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Drug and Therapeutics Bulletin May 1997Mycophenolate mofetil (CellCept-Roche) is a new immunosuppressant indicated "in combination with cyclosporin and corticosteroids for the prophylaxis of acute transplant... (Review)
Review
Mycophenolate mofetil (CellCept-Roche) is a new immunosuppressant indicated "in combination with cyclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal transplants". Here we review mycophenolate mofetil and assess whether it offers any additional benefits to conventional therapy.
Topics: Acute Disease; Drug Costs; Drug Interactions; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid
PubMed: 9282420
DOI: 10.1136/dtb.1997.35538 -
Drug Safety Aug 1997Mycophenolate mofetil (the morpholinoethyl ester of mycophenolic acid) inhibits de novo purine synthesis via the inhibition of inosine monophosphate dehydrogenase. Its... (Review)
Review
Mycophenolate mofetil (the morpholinoethyl ester of mycophenolic acid) inhibits de novo purine synthesis via the inhibition of inosine monophosphate dehydrogenase. Its selective lymphocyte antiproliferative effects involve both T and B cells, preventing antibody formation. Mycophenolate mofetil has immuno-suppressive effects alone, but is used most commonly in combination with other immunosuppressants. Mycophenolate mofetil, in combination with cyclosporin and corticosteroids, has been studied in large, randomised clinical trials involving nearly 1500 renal allograft transplant recipients. These trials demonstrated that mycophenolate mofetil is significantly more effective in reducing treatment failure and acute rejection episodes than placebo or azathioprine. Additionally, mycophenolate mofetil may be able to reduce the occurrence of chronic rejection. Mycophenolate mofetil is relatively well tolerated. The most common adverse effect reported is gastrointestinal intolerance; haematological aberrations have also been noted. The reversible cytostatic action of mycophenolate mofetil allows for dose adjustment or discontinuation, preventing serious toxicity or an overly suppressed immune system. Cytomegalovirus tissue invasive disease and the development of malignancies are concerns that merit evaluation in long term follow-up studies. Mycophenolate mofetil does not cause the adverse effects typically associated with other commercially available immunosuppressant medications such as nephrotoxicity, hepatotoxicity, hypertension, nervous system disturbances, electrolyte abnormalities, skin disorders, hyperglycaemia, hyperuricaemia, hypercholesterolaemia, lipid disorders and structural bone loss. Based on preliminary information, a positive benefit-risk ratio has been demonstrated with the use of mycophenolate mofetil in the prophylaxis of rejection in cadaveric renal allograft transplantation. Data from studies in other types of organ transplants are promising, but are too limited to draw clear conclusions. Long term follow-up studies are required to confirm these observations. Although mycophenolate mofetil is expensive, the beneficial effects on the reduction of rejection, treatment failure and related expenses suggest that it is most likely to be cost effective.
Topics: Animals; Graft Rejection; Humans; Immunosuppressive Agents; Lymphocyte Activation; Mycophenolic Acid; Prodrugs; Risk Factors; Transplantation Immunology
PubMed: 9285199
DOI: 10.2165/00002018-199717020-00001 -
Clinical Pharmacokinetics Jun 1998The pharmacokinetics of the immunosuppressant mycophenolate mofetil have been investigated in healthy volunteers and mainly in recipients of renal allografts. Following... (Review)
Review
The pharmacokinetics of the immunosuppressant mycophenolate mofetil have been investigated in healthy volunteers and mainly in recipients of renal allografts. Following oral administration, mycophenolate mofetil was rapidly and completely absorbed, and underwent extensive presystemic de-esterification. Systemic plasma clearance of intravenous mycophenolate mofetil was around 10 L/min in healthy individuals, and plasma mycophenolate mofetil concentrations fell below the quantitation limit (0.4 mg/L) within 10 minutes of the cessation of infusion. Similar plasma mycophenolate mofetil concentrations were seen after intravenous administration in patients with severe renal or hepatic impairment, implying that the de-esterification process had not been substantially affected. Mycophenolic acid, the active immunosuppressant species, is glucuronidated to a stable phenolic glucuronide (MPAG) which is not pharmacologically active. Over 90% of the administered dose is eventually excreted in the urine, mostly as MPAG. The magnitude of the MPAG renal clearance indicates that active tubular secretion of MPAG must occur. At clinically relevant concentrations, mycophenolic acid and MPAG are about 97% and 82% bound to albumin, respectively. MPAG at high (but clinically realisable) concentrations reduced the plasma binding of mycophenolic acid. The mean maximum plasma mycophenolic acid concentration (Cmax) after a mycophenolate mofetil 1 g dose in healthy individuals was around 25 mg/L, occurred at 0.8 hours postdose, decayed with a mean apparent half-life (t1/2) of around 16 hours, and generated a mean total area under the plasma concentration-time curve (AUC infinity) of around 64 mg.h/L. Intra- and interindividual coefficients of variation for the AUC infinity of the drug were estimated to be 25% and 10%, respectively. Intravenous and oral administration of mycophenolate mofetil showed statistically equivalent MPA AUC infinity values in healthy individuals. Compared with mycophenolic acid, MPAG showed a roughly similar Cmax about 1 hour after mycophenolic acid Cmax, with a similar t1/2 and an AUC infinity about 5-fold larger than that for mycophenolic acid. Secondary mycophenolic acid peaks represent a significant enterohepatic cycling process. Since MPAG was the sole material excreted in bile, entrohepatic cycling must involve colonic bacterial deconjugation of MPAG. An oral cholestyramine interaction study showed that the mean contribution of entrohepatic cycling to the AUC infinity of mycophenolic acid was around 40% with a range of 10 to 60%. The pharmacokinetics of patients with renal transplants (after 3 months or more) compared with those of healthy individuals were similar after oral mycophenolate mofetil. Immediately post-transplant, the mean Cmax and AUC infinity of mycophenolic acid were 30 to 50% of those in the 3-month post-transplant patients. These parameters rose slowly over the 3-month interval. Slow metabolic changes, rather than poor absorption, seem responsible for this nonstationarity, since intravenous and oral administration of mycophenolate mofetil in the immediate post-transplant period generated comparable MPA AUC infinity values. Renal impairment had no major effect on the pharmacokinetic of mycophenolic acid after single doses of mycophenolate mofetil, but there was a progressive decrease in MPAG clearance as glomerular filtration rate (GFR) declined. Compared to individuals with a normal GFR, patients with severe renal impairment (GFR 1.5 L/h/1.73m2) showed 3-to 6-fold higher MPAG AUC values. In rental transplant recipients during acute renal impairment in the early post-transplant period, the plasma MPA concentrations were comparable to those in patients without renal failure, whereas plasma MPAG concentrations were 2- to 3-fold higher. Haemodialysis had no major effect on plasma mycophenolic acid or MPAG. Dosage adjustments appear to not be necessary either in renal impairment or during dialysis. (ABSTRACT TRUN
Topics: Absorption; Arthritis, Rheumatoid; Drug Administration Routes; Drug Interactions; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Failure; Mycophenolic Acid; Protein Binding; Renal Insufficiency
PubMed: 9646007
DOI: 10.2165/00003088-199834060-00002 -
Nefrologia : Publicacion Oficial de La... 2008
Review
Topics: Chronic Disease; Humans; Kidney Diseases; Kidney Glomerulus; Mycophenolic Acid; Remission Induction
PubMed: 18336137
DOI: No ID Found -
Expert Review of Gastroenterology &... Aug 2011Autoimmune hepatitis (AIH) is a chronic liver disease of unknown etiology that is responsive to steroid and azathioprine treatment in more than 80% of patients after 3... (Review)
Review
Autoimmune hepatitis (AIH) is a chronic liver disease of unknown etiology that is responsive to steroid and azathioprine treatment in more than 80% of patients after 3 years of treatment. There are few alternative treatment options for individuals with AIH who are unresponsive to steroids and azathioprine, and research on this is limited to open-label studies of a variety of immunosuppressive agents that involve only small numbers of patients. Mycophenolate mofetil is one of the most frequently used alternative agents for the treatment of AIH patients not responsive to standard therapy. In this article, we review and summarize currently available data regarding the use of mycophenolate mofetil as an alternative treatment option for patients with AIH.
Topics: Azathioprine; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Prednisolone; Treatment Outcome
PubMed: 21780898
DOI: 10.1586/egh.11.45 -
The American Journal of the Medical... Apr 2002Mycphenolate mofetil is a suppressor of T cell proliferation and adhesion. Its primary mode of action is inhibition of inosine monophosphate dehydrogenase, a purine... (Review)
Review
Mycphenolate mofetil is a suppressor of T cell proliferation and adhesion. Its primary mode of action is inhibition of inosine monophosphate dehydrogenase, a purine salvage pathway required by T lymphocytes. Although the role of T cells in rheumatoid arthritis (RA) has been controversial, a preliminary report of mycophenolate mofetil's successful use in RA patients clearly suggests that its efficacious properties need further investigation. Its favorable risk/benefit ratio, a broad clinical experience in kidney transplantation, and its recent extension to other rheumatic diseases suggests that this new antirheumatic agent has significant therapeutic potential for suppression of synovial inflammation.
Topics: Cell Adhesion; Cell Division; Graft Rejection; Humans; Immunosuppressive Agents; Mycophenolic Acid; T-Lymphocytes
PubMed: 12003374
DOI: 10.1097/00000441-200204000-00005 -
Transplantation Jan 1997
Topics: Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid
PubMed: 9000687
DOI: 10.1097/00007890-199701150-00038 -
Therapeutic Drug Monitoring Dec 1995Mycophenolate mofetil is a prodrug which is rapidly converted to mycophenolic acid (MPA), a potent and reversible uncompetitive inhibitor of inosine monophosphate... (Review)
Review
Mycophenolate mofetil is a prodrug which is rapidly converted to mycophenolic acid (MPA), a potent and reversible uncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH). In the de novo purine synthesis pathway, IMPDH is the first of two enzymes responsible for the conversion of inosine monophosphate (IMP) to guanosine monophosphate (GMP), which is normally converted to GDP, GTP, and dGTP. IMPDH is not involved in the salvage pathway of purine biosynthesis. It has been proposed that, since lymphocytes are relatively independent of the salvage pathway of nucleotide biosynthesis, MPA treatment should reduce guanine nucleotide pools in lymphocytes. Measurements show that MPA causes a reduction of GTP and dGTP in lymphocytes but not neutrophils. The consequences of the reduction in guanine nucleotides in lymphocytes, such as the inhibition of DNA synthesis, and GTP-dependent metabolic events, is discussed.
Topics: Animals; Enzyme Inhibitors; Humans; IMP Dehydrogenase; Immunosuppressive Agents; Mycophenolic Acid
PubMed: 8588241
DOI: 10.1097/00007691-199512000-00023 -
Drugs Jul 2012Whether mycophenolate mofetil is superior to cyclophosphamide as induction therapy for lupus nephritis (LN) remains controversial. (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Whether mycophenolate mofetil is superior to cyclophosphamide as induction therapy for lupus nephritis (LN) remains controversial.
OBJECTIVE
Our objective was to investigate the efficacy and safety of mycophenolate mofetil compared with cyclophosphamide as induction therapy for LN patients.
METHODS
Randomized controlled trials (RCTs) on humans were identified in searches of PubMed/MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (all to 1 December 2011). Studies that compared the efficacy and safety between mycophenolate mofetil and cyclophosphamide as induction therapy in LN patients were selected. Methodological quality of the included trials was assessed according to Cochrane criteria and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The fixed effects model was applied for pooling where there was no significant heterogeneity, otherwise the random effects model (Dersimonian and Laird method) was performed.
RESULTS
Seven trials were identified, including 725 patients. The Dersimonian and Laird method was applied for renal remission in the presence of significant heterogeneity, and no statistically significant differences were distinguished between mycophenolate mofetil and cyclophosphamide. To explore the possible source of heterogeneity, meta-regression was performed. It was suggested that no obvious study- or patient-level factors could explain interstudy heterogeneity with statistical significance. Among all these factors, the mode of administration of cyclophosphamide could explain most of the heterogeneity, although the coefficient was insignificant. Therefore, we performed a sensitivity analysis by excluding the trial in which cyclophosphamide was administered orally instead of intravenously, which suggested that mycophenolate mofetil was more effective than intravenous cyclophosphamide for inducing complete remission (relative risk [RR] 1.72; 95% CI 1.17, 2.55; p = 0.006) and complete or partial remission (RR 1.18; 95% CI 1.04, 1.35; p = 0.01). In addition, mycophenolate mofetil was superior to cyclophosphamide for significantly reducing end-stage renal disease (ESRD) or death (RR 0.64; 95% CI 0.41, 0.98; p = 0.04). For the safety comparison, lower risks of leukopenia, amenorrhoea and alopecia, and a higher risk of diarrhoea were found with mycophenolate mofetil. No statistical differences in infection and gastrointestinal symptoms were distinguished between mycophenolate mofetil and cyclophosphamide. The relatively small number and the open-label fashion of eligible RCTs may limit the value of our meta-analysis.
CONCLUSIONS
Mycophenolate mofetil is superior to intravenous cyclophosphamide for inducing renal remission, and has a significant advantage over cyclophosphamide for reducing ESRD or death. Furthermore, mycophenolate mofetil has lower risks of leukopenia, amenorrhoea and alopecia, but a higher risk of diarrhoea than cyclophosphamide. However, our conclusions need to be proved further in larger well designed trials.
Topics: Adult; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Male; Mycophenolic Acid; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome; Young Adult
PubMed: 22818016
DOI: 10.2165/11635030-000000000-00000 -
Clinical Nephrology May 2023We report a case of mycophenolate mofetil-induced collagenous ileitis in a kidney transplant patient. A 38-year-old Chinese man who had received a kidney transplant 3...
We report a case of mycophenolate mofetil-induced collagenous ileitis in a kidney transplant patient. A 38-year-old Chinese man who had received a kidney transplant 3 years earlier was admitted to our department for severe diarrhea and rapid weight loss. Infection studies were negative, and tumors were ruled out, so drug-induced factors were suspected. He had been taking mycophenolate mofetil for immunosuppression, which was then suspended, and he had a rapid resolution of diarrhea. Pathological findings of gastrointestinal endoscopy biopsy showed the presence of thickened collagen bands in the subepithelium of the terminal ileum. This is the first report of collagenous ileitis caused by mycophenolate mofetil in a patient with a kidney transplantation, adding another reversible cause to this rare condition. It is important for clinicians to recognize and treat it promptly.
Topics: Humans; Male; Adult; Ileitis; Kidney Transplantation; Immunosuppressive Agents; Mycophenolic Acid; Diarrhea
PubMed: 36871227
DOI: 10.5414/CN111055