMF from 10 to 30 mg/kg tended to increase area under the curve (AUC) and the apparent oral clearance by 45 and 110%, respectively. Doses applied had no linear association with MPA concentration or blood trough level. No significant drug accumulation occurred over time. Using a twice daily MMF regimen, we conclude that an AUC of 30–60 μg/ml h as recommended for SOT cannot be reached in HSCT. Toxicities did not permit single doses higher than 30 mg/kg. Thus, if larger AUCs are desired in order to assure sufficient immunosuppression in HSCT, MMF might have to be administered at least three times daily.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Sollinger HW, Belzer FO, Deierhoi MH, Diethelm AG, Gonwa TA, Kauffman RS et al. S-61443 (mycophenolate mofetil). A multicenter study for refractory kidney transplant rejection. Ann Surg 1992; 216: 513–518.
Ensley RD, Bristow MR, Olsen SL, Taylor DO, Hammond EH, O'Connell JB et al. The use of mycophenolate mofetil (RS-61443) in human heart transplant recipients. Transplantation 1993; 56: 75–82.
Staatz CE, Tett SE . Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet 2007; 46: 13–58.
Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem HP et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 1997; 89: 3048–3054.
Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 2003; 102: 2021–2030.
Jacobson P, Rogosheske J, Barker JN, Green K, Ng J, Weisdorf D et al. Relationship of mycophenolic acid exposure to clinical outcome after hematopoietic cell transplantation. Clin Pharmacol Ther 2005; 78: 486–500.
Jenke A, Renner U, Richte M, Freiberg-Richter J, Platzbecker U, Helwig A et al. Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation. Clin Transplant 2001; 15: 176–184.
Giaccone L, McCune JS, Maris MB, Gooley TA, Sandmaier BM, Slattery JT et al. Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation. Blood 2005; 106: 4381–4388.
Lindblad-Toh K, Wade CM, Mikkelsen TS, Karlsson EK, Jaffe DB, Kamal M et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 2005; 438: 803–819.
Mack GS . Cancer researchers usher in dog days of medicine. Nat Med 2005; 11: 1018.
Hilgendorf I, Weirich V, Zeng L, Koppitz E, Wegener R, Freund M et al. Canine haematopoietic chimerism analyses by semiquantitative fluorescence detection of variable number of tandem repeat polymorphism. Vet Res Commun 2005; 29: 103–110.
Lange S, Brandt B, Riebau F, Vogel H, Weirich V, Hilgendorf I et al. Hematopoietic cell lysate vaccinations and bone marrow enrichment with donor-derived dendritic cells for engraftment promotion after non-myeloablative hematopoietic stem cell transplantation. Bone Marrow Transplant 2006; 37 (Suppl 1): S62 (abstract 386).
Shaw LM, Holt DW, Oellerich M, Meiser B, van Gelder T . Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion. Ther Drug Monit 2001; 23: 305–315.
Nash RA, Johnston L, Parker P, McCune JS, Storer B, Slattery JT et al. 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.
Jacobson P, Green K, Rogosheske J, Brunstein C, Ebeling B, DeFor T et al. Highly variable mycophenolate mofetil bioavailability following nonmyeloablative hematopoietic cell transplantation. J Clin Pharmacol 2007; 47: 6–12.
van Hest RM, Doorduijn JK, de Winter BC, Cornelissen JJ, Vulto AG, Oellerich M et al. Pharmacokinetics of mycophenolate mofetil in hematopoietic stem cell transplant recipients. Ther Drug Monit 2007; 29: 353–360.
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.
van Hest RM, van Gelder T, Vulto AG, Mathot RA . Population pharmacokinetics of mycophenolic acid in renal transplant recipients. Clin Pharmacokinet 2005; 44: 1083–1096.
Bullingham RE, Nicholls AJ, Kamm BR . Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34: 429–455.
Arns W, Cibrik DM, Walker RG, Mourad G, Budde K, Mueller EA et al. Therapeutic drug monitoring of mycophenolic acid in solid organ transplant patients treated with mycophenolate mofetil: review of the literature. Transplantation 2006; 82: 1004–1012.
Langman LJ, Shapiro AM, Lakey JR, LeGatt DF, Kneteman NM, Yatscoff RW . Pharmacodynamic assessment of mycophenolic acid-induced immunosuppression by measurement of inosine monophosphate dehydrogenase activity in a canine model. Transplantation 1996; 61: 87–92.
Lupu M, McCune JS, Kuhr CS, Gooley T, Storb R . Pharmacokinetics of oral mycophenolate mofetil in dog: bioavailability studies and the impact of antibiotic therapy. Biol Blood Marrow Transplant 2006; 12: 1352–1354.
Smak Gregoor PJ, van Gelder T, Hesse CJ, van der Mast BJ, van Besouw NM, Weimar W . Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a cross-sectional study. Nephrol Dial Transplant 1999; 14: 706–708.
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: 2937–2944.
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. Transplant Proc 2005; 37: 1748–1750.
Pawinski T, Durlik M, Szlaska I, Urbanowicz A, Majchrnak J, Gralak B . Comparison of mycophenolic acid pharmacokinetic parameters in kidney transplant patients within the first 3 months post-transplant. J Clin Pharm Ther 2006; 31: 27–34.
Osunkwo I, Bessmertny O, Harrison L, Cheung YK, Van de Ven C, del Toro G et al. 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.
Maris MB, Sandmaier BM, Storer BE, Maloney DG, Shizuru JA, Agura E et al. Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of postgrafting mycophenolate mofetil dosing. Biol Blood Marrow Transplant 2006; 12: 454–465.
Hummel M, Yonan N, Ross H, Miller LW, Sechaud R, Balez S et al. Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients. Clin Transplant 2007; 21: 18–23.
Filler G . Drug interactions between mycophenolate and cyclosporine. Pediatr Transplant 2004; 8: 201–204.
Pape L, Froede K, Strehlau J, Ehrich JH, Offner G . Alterations of cyclosporin A metabolism induced by mycophenolate mofetil. Pediatr Transplant 2003; 7: 302–304.
John U, Ullrich S, Roskos M, Misselwitz J . Two-hour postdose concentration: a reliable marker for cyclosporine exposure in adolescents with stable renal transplants. Transplant Proc 2005; 37: 1608–1611.
Acknowledgements
We are very grateful to the highly dedicated technicians of the shared animal facility of the University of Rostock. Furthermore we thank Dirk Steffen DVM for the veterinary support provided. This work was supported by grants of the German Research Council (Deutsche Forschungsgemeinschaft) JU 417/2-1, 2-2.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lange, S., Mueller, S., Altmann, S. et al. Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 41, 667–674 (2008). https://doi.org/10.1038/sj.bmt.1705958
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bmt.1705958
Keywords
This article is cited by
-
MTX or mycophenolate mofetil with CsA as GVHD prophylaxis after reduced-intensity conditioning PBSCT from HLA-identical siblings
Bone Marrow Transplantation (2010)
-
Mycophenolate mofetil combined with tacrolimus and minidose methotrexate after unrelated donor bone marrow transplantation with reduced-intensity conditioning
International Journal of Hematology (2009)