Mycophenolate Ciclosporin

MYCOPHENOLATE CICLOSPORIN l plasma concentrations of mycophenolate and of its active metabolite mycophenolic acid Cidosporin is thought to interrupt the enterohepatic circulation of mycophenolate by inhibiting MRP-2 in the biliary tract, which prevents the excretion of its glucuronide Watch for poor response to mycophenolate if cidosporin is added conversely, watch for early features of toxicity if cidosporin is stopped... 

Ciclosporin is known to inhibit the metabolism of mycophenolate, producing lower levels of mycophenolic acid, see Mycophenolate + Ciclosporin or Tacrolimus , p.l067. Whether sirolimus specifically raises mycopheno-lafe levels compared wifh mycophenolafe faken on its own is unclear, however raised mycophenolic acid levels have been associated with an increased risk of adverse effects. " The authors of one of the studies suggest that the mycophenolate dose should be reduced from 1 g to 750 mg twice daily in patients taking sirolimus, as this produced comparable myeophenolie acid levels values with the recommended dose of mycopheno-... 

Multiorgan damage Drug reaction with eosin-ophilia and systemic symptoms (DRESS) has been attributed to minocycline in a 38-year-old woman and resulted in acute renal failure, transient thyroiditis, raised aminotransferases, and a persistent lymphocytic myocarditis resulting in congestive heart failure plasmapheresis and rituximab were effective after treatment with methylpred-nisolone, mycophenolate, ciclosporin, and muromonab had failed [69" ]. Another case has been reported in a 14-year-old boy [70 ]. 

A 59-year-old woman taking pravastatin 20 mg/day tolerated immunosuppression with ciclosporin, prednisone, and mycophenolate mofetil for 4 years after heart transplantation. After switching from pravastatin to simvastatin she developed severe muscle weakness and laboratory evidence of muscle breakdown. The biochemical markers of rhabdomyolysis did not normalize until after repeat hemodialysis. Clinical improvement did not occur until after 5 months. 

Tacrolimus + sirolimus, tacrolimus + mycophenolate mofetil, and ciclosporin + sirolimus have been compared in recipients of their first kidney transplant (52). One-year patient and graft survival did not differ. Ciclosporin + sirolimus was associated with increased serum creatinine concentrations, reduced creatinine clearance, more frequent protocol discontinuation, more antihyperlipidemic drug therapy, and a higher incidence of post-transplant diabetes mellitus. 

Picard N, Premaud A, Rousseau A, et al. A comparison of the effect of ciclosporin and sirolimus on the pharmokinetics of mycophenolate in renal transplant patients. Br J Clin Pharmacol 2006 62(4) 477 484. 

ACICLOVIR/ VALACICLOVIR ANTICANCER AND IMMUNOMODULATING DRUGS- 1. CICLOSPORIN 2. MYCOPHENOLATE 3. TACROLIMUS 1.1 nephrotoxicity 2. Possible T efficacy 3. t levels with protease inhibitors 1. Additive side-effect 2. Competition for renal excretion 3. Inhibition of CYP3A4-mediated metabolism of tacrolimus 1. Monitor renal function prior to concomitant therapy and monitor cidosporin levels 2. Monitor renal function particularly if on >4g valaciclovir 1 dose of aciclovir if there is a background of renal failure 3. Monitor clinical effects closely check levels... 

A 47-year-old multiparous Hispanic woman received a living-unrelated kidney transplant for end-stage renal disease secondary to polycystic kidney disease. On the day of transplantation she received intravenous daclizumab 1 mg/kg plus methylprednisolone 300 mg and mycophenolate mofetil 3 g/day, and on day 3 ciclosporin emulsion 4 mg/kg/day. On day 8 she developed thrombotic microangiopathy without evidence of rejection. Ciclosporin was withdrawn. Plasmapheresis with fresh frozen plasma was started. Daclizumab on day 14 was postponed for 24 hours and plasmapheresis was stopped to avoid clearance of daclizumab. Thereafter she was given tacrolimus, without recurrence of hemolysis. 

A 44-year-old black woman with a living-related renal transplant had an acute rejection within 3 months and was given muromonab but was from then on stable. She was later given oral ciclosporin (Neoral 2 mg/kg bd), mycophenolate mofetil 1000 mg bd, and prednisolone 7.5 mg/day. Over 6 months her ciclosporin blood concentrations were consistently below the target concentration of 200 ng/ml. It was then discovered that she had also been taking 2-3 tablets/day of St. John s wort (Your Life, Leiner Health Products, Carson CA, 300 mg standardized to 0.3% hypericin). The St. John s wort was withdrawn and her blood ciclosporin concentrations reached the target within 2 weeks. 

The interaction of ciclosporin with mycophenolate mofetil was investigated in 52 renal transplant patients taking triple therapy (ciclosporin, mycophenolate mofetil, and prednisone), who continued taking the same treatment (n = 19) or underwent elective ciclosporin withdrawal (n = 19) or prednisolone withdrawal (n = 14) 6 months after transplantation (275). Median mycophenolate mofetil trough concentrations 3 months later were about two-fold higher in patients who had discontinued ciclosporin compared with patients who continued to take triple therapy and patients who had discontinued prednisone. No clear mechanism readily explains these changes. 

A 52-year-old male renal transplant recipient on stable therapy (4.5 months) with ciclosporin, myco-phenolate mofetil, and co-trimoxazole developed erythrocytosis and hypertension. His leukocyte count fell 19 days after he started to take enalapril. Enalapril was withdrawn, the dose of co-trimoxazole was halved, and the dose of mycophenolate was first reduced and then withdrawn on day 25. On day 28 the leukocyte and neutrophil counts were so low that granulocyte-stimulating factor had to be used. The leukocyte count normalized during continued treatment with ciclosporin and co-trimoxazole. CMV tests were negative. 

Mycophenolate mofetil, the morphohnoethyl ester of mycophenolic acid (rINN), is an antimetabohte that interferes with the synthesis of nucleic acids and selectively inhibits the proliferation of T and B lymphocytes. It has been used to treat psoriasis and to prevent acute renal allograft rejection in combination with ciclosporin and glucocorticoids. 

In 16 renal transplant patients with suspected ciclosporin nephrotoxicity, the addition of mycophenolate allowed safe reduction in the dosage of ciclosporin, with subsequent improvement in renal function and arterial blood pressure over 6 months (1). It might allow the rapid withdrawal of glucocorticoids in patients taking ciclosporin or tacrolimus, and therefore reduce the incidence of glucocorticoid-induced post-transplant diabetes, hypercholesterolemia, and hypertension (2). There have been several reports of patients with ciclosporin-associated thrombotic micro-angiopathy/hemolytic-uremic syndrome in whom mycophenolate was successfully substituted (3,4). 

When mycophenolate replaced ciclosporin in 17 renal transplant patients with ciclosporin nephropathy, serum creatinine concentrations fell by a mean of 26% (5). There were no cases of acute allograft rejection. Adverse effects of mycophenolate were not mentioned. 

There were beneficial effects on blood pressure, lipid profile, and glomerular hemodynamics by switching from ciclosporin to mycophenolate in an open study in 17 renal transplant patients with stable renal function who took ciclosporin and prednisone in two steps (6). In step I mycophenolate was added and the dose of ciclosporin... 

In three pivotal clinical trials of mycophenolate mofetil in kidney transplant recipients, adverse effects were in accordance with the known antiproliferative effect of mycophenolate, namely gastrointestinal disorders, leukopenia, and opportunistic infections, in particular cytomegalovirus tissue invasive disease (SED-13, 1130) (SEDA-20,346). Nephrotoxicity was not observed in clinical trials, and renal function significantly improved in six patients converted to mycophenolate for ciclosporin nephrotoxicity (8). 

A 42-year-old woman with a renal transplant taking triple immunosuppression (azathioprine, ciclosporin, and glucocorticoids) was converted after 7 years from azathioprine plus ciclosporin to mycophenolate (2 g/ day) because of ciclosporin nephrotoxicity (15). Within 2 months she had developed severe persistent watery diarrhea (5-10 stools/day) and lost 7 kg over 2 months. Investigations ruled out an infectious cause and there were features of duodenal villous atrophy on histological examination. Diarrhea disappeared after mycophenolate withdrawal and two subsequent duodenal biopsies showed improvement 2 months later and further complete recovery 6 months later. 

A 49-year-old woman taking ciclosporin, prednisolone, and mycophenolate developed acute refractory rejection 4 days after renal transplantation. After an unsuccessful glucocorticoid pulse, her immunosuppressive regimen was successively changed to muromonab and tacrolimus with mycophenolate maintenance. Twelve days after transplantation she had abdominal pain and watery/bloody diarrhea. Colonoscopy showed multiple ulcers with mucosal injection and colon edema. A biopsy suggested ischemic cohtis and cytomegalovirus infection was ruled out. Her sjmptoms persisted until mycophenolate was withdrawn and further colonoscopy showed complete resolution. 

In two renal transplant patients, serum bilirubin concentrations increased to 46 and 63 pmol/l within 3-7 days of mycophenolate treatment, and further increased to 98 pmol/l in one patient after the dose was increased (19). The bilirubin concentration returned to normal or pretreatment values after withdrawal or dosage reduction. Although both patients also received ciclosporin, which has been associated with hyperbilirubinemia, the temporal relation and a possible dose-dependent effect favored a causative role of mycophenolate. 

A 45-year-old woman with a liver transplant began to take mycophenolate mofetil (2 g/day) before planned ciclosporin withdrawal. After 3 days she developed pruritus and a bullous eruption on her hands and feet. The lesions improved after mycophenolate was withdrawn, but soon reappeared after readministration of a lower dose (500 mg/day). A skin biopsy showed dyshidrotic eczema and a skin test with mycophenolate mofetil produced recurrence. 

Alopecia has been noted in two patients converted from ciclosporin to mycophenolate (SEDA-22, 418). 

In 11 patients with orthotopic hver transplants who had adverse effects from ciclosporin or tacrolimus, mycophenolate mofetil monotherapy for 1 year was successful. This was followed by a randomized, controlled trial in 18 patients, of whom nine were given mycophenolate mofetil (23). Five patients completed the 3 month trial. Of these, two had an episode of acute rejection, one after 2 months and one after 3 months, which did not respond to the reintroduction of tacrohmus and intravenous glucocorticoids. One had a glucocorticoid-responsive episode of severe acute rejection after 3 weeks. The other two patients had normal liver function tests after 2 weeks and 2 months respectively, when the trial was stopped. Mycophenolate mofetil allows a reduction of the dose of... 

As the skin of most patients with atopic dermatitis can be colonized with Staphylococcus aureus, the authors suggested caution in using mycophenolate, which can also cause leukopenia. This patient had previously taken ciclosporin and azathioprine, which were ineffective, but without apparent infectious complications. A specific role of mycophenolate is therefore debatable and the occurrence of bacterial septicemia may have been purely coincidental. 

Mycophenolate mofetil has been compared with azathioprine in combination with ciclosporin and glucocorticoids in 65 children after kidney transplantation (32). The main adverse effects of this treatment were infections of the urinary tract and the upper respiratory tract, abdominal pain, and diarrhea. Opportunistic infections with cytomegalovirus or cytomegalovirus syndrome occurred in 20% within the first 6 months and tissue-invasive cytomegalovirus disease in 3.1%. These results were similar to those in adults. 

Isolated and intermittent drug fever with a spiking pattern has been attributed to mycophenolate in a 41-year-old man with a renal transplant (38). The relation to treatment was confirmed by the exclusion of numerous infectious causes, the persistence of fever despite ciclosporin withdrawal, subsidence of fever after mycophenolate withdrawal, and the absence of further episodes of fever during follow-up. 

Kaposi s sarcoma recurred 4 months after starting mycophenolate in a 58-year-old renal transplant patient who 7 years before had had similar lesions that reversed on withdrawal of ciclosporin (39). 

In 52 patients taking mycophenolate mofetil 1 g bd, prednisone, and ciclosporin to a target blood concentration of 125-175 ng/ml for 6 months after transplantation, withdrawal of ciclosporin resulted in almost a doubling of mycophenolic acid trough concentrations (43). 

The authors noted that an interaction between vancomycin and other medications (cefazoUn, aztreonam, ciclosporin, prednisone, mycophenolate mofetU, and co-trimoxazole) could not be ruled out. 

The concurrent use of basiliximab with azathioprine, muromon-ab-CD3 or mycophenolate is not associated with an increase in adverse effects or infections. The dose requirements of ciclosporin or tacrolimus may be altered by basiliximab. Basiliximab is reported not to interact with analgesics, anti-infective drugs, diuretics, beta blockers or calcium-channel blockers. 

Azathioprine, added to regimens including basiliximab, ciclosporin microemulsion and corticosteroids, reduced the clearance of basiliximab by 51%. However, the use of basiliximab in triple regimens with mycophenolate did not increase adverse effects or infections. ... 

However, in one clinical study in heart transplant patients taking ciclosporin, mycophenolate, and corticosteroids, use of daclizumab with another antilymphocyte (such as mnromonab-CD3 or antithymocyte immunoglobniin) appeared to be associated with a higher incidence of fatal infection 8 of 40 patients died, compared with 2 of 37 who received an antilymphocyte and placebo. The manufacturer suggests that concurrent use of daclizumab with another antilymphocyte antibody in patients receiving intensive immunosuppression may be a factor leading to fatal infection. Caution may be warranted, and more study is needed. 

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