To review the pharmacology, pharmacokinetics, efficacy, and safety of mycophenolate sodium, everolimus, and FTY720.
Study Selection and Data Extraction
Clinical trials and abstracts evaluating mycophenolate sodium, everolimus, and FTY720 in solid-organ transplantation were considered for evaluation. English-language studies and published abstracts were selected for inclusion.
Data Synthesis
Mycophenolate sodium has recently been approved by the Food and Drug Adminstration for marketing in the United States; everolimus and FTY720 are immunosuppressive agents that may soon be available in the United States. These agents have proven efficacy in reducing the incidence of acute rejection in solid-organ transplantation. Clinical trials have shown that these newer agents are relatively well tolerated. The most common adverse events associated with these agents were gastrointestinal and hematologic effects (mycophenolate sodium); hyperlipidemia, increased serum creatinine, and hematologic effects (everolimus); and gastrointestinal effects, headache, and bradycardia (FTY720).
Conclusion
Mycophenolate sodium has been approved in some European countries and the United States. Everolimus has been approved in some European countries and a new drug application has been submitted to the Food and Drug Administration. FTY720 is currently in phase III clinical trials and submission to the Food and Drug Administration for approval is a few years away. The approval of these agents will furnish the transplant practitioner with even more options for immunosuppression.
Get full access to this article
View all access options for this article.
References
1.
United Network of Organ Sharing. Available at: http://www.unos.org/data. Accessed August 30, 2003.
2.
HeldermanJHGoralS. Transplantation immunobiology. In: DanovitchGM, ed. Handbook of Kidney Transplantation.2nd ed.New York, NY: Little, Brown and Company; 1996:14–31.
3.
HumarAPayneWESutherlandDEMatasAJ. Clinical determinants of multiple acute rejection episodes in kidney transplant recipients. Transplantation.2000;69:2357–2360.
4.
Meier-KriescheHUOjoAOHansonJA. Increased impact of acute rejection on chronic allograft failure in recent era. Transplantation.2000;70:1098–1100.
5.
HumarAKerrSGillinghamKJMatasAJ. Features of acute rejection that increase risk of chronic rejection. Transplantation.1999;68:1200–1203.
6.
MatasAJHumarAPayneWD. Decreased acute rejection in kidney transplant recipients is associated with decreased chronic rejection. Ann Surg.1999;230:493–498.
7.
PaulLC. Chronic allograft nephropathy: An update. Kidney Int.1999;56:783–793.
8.
AllisonACEuguiEM. Immunosuppressive and other effects of mycophenolic acid and ester prodrug, mycophenolate mofetil. Immunol Rev. December 1993;136:5–28.
9.
AllisonACKowalskiWJMullerCDEuguiEM. Mechanisms of action of mycophenolic acid. Ann NY Acad Sci. November 1993;696:63–87.
10.
NatsumedaYCarrSF. Human type I and II IMP dehydrogenase as targets. Ann NY Acad Sci.1993;696:88–93.
11.
SollingerHWEuguiEMAllisonAC. RS-61443: Mechanism of action, experimental and early clinical trial results. Clin Transplant.1991;5:523–526.
12.
AllisonACAhlmquistSJMullerCDEuguiEM. In vitro immunosuppressive effects of mycophenolate acid and an ester prodrug, RS-61443. Transplant Proc.1991;23:10.
13.
EuguiEMMirkovichAAllisonAC. Lymphocyte-selective antiproliferative and immunosuppressive effects of mycophenolic acid in mice. Scand J Immunol.1991;33:175–183.
14.
LaurentAFDumontSPoindronPMullerCD. Mycophenolic acid suppresses protein N-linked glycosylation in human monocytes and their adhesion to endothelial cells and to some substrates. Exp Hematol. January 1996;24:59–67.
15.
WooJZeeviAYaoGZStrednakJTodoSThomsonAW. Effects of FK-506, mycophenolic acid and bredinin on OKT3-, PMA-, and alloantigen-induced activation molecule expression on cultured CD4+ and CD8+ human lymphocytes. Transplant Proc.1991;23:2939–2940.
16.
ZeeviAWoanMYaoGZ. Comparative in vitro studies on the immunosuppressive activities of mycophenolic acid, bredinin, FK-506, cyclosporine, and rapamycin. Transplant Proc.1991;23:2928–2930.
17.
ZeeviAYaoGZVenkataramananR. Comparative in vitro studies on the immunosuppressive effects of purine and pyrimidine synthesis inhibitors. Transplant Proc.1993;25:781.
SchmouderRIFauchaldPArnsW. Systemic exposure of mycophenolic acid (MPA) is greater Myfortic than MMF [abstract]. Am J Transplant.2002;2(suppl 3):398.
20.
BuddeKGlanderPHahnU. Pharmacokinetic and pharmacodynamic comparison of mycophenolate mofetil and enteric-coated mycophenolate sodium in maintenance renal transplant patients [abstract]. Am J Transplant.2002;2 (suppl 3):399.
21.
GrangerDK. Enteric-coated mycophenolate sodium: Results of two pivotal global multicenter trials. Transplant Proc.2001;33:3241–3244.
22.
SalvadoriM. Therapeutic equivalence of mycophenolate sodium versus mycophenolate mofetil in de novo renal transplant recipients. Transplant Proc.2001;33:3245–3247.
23.
BehrendM. Adverse gastrointestinal effects of mycophenolate mofetil: Aetiology, incidence and management. Drug Saf.2001;24:645–663.
ZhuWArnsWCarpenterP. Cyclosporine is associated with decreased absolute bioavailability of mycophenolic acid [abstract]. Am J Transplant.2001;1(suppl 1):985.
26.
MoriiMUenoKOgawaA. Impairment of mycophenolate mofetil absorption by iron ion. Clin Pharmacol Ther.2000;68:613–616.
27.
CatalanoCFabbianFBordinVDi LandroD. Mycophenolate mofetil toxicity in an anorexic kidney transplant patient treated with sulphinpirazone. Nephrol Dial Transplant.1997;12:2467–2468.
28.
SedraniRCottensSKallenJSchulerW. Chemical modification of rapamycin: The discovery of SDZ RAD. Transplant Proc.1998;30:2192–2194.
29.
NashanB. Early clinical experience with a novel rapamycin derivative. Ther Drug Monit. February 2002;24:53–58.
30.
SchulerWSedraniRCottensS. SDZ RAD, a new rapamycin derivative. Transplantation.1997;64:36–42.
31.
KahanBDWongRLCarterC. A phase I study of a 4-week course of SDZ-RAD (RAD) quiescent cyclosporine-prednisone-treated renal transplant recipients. Transplantation.1999;68:1100–1106.
32.
KirchnerGIWinklerMMuellerL. Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites in seven kidney graft patients after the first dose of SDZ RAD. Br J Clin Pharmacol.2000;50:449–454.
33.
KovarikJMKahanBDKaplanB. Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year: Pharmacokinetics, exposure-response relationships, and influence on cyclosporine. Clin Pharmacol Ther. January 2001;69:48–56.
34.
NeumayerHHParadisKKornA. Entry-into-human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients. Br J Clin Pharmacol.1999;48:694–703.
35.
KovarikJMHartmannSFigueiredoJ. Effect of food on everolimus absorption: Quantification in healthy subjects and confirmatory screening in patients with renal transplants. Pharmacotherapy.2002;22:154–159.
KovarikJMHsuCHMcMahonLBerthierSRordorfC. Population pharmacokinetics of everolimus in de novo renal transplant patients: Impact of ethnicity and comedications. Clin Pharmacol Ther.2001;70:247–254.
38.
HausenBBoekeKBerryGJSegarraITChristiansUMorrisRE. Suppression of acute rejection in allogenic rat lung transplantation: A study of the efficacy and pharmacokinetics of rapamycin derivative (SDZ RAD) used alone and in combination with a microemulsion formulation of cyclosporine. J Heart Lung Transplant.1999;18:150–159.
39.
HausenBIkonenTBriffaN. Combined immunosuppression with cyclosporine (neoral) and SDZ RAD in non-human primate lung transplantation: Systematic pharmacokinetic-based trials to improve efficacy and tolerability. Transplantation.2000;69:76–86.
40.
SerkovaNHausenBBerryGJ. Tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD and its metabolites in monkey lung transplant recipients: Interaction with cyclosporine. J Pharmacol Exp Ther.2000;294:323–332.
41.
KirchnerGIVidalCWinklerM. LC/ESI-MS allows simultaneous and specific quantification of SDZ RAD and cyclosporine, including groups of their metabolites in human blood. Ther Drug Monit.1999;21:116–122.
42.
KovarikJMSabiaHRouillyM. Influence of renal and hepatic impairment of everolimus pharmacokinetics: Are dose adjustments necessary [abstract]?Am J Transplant.2001;1(suppl 1):989.
43.
KovarikJMSabiaHDFigueiredoJ. Influence of hepatic impairment on everolimus pharmacokinetics: Implications for dose adjustment. Clin Pharmacol Ther.2001;70:425–430.
44.
EisenHDorentRManciniD. Safety and efficacy of everolimus (RAD) as part of a triple immunosuppressive regimen in de novo cardiac transplant recipients: Six-month analysis [abstract]. J Heart Lung Transplant.2002;21:55.
45.
ValentineRBLoveGISnellPVAllanRGUlrichP. Multicenter, randomized, double-blind study of everolimus (RAD) vs. azathioprine to inhibit the decline of pulmonary function in stable lung transplant recipients—one-year results [abstract]. Am J Transplant.2003;3(suppl 5):387.
46.
KahanBDKaplanBLorberMIWinklerMCambonNBogerRS. RAD in de novo renal transplantation: Comparison of three doses on the incidence and severity of acute rejection. Transplantation.2001;71:1400–1406.
47.
VitkoSMargreiterRWeimarW. International, double-blind, parallel group study of the safety and efficacy of certican (RAD) versus mycophenolate mofetil (MMF) in combination with neoral and steroids [abstract]. Am J Transplant.2001;1(suppl 1):474.
48.
KaplanBTedesco-SilvaHMendezR. North/South American, double-blind, parallel group study of the safety and efficacy of certican (RAD) versus mycophenolate mofetil (MMF) in combination with neoral and corticosteroids [abstract]. Am J Transplant.2001;1(suppl 1):475.
49.
CurtisJNashanBPonticelliCMouradGBogerR. One year results of a multicenter, open-label trial on safety and efficacy of certican (RAD) used in combination with simulect, corticosteroids, and full or reduced dose neoral in renal transplantation [abstract]. Am J Transplant.2001;1(suppl 1):474.
50.
ViklickyOZouHMullerVLachaJSzaboAHeemannU. SDZ-RAD prevents manifestation of chronic rejection in rat renal allografts. Transplantation.2000;69:497–502.
51.
ColeOJShehataMRiggKM. Effect of SDZ RAD on transplant arteriosclerosis in the rat aortic model. Transplant Proc.1998;30:2200–2203.
52.
SalminenUSMaasiltaPKTaskinenEIAlhoHSIkonenTSHarjulaAL. Prevention of small airway obliteration in a swine heterotopic lung allograft model. J Heart Lung Transplant.2000;19:193–206.
53.
SchuurmanHJPallyCWeckbeckerGSchulerWBrunsC. SDZ RAD inhibits cold ischemia-induced vascular remodeling. Transplant Proc.1999;31:1024–1025.
54.
Vfend (voriconazole) [package insert].New York, NY: Pfizer Inc; 2003.
55.
KovarikJMKalbagJFigueiredoJRouillyMFrazierOLRordorfC. Differential influence of two cyclosporine formulations on everolimus pharmacokinetics: A clinically relevant pharmacokinetic interaction. J Clin Pharmacol. January 2002;42:95–99.
56.
KovarikJMHartmannSHubertM. Pharmacokinetic and pharmacodynamic assessments of HMG-CoA reductase inhibitors when coadministered with everolimus. J Clin Pharmacol.2002;42:222–228.
57.
KovarikJMHartmannSFigueiredoJRouillyMPortARordorfC. Effect of rifampin on apparent clearance of everolimus. Ann Pharmacother.2002;36:981–985.
58.
BrinkmannVPinschewerDChibaKFengL. FTY720: A novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharmacol Sci. February 2000;21:49–52.
59.
BrinkmannVPinschewerDFengLChenS. FTY720: Altered lymphocyte traffic results in allograft protection. Transplantation.2001;72:764–769.
60.
BuddeKSchmouderRLBrunkhorstR. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol.2002;13:1073–1083.
61.
TroncosoPKahanB. Preclinical evaluation of a new immunosuppressive agent, FTY720. Clin Biochem.1998;31:369–373.
62.
NapoliKL. The FTY720 story. Ther Drug Monit. February 2000;22:47–51.
63.
KahanBD. Update on pharmacokinetic/pharmacodynamic studies with FTY720 and sirolimus. Ther Drug Monit.2002;24:47–52.
64.
KovarikJMSkerjanecAZimmerlinA. Screening for a drug interaction of FTY720 on cyclosporine in renal transplant patients [abstract]. Am J Transplant.2003;3(suppl 5):483.
65.
FergusonRMMulgaonkarSTedescoH. High efficacy of FTY720 with reduced cyclosporine dose in preventing rejection in renal transplantation: 12-month preliminary results. Am J Transplant.2003;3(suppl 5):311.
