Cellcept

Objective-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 Administration 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 hematologie 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. (Progress in Transplantation. 2004;14:148-156)

For more than half a century, medical immunosuppression has been the cornerstone of posttransplant care. Azathioprine (AZA) and corticosteroids were some of the earliest agents used, and corticosteroids are still employed in many maintenance regimens today. However, one reason for the success of solid-organ transplantation over the past 20 years is the introduction of cyclosporine (Sandimmune and Neoral), which helped to improve overall graft survival.1 Several new immunosuppressant drugs have been approved for use in recent years, including tacrolimus (Prograf), mycophenolate mofetil (MMF; CellCept), sirolimus (Rapamune), daclizumab (Zenapax), basiliximab (Simulect), and rabbit antithymocyte globulin (Thymoglobulin). With the introduction of more potent and specific immunosuppressant agents, allograft rejection has dramatically decreased and 5-year graft survival rates have steadily increased.1 Despite the widespread success of immunosuppressive therapies, these agents have been associated with numerous adverse events, including nephrotoxicity, cardiovascular disease, and severe gastrointestinal (GI) distress.

Recently, immunological research has focused on agents that prevent acute rejection and limit the occurrence of chronic rejection. Prevention of acute rejection, an immunologie process associated with graft recognition and cytokine release, has been the primary Focus of transplant practitioners for many years.2,3 Several signs and symptoms are seen with this inflammatory disorder, including fevers, chills, myalgias, and allograft dysfunction. Acute rejection, although reversible, is a major contributing factor to the development of chronic rejection.4-6

Chronic rejection is a process that leads to progressive loss of graft function.2,4-7 The etiology of chronic rejection is poorly understood, but it is thought to comprise both immunologic and nonimmunologic mechanisms. Besides acute rejection, several other factors contribute to the development of chronic rejection, including allograft vascular remodeling, drug-induced toxicities, and cytomegalovirus (CMV) infections.4-7 Currently, no medicinals exist that arc effective in preventing or treating chronic rejection.

This review focuses on 3 newer immunosuppressive agents: mycophenolate sodium, everolimus, and FTY720. These agents may play a vital role in further preventing acute rejection, but also in potentially preventing chronic rejection and graft loss. Mycophenolate sodium was chosen for inclusion in this review because of the approval from the Food and Drug Administration (FDA) for this drug in March 2004. Everolimus was chosen for discussion because of its recent submission for approval to the FDA. FTY720 was selected because of its unique mechanism of action. The Table presents a summary of these agents.

Mycophenolate Sodium

Mechanism of Action

Mycophenolate sodium (Myfortic) is the entericcoated prodrug of mycophenolic acid (MPA), which is the same active component of MMF. MPA inhibits inosinc monophosphate dehydrogenase, which is a vital enzyme in purine nucleotide biosynthesis. Purine nucleotides serve fundamental roles in cellular proliferation, gene transcription, and protein synthesis. In vitro, inosine monophosphate dehydrogenase-inhibition results in decreased T- and B-lymphocyte proliferation upon antigen challenge.8-17

Pharmacokinetics

Over a dosing range of 180 to 2160 mg, mycophenolate sodium exhibits dose-proportional and linear pharmacokinetics.18 The mean absolute bioavailability of MPA from mycophenolate sodium is 71%. On an empty stomach, MPA peak plasma concentrations (C^sub max^) generally occur within 1.5 to 2 hours. High fat meals have no effect on systemic exposure (area under the curve [AUC]) of MPA when compared to an equivalent dose in a fasting state. However, administration of a high fat meal does decrease C^sub max^ by 33%. The steady-state volume of distribution is 50 L.18 It has been shown that at equimolar doses, mycophenolate sodium produces a higher MPA C^sub max^ and AUC compared with MMF.19

MPA is primarily metabolized via hepatic glucuronyl transferase to mycophenolic acid glucuronide (MPAG), which is inactive.18 MPAG is secreted in bile and may be hydrolyzed back to MPA in the intestines and reabsorbed. This explains the second MPA peak observed approximately 8 hours following administration. Both MPA (97%) and MPAG (82%) are protein bound.18 MPA is primarily excreted as MPAG in the urine, with only a small fraction excreted in feces. The mean half-lives of MPA and MPAG are 11.7 and 15.7 hours, respectively, with a mean clearance of 8.6 L/h and 0.45 L/h, respectively.18

Clinical Efficacy

Two phase III clinical trials have been completed analyzing the safety and efficacy of mycophenolate sodium in kidney transplant recipients. Of note, 720 m g of mycophenolate sodium contains equimolar amounts of MPA compared with 1000 mg of MMF.20

The safety and efficacy of mycophenolate sodium compared to MMF, in conjunction with cyclosporine modified and prednisone, were evaluated in a 12-month, double-blind, randomized, multicenter, parallel group study of 423 de novo kidney allograft recipients.21,22 Patients were randomized to receive either 720 mg of mycophenolate sodium twice daily (n = 213) or 1000 mg of MMF twice daily (n = 210). The overall incidence of efficacy failure (universally defined throughout all studies discussed, unless otherwise noted, as biopsy-proven acute rejection [BPAR], graft loss, death, or loss to follow-up) observed in the mycophenolate sodium and MMF groups were comparable at 6 months (28.2 % and 28.1%; P = NS). BPAR rates were similar at 22.5% for mycophenolate sodium and 24.3% for MMF at 12 months (P = NS). The incidence of graft loss, patient death, and reported adverse events were similar in both groups. The incidence of GI adverse events was 78.4% with mycophenolate sodium and 78.1% with MMF (P = NS). The frequency of dosage reductions, discontinuation, or temporary interruptions of therapy secondary to GI toxicities were comparable (13.1% for mycophenolate sodium versus 17.6% for MMF; P = NS). Infection rates were similar in both groups. The authors concluded that mycophenolate sodium is therapeutically equivalent to MMF at equimolar MPA doses.21,22

A second study evaluated the safety and efficacy of the conversion from MMF to mycophenolate sodium in 322 kidney transplant recipients at least 6 months after transplantation.21 Patients, currently maintained on eyclosporine modified with or without corticosteroids, were randomized to receive mycophenolate sodium 720 mg twice daily (n = 159) or MMF 1000 mg twice daily (n = 163). This analysis revealed no statistically significant difference in the incidence of any adverse events between mycophenolate sodium and MMF (93.7% and 92.6%, respectively; P=NS). The incidence of GI toxicities was similar between the groups at 29% versus 28% (6 months) and 60% versus 61% (12 months), for mycophenolate sodium and MMF, respectively (P = NS). The prevalence of neutropenia was 0.6% for mycophenolate sodium and 3.1% for MMF (P = NS). Rates and severity of infection were also equivalent between the groups (mycophenolate sodium, 58.5%; MMF, 58.9%; P = NS). Efficacy failure at 12 months was 6.1 % with MMF compared to 2.5% with mycophenolate sodium (P value not provided). It was concluded that stable kidney transplant recipients can be converted to mycophenolate sodium from MMF without compromising safety and efficacy.21

Toxicity and Safety Profile and Precautions

It is evident from the clinical trials that mycophenolate sodium and MMF have similar toxicity profiles. Diarrhea (23.5%) and leukopenia (19.2%) were the most commonly seen adverse events in the phase III trials (n = 745).21,22

GI Effects. GI toxicities are common with mycophenolate sodium administration; however, the exact etiology of MPA-induced GI upset is unknown. Some have postulated that it may be secondary to several factors, including, direct GI irritation, subclinical GI infections, concomitant GI CMV disease, or impairment of enterocyte maturation and proliferation.23 The latter theory may prove to be most accurate, because enterocytes rely heavily on the de novo pathway for purine biosynthesis.

Infection. CMV, oral candidiasis, and cutaneous herpes simplex virus infections were the most commonly reported opportunistic infections in the clinical trials. The incidence of CMV infection was 21.6% in de novo transplant recipients and 1.9% in maintenance patients.18

Malignancy. As noted in their respective package inserts, the incidence of posttransplant lymphoproliferative disorder (PTLD) with mycophenolate sodium therapy is 0.3%18 compared with 0.4% to 1.0% with MMF.24 Nonmelanoma skin cancer incidence was 0.8% with mycophenolate sodium18 and 1.6% to 4.2% with MMF.24

Precautions. Patients with Lesch-Nyhan or Kelly-Sugmiller syndrome, rare disorders involving altered purine metabolism, should avoid the use of mycophenolate sodium. This agent is contraindicated during pregnancy because of fetal abnormalities observed in animal models. MPA concentrations in breast milk are unknown; therefore, breast-feeding is discouraged.18

Drug Interactions

Mycophenolate sodium has been studied for druginteractions with some medications that are commonly administered in the posttransplant period. Of note, no interactions exist with either ganciclovir or oral contraceptives.18

Acyclovir. This agent inhibits renal tubular secretion and may increase the risk of toxicities by increasing MPA concentrations. Patients receiving acyclovir, or other inhibitors of tubular secretion, should be monitored closely for adverse events.18

Antacids. Concomitant administration of mycophenolate sodium and magnesium and aluminum-containing antacids has resulted in a reduction in C^sub max^ and AUC by 25% and 37%, respectively. It is recommended that mycophenolate sodium not be administered with cation-containing antacids.18

Cholestymmine. Concurrent administration of mycophenolate sodium and bile acid sequestrants may reduce the absolute bioavailability and enterohepatic recirculation of MPA.18

Cydosporine. Chronic coadministration of cyclosporine with mycophenolate sodium has resulted in a 20% to 30% reduction in MPA absolute bioavailability and a significant reduction in AUC.25

Other Potential Interactions. The manufacturer warns of potential increases in MPA concentrations when mycophenolate sodium is given with highly protein-bound medications, although, no data have been published further evaluating this interaction.18 It is also important to note that some drug-drug interactions that exist with MMF, such as ferrous sulfate and sulfinpyrazone, may also exist with mycophenolate sodium.26,27 No drug interaction studies have been conducted with other commonly administered posttransplant medications, including cotrimoxazole, tacrolimus, or sirolimus.

Everolimus

Mechanism of Action

Everolimus (Certican), a proliferation signal inhibitor, has a similar mechanism of action as sirolimus. Everolimus binds with high affinity to FK-binding protein-12 (FKBP), generating an immunosuppressive complex that subsequently binds to FKBP-rapamycin-associated protein.28 This results in the inhibition of cytokine-driven proliferation of human T- and B-lymphocytes and vascular smooth muscle cells.28-30

Pharmacokinetics

Everolimus C^sub max^ is reached 1 to 3 hours after oral administration.31-34 C^sub max^ and AUC rise proportionally over a dosage range of 0.25 to 20 mg.31-34 In a single-dose study, consumption of a high fat meal delayed time to maximum concentration by 1.25 hours and reduced C^sub max^ by 60% and AUC by 16% compared to the same dose in a fasting state.35 In contrast, when sirolimus tablets are administered with a high fat meal there is a 23% increase in AUC.36 Steady-state was reached within 4 to 7 days with continuous everolimus therapy.31,33 Notably, race significantly altered clearance. Nonblack patients had a 20% lower clearance of everolimus than black patients.37 Another notable difference between everolimus and sirolimus are their half-lives, 16 to 19 hours31 and 62 hours,36 respectively.

More than 75% of everolimus is bound to red blood cells, with nearly three quarters of the remaining plasma fraction bound to plasma proteins.31-34 Everolimus is a substrate of P-glycoprotein and is primarily hepatically metabolized by the cytochrome P450 3A4 isozyme (CYP3A4).38-40 Four everolimus metabolites have been identified in vivo, but their activity is unknown.32,41 Only a small fraction of everolimus is renally excreted, as it is primarily eliminated in feces.31-34 Renal function does not influence everolimus clearance.42 Patients with hepatic impairment exhibit a higher everolimus AUC and longer half-life and doses should therefore be reduced in this patient population.43

Clinical Efficacy

Cardiac Transplantation. The safety and efficacy of everolimus compared to AZA was evaluated in 634 de novo cardiac allograft recipients in a 12-month, double-blind, multicenter study.44 Patients were randomized to receive everolimus 0.75 mg (n = 209) or 1.5 mg (n = 211) twice daily or 1 to 3 mg/kg per day of AZA (n-214), along with cyclosporine modified and prednisone. Acute rejection rates at 6 months after transplantation were significantly lower for patients receiving everolimus (1.5 mg/day, 36.4%; 3 mg/day, 27%) than for those receiving AZA (47.7%; P = .023 for 1.5 mg/day and P

Lung Transplantation. In a 36-month, open-label, multicenter, parallel-group trial,45 everolimus (3 mg/day; n = 101) was compared with AZA (1-3 mg/kg/day; n = 112) in 213 stable lung transplant recipients, receiving cyclosporine modified and corticosteroids.45 At 12 months, everolimus was associated with a lower incidence of efficacy failure (defined as graft loss or death at 1 year, decline in forced expiratory volume in 1 second [FEV^sub 1^] over time, and the incidence of bronchiolitis obliterans syndrome; everolimus, 21.8%; AZA, 33.9%; P = .0455). There was less of a decline in FEV^sub 1^ from baseline with everolimus compared with AZA (15.8% vs 27.7%, respectively; P = .05). Analysis of adverse events shows that everolimus was associated with severe adverse drug reactions (definition not provided) in 54.1% of patients compared with 26.1% in AZA-treated patients. The investigators found a difference in bacterial (everolimus 35.1% vs AZA 17.1%; P value not provided) and fungal infections (everolimus 27.9% vs 14.4%; P value not provided). The authors also noted a statistically significant increase in serum creatinine values with everolimus administration compared to AZA.45

Kidney Transplantation. Kahan et al46 completed a 6-month, multicenter, double-blind, dose-finding study of everolimus in 103 de novo kidney transplant recipients. Patients were randomized to receive 1 mg (n = 34), 2 mg (n = 34), or 4 mg (n = 35) of everolimus daily in 2 divided doses, while taking cyclosporine modified and prednisone. The incidence of BPAR was comparable between 2 and 4 mg/day (14.7 % vs 25.7%, respectively; P = NS). BPAR rates were highest in the 1 mg/day group (32.4%; P values not provided). Overall graft loss and patient death were similar in all groups.

Mean platelet counts were low for all everolimus doses, but were noted to be dose-dependent and reversible. The occurrence of thrombocytopenia (

In a 12-month, double-blind, multicenter, parallel-group study,47 588 de novo kidney allograft recipients were randomized to receive everolimus 0.75 mg (n = 194), everolimus 1.5 mg (n = 198), or MMF 1 g (n = 196) all twice daily, concomitantly with cyclosporine modified and corticosteroids. Efficacy failure rates were similar between all groups (everolimus 1.5 mg/day, 29.9%; everolimus 3 mg/day, 30.3%; MMF, 31.1%; P = NS). Patient and graft survival were high among all treatment groups (95%). Examination of adverse events revealed that hyperlipidemia, decreased platelets and elevated serum creatinine were more often associated with everolimus (P values not given). The incidence of CMV was highest with MMF (19.4%; everolimus 1.5 mg/day, 5.2%, and everolimus 3 mg/day, 7.6%; P values not provided).47

Kaplan et al48 conducted a similar trial with 583 de novo kidney transplant recipients randomized to receive everolimus 1.5 mg/day (n=193), everolimus 3 mg/day (n=194), or MMF 2 g/day (n = 196).48 Patients also received cyclosporine modified and corticosteroids. The overall incidence of BPAR was similar between the groups (MMF, 24%; everolimus, 19%; and everolimus, 22%; P = NS). Graft loss or patient death rates were also similar (MMF, 6.6%; everolimus, 10.9%; and everolimus, 7.7%; P = NS). Serum creatinine levels were elevated in both everolimus groups compared to MMF (P values not given). Everolimus was also associated with higher lipids. The authors concluded that everolimus at doses of 1.5 and 3 mg/day were as effective as 2 g/day of MMF.48

Kidney Transplantation With Reduced-Dose Cyclosporine. Everolimus was studied in 111 de novo kidney transplant recipients in combination with basiliximab, corticosteroids, and full- or reduced-dose cyclosporine modified in a 12-month, open-label, multi-center, parallel-group trial.49 Patients were randomized to receive 3 mg/day of everolimus with full-dose cyclosporine (n = 54) or 3 mg/day of everolimus with reduced-dose cyclosporine (n = 57). The incidence of efficacy failure was higher in the full-dose cyclosporine group (27.8%) compared with the reduced-dose cyclosporine group (8.8%; P = .013). There was a slight increase in serum creatinine associated with full-dose cyclosporine; however, this difference was not shown to be statistically significant. Serum lipid levels were markedly higher in patients receiving full-dose cyclosporine (P values not provided). It was concluded that everolimus, in combination with low-dose cyclosporine, reduces the risk of cyclosporine-induced nephrotoxicity, which may improve long-term graft survival among kidney transplant recipients.49

Chronic Rejection. Everolimus has been studied in animal models, in which it has been associated with fewer manifestations of chronic rejection by exhibiting the ability to inhibit vascular smooth muscle cell proliferation, intimal thickening, obliterative lesions and transplant arteriosclerosis.50-53 To date, everolimus has not been studied in humans for this purpose.

Toxicity and Safety Profile and Precautions

The primary adverse events associated with everolimus were dose-related hematologic changes, hyperlipidemia, and increased serum creatinine.44,46-49' A more favorable adverse event profile was revealed when everolimus was administered with reduced-close cyclosporine.49

Hematologic Effects. Significant thrombocytopenia and leukopenia are uncommon. However, all hematologie changes were associated with higher everolimus doses. These changes were reversible upon withdrawal of everolimus.44,46

Hyperlipidemia. Hyperlipidemia occurred frequently in patients receiving everolimus. Serum lipids often peaked after 2 to 3 months, but were manageable with lipid-lowering therapies.44,46-49 Administration of lipid-lowering medications were considered part of the standard protocol in most everolimus studies.

Infection. CMV was the most common opportunistic infections seen in clinical trials, occurring in 5.2% to 8% of patients receiving everolimus.44,47 However, opportunistic bacterial and fungal infections were also seen in patients receiving everolimus.45

Malignancy. The risk of developing PTLD or other malignancies has not been documented.

Kidney Dysfunction. Elevated serum creatinine levels have been reported in several everolimus studies. In combination with full-dose cyclosporine modified, everolimus therapy resulted in an elevated serum creatinine when compared to either MMF or AZA.44,47,48

Precautions. Sirolimus is a macrolide immunosuppressant that should be avoided in patients with a hypersensitivity to macrolide antibiotics (ie, erythromycin, clarithromycin, azithromycin).36 As a derivative of sirolimus, this warning must also be present with everolimus. Women who are pregnant or breast-feeding should not be encouraged to take everolimus because data are lacking in these populations.

It should be noted that a "black box" warning for use in liver and lung transplant recipients is present in the sirolimus package insert.36 In liver transplant recipients, the combination of tacrolimus and sirolimus has led to the development of hepatic artery thrombosis, graft loss and patient death. In lung transplant recipients, bronchial anastomotic dehiscence, often resulting in patient death, has occurred in patients receiving sirolimus.36 To date, these adverse reactions have not been reported in everolimus studies of liver or lung transplant recipients, although everolimus has yet to be studied in de novo lung transplant recipients.

Drug Interactions

Everolimus is a substrate of P-glycoprotein and CYP3A4.43 Inhibitors, inducers, or substrates of P-glycoprotein or CYP3A4 could potentially alter everolimus blood concentrations. This agent has been studied in conjunction with a number of other medications.

Azole Antifungals. In an analysis with fluconazole and itraconazole there was a nonsignificant reduction in everolimus clearance in fluconazole-treated patients, but a 74% reduction in clearance in 1 patient receiving itraconazole.37 The coadministration of sirolimus with the newest azole antifungal, voriconazole, is contraindicated because of an 11-fold increase in sirolimus levels.54 To date, evaluation of this interaction with everolimus has not been reported.

Calcium Channel Blockers. Coadministration of the non-dihydropyridine calcium channel blockers (verapamil and diltiazem), known CYP3A4 inhibitors, had no effect on everolimus concentrations. The dihydropyridine calcium channel blockers (amlodipine, isradipine, nifedipine) did not influence everolimus clearance.37

Cyclosporine. Kovarik et al55 assessed the influence of cyclosporine and cyclosporine modified on everolimus pharmacokinetics. When given with cyclosporine, everolimus C^sub max^ increased by only 6% (P= NS), but the average everolimus AUC increased by 74% (range 27%-254%; P = .0001). When given with cyclosporine modified, everolimus C^sub max^ was increased by 82% (P = .0001) and AUC was increased by 168% (range 46%-365%; P = .0001). The results of the study indicate that cyclosporine significantly increases exposure to everolimus.55

A second trial assessed the influence of everolimus on cyclosporine pharmacokinetics in 103 de novo kidney transplant recipients randomized to receive everolimus I mg/day (n = 34), 2 mg/day (n = 35), or 4 mg/day (n = 35) in addition to cyclosporine modified and prednisone.33 Cyclosporine doses, trough concentrations, and AUC were not influenced by coadministration of everolimus at any dose CP = .13, P = .82, and P = .76, respectively). The results of the study indicate that cyclosporine pharmacokinetics are not influenced by everolimus.33

3-Hydroxy-3-Methylglutaryl CoA Reductase Inhibitors. The coadministration of atorvastatin and pravastatin with everolimus was evaluated in a randomized, 3-way crossover trial.56 This study demonstrated that the coadministration of these statins had no clinically relevant interaction with everolimus. In another analysis, simvastatin was also shown to have no affects on everolimus pharmacokinetics.37

Macrolide Antibiotics. Coadministration of erythromycin and azithromycin resulted in a significant decrease in everolimus clearance (22% and 18%, respectively).37

Rifampin. The coadministration of rifampin with everolimus resulted in a 172% increase in everolimus clearance (P value not included). Everolimus C^sub max^, AUC, and half-life were decreased on average by 58% (P=.0001), 63% (P = .0001), and 26% (P = .0001), respectively.57

Other Potential Interactions. Kovarik et al37 also evaluated the influence of coadministration of several other medications with everolimus in 673 kidney transplant recipients. The medications that showed no influence on everolimus clearance included, gemfibrozil, ciprofloxacin, levofloxacin, norfloxacin, ofloxacin, and cotrimoxazole.37

FTY720

Mechanism of Action

FTY720 is the first agent in a new class of drugs called sphingosine 1-phosphate receptor agonists. This agent was synthesized to minimize the toxic properties of the structurally related myriocin. FTY720 alters lymphocyte traffic rather than activation.58-62 Although its precise mechanism of action is not fully understood, FTY720 possesses the ability to protect the allograft without inducing general immunosuppression. Therapeutic doses of FTY720 have demonstrated the ability to sequester T- and B-lymphocytes to lymph nodes and Peyer's patches from the blood, without affecting their functional properties. This process is reversible and results in a reduction in infiltration of lymphocytes into the allograft.58-62

Pharmacokinetics

FTY720 exhibits dose-proportional and linear pharmacokinetics over a dosing range of 0.25 to 3.5 mg.60,63 After oral administration, FTY720 T^sub max^ is 18 to 36 hours, C^sub max^ is 0.2 to 2.8 ng/mL, and AUC is 28 to 434 ng.h/mL. FTY720 has a long half-life, approximately 108 hours (range, 89-157 hours) and a mean volume of distribution of 1407 L.62,64 This agent is metabolized by the CYP450 isozyme 4A/4F. To date, 5 inactive metabolites of FTY720 have been identified and are excreted into the urine and feces.60,61,63

Clinical Efficacy

There are limited data regarding the efficacy of FTY720 in humans. In one trial,65 258 de novo kidney transplant recipients, currently receiving prednisone, were randomized to 1 of 4 groups; group 1 (5 mg/day of FTY720 and reduced-dose cyclosporine modified [n=72]), group 2 (2.5 mg/day of FTY720 and reduced-dose cyclosporine modified [n = 72]), group 3 (2.5 mg/day of FTY720 and full-dose cyclosporine modified [n = 76]), or group 4 (MMF and full-dose cyclosporine modified [n = 38]). An interim analysis of this study revealed a higher incidence of BPAR and graft loss in group 2 (37.5% and 12.5%, respectively) compared with the other groups (group 1, 19.4% and 1.4%, respectively; group 3, 15.8% and 7.9%, respectively; and group 4, 21.1% and 7.9%, respectively; P values not provided). The one notable adverse reaction observed was a higher incidence of bradycardia associated with all of the FTY720 groups compared with MMF (25% vs 5%, P values not provided). The authors concluded that FTY720, in combination with cyclosporine modified, is safe and effective. They also noted that at 5 mg/day, FTY720 allowed for reductions in cyclosporine doses, potentially leading to increased long-term safety and efficacy.65

Toxicity and Safety Profile and Precautions

Several adverse events have been reported with FTY720, including, constipation, nausea, orthopnea, nonproductive cough, herpes zoster, edema, elevated liver function tests, hypertension, bradycardia, and headache.60,61,63,65 Other adverse events, precautions, or contraindications are currently unknown.

Drug Interactions

To date, few drug-drug interactions have been identified with FTY720. This agent is hepatically metabolized via the CYP450 4A isozyme, which is an uncommon pathway for drug metabolism; therefore, a small number of pharmacokinetic drug interactions are believed to exist.60,61,63

Cyclosporine. Chronic coadministration of cyclosporine with FTY720 has been tested in 208 kidney transplant recipients. This analysis revealed no relevant drug-interaction between FTY720 and cyclosporine modified.64

Conclusion

With the approval of newer immunosuppressive agents in the United States, transplant practitioners will be forced to make important decisions about the advantages and disadvantages of these agents over currently available immunosuppressants.

A comparison of mycophenolate sodium and MMF revealed that mycophenolate sodium produces a higher MPA concentration at equivalent oral dosages. However, both formulations are equally effective and safe in kidney transplant recipients. The prevalence of GI toxicities is similar between the 2 MPA prodrugs, despite higher serum concentrations achieved with mycophenolate sodium. On the basis of available literature, mycophenolate sodium does not seem to possess clinical advantages over MMF.

Everolimus has been associated with good over all patient and graft survival, as well as relatively low rates of acute rejection and CMV disease. Because of its unique mechanism of action, everolimus has been found to have an additive immunosuppressive effect when used with cyclosporine, along with the ability to allow for lower maintenance doses of cyclosporine. Low-dose cyclosporine maintenance therapy may reduce the risks of adverse events, especially those that could be detrimental to the allograft (ie, nephrotoxicity). Other potential benefits of treatment with everolimus include inhibition of vascular remodeling and prevention of transplant arteriosclerosis, which may prove beneficial in preventing chronic rejection.

The adverse reaction profile of everolimus appears to be of concern. The long-term effects of everolimus-induced hyperlipidemia need to be further evaluated. Everolimus has been associated with kidney dysfunction. Although the incidence of this adverse event seems to be lower when used in conjunction with low-dose cyclosporine, this is a significant finding and will require a great deal of follow-up. The advantages and disadvantages of everolimus compared to sirolimus are unknown, because the differences between these agents have not been studied in clinical trials; however, the differences in daily administration (everolimus twice daily versus sirolimus once daily) cannot be overlooked.

The newest of the agents discussed, FTY720, possesses some theoretical advantages in transplantation. FTY720 has a unique mechanism of action compared to all other immunosuppressants and has initially tested positively in humans. It appears to have few adverse events; however, its effects on heart rate are of concern and will require further evaluation.

Mycophenolate sodium has recently been granted FDA approval and everolimus is currently under FDA review for marketing approval in the United States. FTY720 is currently in phase III clinical trials, and its submission to the FDA is a number of years away. The release of these new agents is anticipated with the hope that their use will result in the prevention of allograft failure and possibly chronic rejection. Long-term clinical, safety, and pharmacoeconomic outcomes are needed to further define the role of these agents in solid-organ transplant recipients.

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15. Woo J, Zeevi A, Yao GZ, Strednak J, Todo S, Thomson AW. 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. Zeevi A, Woan M, Yao GZ, et al. Comparative in vitro studies on the immunosuppressive activities of mycophenolic acid, bredinin, FK-506, cyclosporine, and rapamycin. Transplant Proc. 1991;23:2928-2930.

17. Zeevi A, Yao GZ, Venkataramanan R, et al. Comparative in vitro studies on the immunosuppressive effects of purine and pyrimidine synthesis inhibitors. Transplant Proc: 1993;25:781.

18. Myfortic (mycophenolate sodium) [package insert]. Berne, Switzerland: Novartis Pharma Schweiz AG; 2002.

19. Schmouder RI, Fauchald P, Arns W, et al. Systemic exposure of mycophenolic acid (MPA) is greater Myfortic than MMF [abstract]. Am J Transplant. 2002;2(suppl 3):398.

20. Budde K, dander P, Hahn U, et al. Phannacokinetic 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. Granger DK. Enteric-coated mycophenolate sodium: results of two pivotal global mullicenter trials. Transplant Proc. 2001;33:3241-3244.

22. Salvadori M. Therapeutic equivalence of mycophenolate sodium versus mycophenolate mofetil in de novo renal transplant recipients. Transplant Proc. 2001;33:3245-3247.

23. Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf. 2001;24:645-663.

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25. Zhu W, Arns W, Carpenter P, et al. Cyclosporine is associated with decreased absolute bioavailability of mycophenolic acid [abstract]. Am J Transplant. 2001;1(suppl 1):985.

26. Morii M, Ueno K, Ogawa A, et al. Impairment of mycophenolate mofetil absorption by iron ion. Clin Pharmacol Ther. 2000;68:613-616.

27. Catalano C, Fabbian F, Bordin V, Di Landro D. Mycophenolate mofetil toxicity in an anorexic kidney transplant patient treated with sulphinpirazone. Nephrol Dial Transplant. 1997;12:2467-2468.

28. Sedrani R, Cottens S, Kallen J, Schuler W. Chemical modification of rapamycin: the discovery of SDZ RAD. Transplant Proc. 1998;30:2192-2194.

29. Nashan B. Early clinical experience with a novel rapamycin derivative. Ther Drug Monit. February 2002;24:53-58.

30. Schuler W, Sedrani R, Coltens S, et al. SDZ RAD, a new rapamycin derivative. Transplantation. 1997;64:36-42.

31. Kahan BD, Wong RL, Carter C, et al. 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. Kirchner GI, Winkler M, Mueller L, et al. 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. Kovarik JM, Kahan BD, Kaplan B, et al. 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. Neumayer HH, Paradis K, Korn A, et al. Entry-into-human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients. Br J Clin Pharmacol. 1999;48:694-703.

35. Kovarik JM, Hartmann S, Figueiredo J, et al. Effect of food on everolimus absorption: quantification in healthy subjects and confirmatory screening in patients with renal transplants. Pharmacotherapy. 2002;22:154-159.

36. Rapamune (sirolimus) [package insert]. Philadelphia, Pa: Wyeth-Ayerst Pharmaceuticals, Inc; 2003.

37. Kovarik JM, Hsu CH, McMahon L, Berthier S, Rordorf C. Population pharmacokinetics of everolimus in de novo renal transplant patients: Impact of ethnicity and comedications. Clin Pharmacol Ther. 2001;70:247-254.

38. Hausen B, Boeke K, Berry GJ, Segarra IT, Christians U, Morris RE. 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. Hausen B, Ikonen T, Briffa N, et al. 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. Serkova N, Hausen B, Berry GJ, et al. Tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD and its metabolites in monkey lung transplant recipients: interaction with cyelosporine. J Phannacol Exp Ther. 2000;294:323-332.

41. Kirchner GI, Vidal C, Winkler M, et al. LC/ESI-MS allows simultaneous and specific quantification of SDZ RAD and cyelosporine, including groups of their metabolites in human blood. Ther Drug Monit. 1999;21:116-122.

42. Kovarik JM, Sabia H, Rouilly M. Influence of renal and hepatic impairment of everolimus pharmacokinetics: are dose adjustments necessary [abstract]? Am J Transplant. 2001;1(suppl 1):989.

43. Kovarik JM, Sabia HD, Figueiredo J, et al. Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment. Clin Phannacol Ther. 2001;70:425-430.

44. Eisen H, Dorent R, Mancini D, et al. 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. Valentine RB, Love GI, Snell PV, Allan RG, Ulrich P. 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. Kahan BD, Kaplan B, Lorber MI, Winkler M, Cambon N, Boger RS. RAD in de novo renal transplantation: comparison of three doses on the incidence and severity of acute rejection. Transplantation. 2001;71:1400-1406.

47. Vitko S, Margreiter R, Weimar W, et al. 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. Kaplan B, Tedesco-Silva H, Mendez R, et al. 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. Curtis J, Nashan B, Ponticelli C, Mourad G, Boger R. 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. Viklicky O, Zou H, Muller V, Lacha J, Szabo A, Heemann U. SDZ-RAD prevents manifestation of chronic rejection in rat renal allografts. Transplantation. 2000;69:497-502.

51. Cole OJ, Shehata M, Rigg KM. Effect of SD7. RAD on transplant arteriosclerosis in the rat aortic model. Transplant Proc. 1998;30:2200-2203.

52. Salminen US, Maasilta PK, Taskinen EI, Alho HS, Ikonen TS, Harjula AL. Prevention of small airway obliteration in a swine heterotopic lung allograft model. J Heart Lung Transplant. 2000;19:193-206.

53. Schuurman HJ, Pally C, Weckbecker G, Schuler W, Bruns C. 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. Kovarik JM, Kalbag J, Figueiredo J, Rouilly M, Frazier OL, Rordorf C. Differential influence of two cyclosporine formulations on everolimus pharmacokinetics: a clinically relevant pharmacokinetic interaction. J Clin Pharmacol. January 2002;42:95-99.

56. Kovarik JM, Hartmann S, Hubert M, et al. Pharmacokinetic and pharmacodynamic assessments of HMG-CoA reductase inhibitors when coadministered with everolimus. J Clin Pharmocol. 2002;42:222-228.

57. Kovarik JM, Hartmann S, Figueiredo J, Rouilly M, Port A, Rordorf C. Effect of rifampin on apparent clearance of everolimus. Ann Pharmacother. 2002;36:981-985.

58. Brinkmann V. Pinschewer D, Chiba K, Feng L. FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharmacol Sci. February 2000;21:49-52.

59. Brinkmann V, Pinschewer D, Feng L, Chen S. FTY720: altered lymphocyte traffic results in allograft protection. Transplantation. 2001;72:764-769.

60. Budde K, Schmouder RL, Brunkhorst R, et al. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol. 2002;13:1073-1083.

61. Troncoso P, Kahan B. Preclinical evaluation of a new immunosuppressive agent, FTY720. Clin Biochem. 1998;31:369-373.

62. Napoli KL. The FTY720 story. Ther Drug Monit. February 2000;22:47-51.

63. Kahan BD. Update on pharmacokinetic/pharmacodynamic studies with FTY720 and sirolimus. Ther Drug Monit. 2002;24:47-52.

64. Kovarik JM, Skerjanec A, Zimmerlin A, et al. Screening for a drug interaction of FTY720 on cyclospohne in renal transplant patients [abstract], Am J Transplant. 2003;3(suppl 5):483.

65. Ferguson RM, Mulgaonkar S, Tedesco H, et al. 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.

Steven Gabardi, PharmD, BCPS, Jeffrey Cerio, PharmD

Brigham and Women's Hospital, Boston, Mass (SG), Bouve College of Health Sciences, Northeastern University, Boston, Mass (SG), Walgreens Pharmacies, Austin, Tex (JC)

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