Microemulsion Formulation Of Cyclosporine Research Articles

Development of cyclosporine A microemulsion for parenteral delivery

The goal of this study was to develop a parenteral microemulsion formulation of cyclosporine A (CyA). The CyA solubility in caprylic capric triglyceride (GTCC), ethyl oleate and soybean oil were determined. The pseudo-ternary diagrams of oil (GTCC), surfactant (Solutol® HS-15), cosurfactants (ethanol/polyethylene glycol 400 [PEG 400] mixture) and water were constructed to identify boundaries for microemulsion existence. The CyA was added at 3, 6 and 9% w/w to the optimal microemulsion composition. Microemulsion particle size, solution viscosity and conductivity were examined. The microemulsion stability and haemolytic potential were examined after dilution in 5% dextrose solution for injection to 1 mg/mL CyA. Microemulsion stability was examined after a three-month storage at 4 and 25 °C. The GTCC was selected as an oil phase for CyA microemulsion based on solubility results. The optimum CyA microemulsion formulation consisted of 2.5% CyA, 9% GTCC, 24% Solutol® HS 15, 8% PEG 400, 4% ethanol and 52.5% water based on weight percent. The average particle sizes of the optimized blank and drug-loaded microemulsions were 68.7 nm and 71.6 nm, respectively and remained unchanged upon 25-fold dextrose dilution. The results of microemulsion physical and CyA chemical were confirmed by a three-month stability study at 4 and 25 °C. In vitro haemolysis studies indicated that CyA microemulsions were well tolerated by erythrocytes. The novel microemulsion formulation of CyA was developed that is suitable for parenteral administration. This new formulation could potentially have less vehicle-associated side effects that current commercial formulation of CyA based on Cremophor® EL and ethanol solution.

Cyclosporine Microemulsion Formulation (Sigmasporin Microral) Effect as First-Line Immunosuppressant on Renal Functions at 3 Years

BackgroundCyclosporine (CsA) remains a mainstay of immunosuppressive maintenance regimens in developing countries, but its effects on long-term kidney allograft survival are still unclear. Our aim was to assess a generic microemulsion CsA (Sigmasporin) for long-term impact on graft function and patient survival among stable renal transplant patients. MethodsOver a 36-month period, patients with transplantations from >6 months earlier were maintained on CsA doses of 2–8 mg/kg/d to keep C2 within the recommended therapeutic range. We assessed 25 efficacy and tolerability parameters of scheduled intervals. ResultsTwenty-seven patients (9 female, 18 male) from 6 centers in 4 Middle-Eastern countries were enrolled between 2004 and 2009. Their average age was 35.1 ± 9.8 years, body mass index ranged from 15.7 to 41.2 kg/m2, and average time from transplantation was 2.2 ± 1.6 years. Within the 36-month observation period the CsA dose was reduced by 17.3% from 2.89 ± 0.88 mg/kg/d to achieve C2 levels of 600–1000 ng/mL. After 36 months the glomerular filtration rate declined by 8.2% from an overall baseline mean of 72.7 ± 23.5 mL/min/1.73 m2. It improved in 11.1% of patients and remained unchanged in 44.4%. No new cases of hypertension or diabetes mellitus were reported, and there was 1 case of borderline hyperlipidemia. Graft functions were stable, apart from 2 incidences of CsA nephrotoxicity. Both graft and patient 3-year survival rates were 100%. ConclusionsOn a 3-year basis, Sigmasporin Microral was effective to maintain stable renal functions in kidney transplant patients, with safety and tolerability profiles similar to those reported in the international literature.

Six-Month Clinical Outcome of Cyclosporine Microemulsion Formulation (Sigmasporin Microral) in Stable Renal Transplant Patients Previously Maintained on Sandimmun Neoral

The trial objective was to investigate the feasibility and safety of conversion to a generic microemulsion cyclosporine in stable renal transplant patients premaintained on Neoral. We enrolled 75 patients from seven centers in five Middle Eastern countries monitored them for 6 months after conversion to Sigmasporin Microral. Readings at 0, 0.5, 1, 2, 3, 4.5, and 6 months included cyclosporine blood level, serum creatinine, liver enzymes, lipid profile, blood sugar, blood pressure and adverse events. Patients included 54 men and 21 women of mean age 38.9 ± 10.7 years at 30.3 ± 29.3 months post-transplantation maintained on Sigmasporin Microral dose of 2.8 ± 1.0 mg/kg per day; they were observed to be stable throughout the study period as reflected by the therapeutic blood C 0 level of 181.6 ± 102.1 and C 2 of 759.2 ± 384.4. Their absorption profile as represented by C 2/C 0 was 4.9 ± 2.8, and C 2/cyclosporine dose of 282.3 ± 128.8. An average serum creatinine level of 116.1 ± 29.5 μmol/L denoted stable graft function and their liver enzymes did not change during the study. No new-onset cases of hypertension, diabetes mellitus, or hyperlipidemia were reported among the patients. Graft function was stable for all patients, except for two incidences of mild acute rejection and two of mild cyclosporine nephrotoxicity; graft and patient survival rates were both 100%. Results of this 6-month study showed that Sigmasporin Microral was effective to maintain stable renal function in kidney transplant patients converted from Neoral with similar safety and tolerability profiles as those reported in the literature.

Therapeutic Equivalence and mg:mg Switch Ability of a Generic Cyclosporine Microemulsion Formulation (Sigmasporin Microral) in Stable Renal Transplant Patients Maintained on Sandimmun Neoral

We tested a hypothesized pharmacokinetic difference between the reference (Sandimmun Neoral) and test (Sigmasporin Microral) products to prove therapeutic equivalence in an open, multiple fixed dose, one-way crossover, multicenter, and multinational study over a period of 29 days. Forty two stable renal transplant recipients maintained on Sandimmun Neoral were enrolled. Whole blood was collected at day 14 of the study at 0, 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after reference dosing and the same schedule was repeated at day 29 after switching on an mg:mg basis to the test product at day 15 of the study. Analysis of variance was performed for the pharmacokinetic parameters (area under the curve [AUC] 0–12, maximum concentration [C max]) of cyclosporine using log-transformed values. Tolerability was assessed by vital signs, adverse events, and laboratory investigations. The 90% confidence interval (CI) test for the Ln-transformed, pharmacokinetic parameters was all within the US Food and Drug Administration acceptable range of 80% to 125%, as Ln area under the steady-state curve (AUC ss) was within the range of 92.56 to 103.55 and Ln C max was within the range of 85.73 to 103.58; the same also applied for AUC 0–4, which may be considered the area of greatest inter- and intra-patient variability. Furthermore, in line with the newly adopted recommendations of the Expert Advisory Committee on Bioavailability and Bioequivalence of Health Canada, the 90% CI for AUC ss was within the narrow range of 90% to 112%. No significant difference in tolerability was recorded between the two products. Sigmasporin Microral (Julphar) was found to be bioequivalent and clinically interchangeable on an mg:mg basis with Sandimmun Neoral (Novartis).

Pharmacokinetics of cyclosporine in recipients of marginal versus standard liver transplants

In the field of transplants, the practice of using marginal donor livers has become widely accepted, yielding good clinical results. This study investigated and compared the pharmacokinetics of cyclosporine in marginal and standard liver transplant recipients. Twenty-four de novo liver transplant patients, 12 with marginal and 12 with standard (normal) grafts, were treated with a microemulsion formulation of cyclosporine (capsules 100 mg) as immunosuppressive therapy. Blood concentration profiles were measured, and pharmacokinetic calculations performed at days 3 and 10 after transplantation. Different sampling strategies to predict drug exposure (AUC 0–12 h ) were compared, and the best limited-sampling strategies to monitor the desired blood levels were determined. Marginal and standard patients showed a significant difference in blood concentration and pharmacokinetic profiles of cyclosporine at the day 10 post-transplantation. Blood concentration at 4 h ( C 4 h ) was the single best timepoint to estimate AUC 0–12 h in marginal liver transplant ( r 2 = 0.700), while C 2 h was confirmed to be the optimal choice with standard graft ( r 2 = 0.720). Two blood samples at 2 and 6 h significantly improved the prediction model in both groups ( r 2 = 0.920). Our data suggest that patients receiving a marginal liver transplant present a different pharmacokinetic profile of cyclosporine from those receiving standard graft, which should be taken into account in dosing the patient to avoid subtherapeutic blood concentrations or toxic effects.

Comparative Bioavailability of the Microemulsion Formulation of Cyclosporine (Neoral) With a Generic Dispersion Formulation (Cicloral) in Young Healthy Male Volunteers

The aim of this study was to compare the bioavailability of cyclosporine (CyA) from the generic dispersion formulation Cicloral (CIC) with the microemulsion formulation Neoral (NEO) and the original Sandimmune (SIM) capsules after single doses of 100, 300, or 600 mg of drug, respectively. The study was performed according to an open 3-period cross-over design with 12 young healthy male volunteers for each dosage. The concentrations of CyA and its main metabolites were determined by high performance liquid chromatography in whole blood and urine up to 48 hours postdosing. Peak concentrations and area under the time-concentration curve were greater for the NEO and CIC formulations compared with SIM, and the mean bioavailability of CIC was significantly (P<0.05) lower compared with NEO. The bioavailability of SIM compared with NEO was 54% to 71%, in agreement with previous results. Bioequivalence was not demonstrated between CIC (test) and NEO (reference) as the 90% confidence intervals were outside the 80% to 125% guidelines based on log-transformed AUCs, and were 75.2% to 87.7% at 100 mg, 79.2% to 91.8% at 300 mg, and 76.6% to 94.5% at 600 mg doses. The respective values for Cmax were 78.9% to 94.6%, 80.7% to 95.0%, and 71.4% to 84.1%. A good correlation was demonstrated between the urinary recovery of CyA and the AUC4. Therefore, the urinary recovery of CyA may be helpful as a surrogate parameter for the systemic exposure of patients to CyA. Whereas the relative amount of hydroxylated metabolites (AM1, AM9, AM1c) was similar for all formulations and doses, the urinary recovery of the N-demethylated metabolite AM4N decreased with increasing dose indicating saturable metabolism. No relationship could be demonstrated between CYP3A activity using dextromethorphan as a probe for the metabolic clearance of CyA.

Population pharmacokinetic analysis of the microemulsion formulation of cyclosporin A (NeoralR) in renal transplant patients

Population pharmacokinetic analysis of the microemulsion formulation of cyclosporin A (NeoralR) in renal transplant patients

Monitoring C 2 Level Predicts Exposure in Maintenance Lung Transplant Patients Receiving the Microemulsion Formulation of Cyclosporine (Neoral)

Dosing of the microemulsion formulation of cyclosporine (Neoral) is conventionally based on trough levels (C(0)). However, experience in renal transplantation has shown that cyclosporine exposure during the absorption phase (AUC(0-4)) is critical for optimizing immunosuppression, and that cyclosporine (CsA) concentration at 2 hours post-dose (C(2)) shows the closest correlation with AUC(0-4). This study evaluated whether C(2) values correlate more closely with AUC(0-4) than C(0) in lung transplant patients. Pharmacokinetic data were collected prospectively from 20 clinically stable adult lung allograft recipients receiving CsA, mycophenolate mofetil and steroids. Indications for transplantation were emphysema (n = 15), idiopathic fibrosis (n = 2), primary pulmonary hypertension (n = 1), cystic fibrosis (n = 1) and lymphangioleiomyomatosis LAM (n = 1). Blood samples were collected at 0, 1, 2, 3 and 4 hours after administration of CsA, and then AUC(0-4) was calculated. The Correlation between cyclosporine concentration at each time-point and AUC(0-4) was also calculated. C(2) showed the closest correlation with AUC(0-4) (r(2) = 0.85). C(0) had the poorest correlation of all time-points (r(2) = 0.64). Two patients with radiologic signs of gastroparesis had no peak cyclosporine levels at all and were excluded from the correlation analysis. Mean AUC(0-4) was 3,700 ng . h/ml during Year 1 post-transplant, 2,400 ng . h/ml during Years 1 to 3, and 1,500 ng . h/ml thereafter. Mean C(2) values were 1.2 microg/ml during Year 1, 0.8 microg/ml during Years 1 to 3, and 0.5 microg/ml thereafter. C(2) is the single time-point that correlates most closely with AUC(0-4) in lung transplant recipients without gastroparesis. It remains to be demonstrated whether monitoring CsA based on C(2) levels results in a lower incidence of rejection without additional toxicity.

Rationale and design of the DIRECT study: a comparative assessment of the hyperglycemic effects of tacrolimus and cyclosporine following renal transplantation

Increased risk of cardiovascular disease contributes significantly to the higher rate of mortality seen in kidney transplant patients compared to the general population. New-onset diabetes mellitus (NODM) is a major risk factor for cardiovascular disease, as well as being associated with significantly increased graft loss and higher health care costs compared to the nondiabetic transplant population. Evidence from large-scale analyses of registry databases has shown that the calcineurin inhibitor, tacrolimus, is associated with approximately a 50% increase in the risk of NODM compared to the microemulsion formulation of cyclosporine (CsA); but to date, little robust evidence is available from clinical trials. The DIRECT (Diabetes Incidence after REnal transplantation: Neoral® C 2 monitoring versus Tacrolimus) study will be the first prospective trial to compare directly the impact of tacrolimus and CsA microemulsion on glucose metabolism in kidney transplant recipients. DIRECT is a 6-month, parallel-group, open-label, randomized trial for which approximately 700 patients will be recruited at around 70 transplant centers worldwide. Patients will be randomized to tacrolimus or CsA microemulsion (using C 2 monitoring), with mycophenolate mofetil or enteric-coated mycophenolic acid, steroids, and basiliximab. Primary endpoints are: (a) a composite of NODM or impaired fasting glucose among patients who are nondiabetic at time of transplantation; and (b) combined incidence of biopsy-proven acute rejection, graft loss, or death with CsA microemulsion C 2 monitoring compared to tacrolimus trough monitoring . Full results are expected in 2006, with interim results available by the end of 2004, and will be awaited with interest by the transplant community.

Switchover to generic cyclosporine in stable renal transplant recipients: A single unit experience

The introduction of the immunosuppressant cyclosporine has significantly improved renal transplant survival. It is an expensive drug and generic alternatives may offer cost advantages. However, generic alternatives must be shown to provide equivalent therapeutic efficacy and safety. This study reports our experience of a switch from the microemulsion formulation of cyclosporine, Neoral (Novartis), to the generic equivalent, Cysporin (Mayne Pharma). A two-period, single-sequence, cross-over study was done to compare cyclosporine blood levels and the area under the curve (AUC) of Neoral with Cysporin 2 weeks after a 1:1 dose switch. cyclosporine blood levels were measured at time points 0, 2, 4 and 8 h (C0, C2, C4, C8) after the switch. The cyclosporine AUC at 0-4 h and 0-12 h were calculated using the trapezoidal method. The two formulations were considered to result in equivalent blood levels if the 95% confidence interval (CI) of the ratio of the two levels was within 0.8-1.25. A total of 38 stable renal transplant patients aged 49.79 +/- 11.38 years (mean +/- SD), who were 7.84 +/- 3.97 years postrenal transplantation, were studied. The Neoral dose at the time of the switch was 2.38 +/- 1.21 mg per kg bodyweight. At all measured time points the 95% CI for the cyclosporine drug level ratio was between 0.9 and 1.15. There were no significant adverse events during the period of study. We conclude that the generic formulation of cylosporin, Cysporin, after a 1:1 switch from Neoral results in equivalent blood levels in stable renal transplant recipients. After switchover cyclosporine levels at C0 or C2 can continue to be monitored as per the institution's current monitoring practice.

Comparison Between C0 And C2 Monitoring in De Novo Renal Transplant Recipients: Retrospective Analysis of a Single-Center Experience

Monitoring immunosuppression with cyclosporine microemulsion formulation (CsA-MEF) by using 2-hour CsA blood levels (C2) has been strongly recommended after kidney transplantation. The aim of our study was to evaluate the impact of C2 monitoring on the clinical outcome early after transplantation in a single-center setting. Nonsensitized, consecutive, de novo cadaveric kidney-transplant recipients were treated with CsA-MEF, mycophenolate mofetil, and steroids. Patients receiving transplants after January 2002 (n=89) were prospectively monitored by C2 levels (target: 1,500+/-200 ng/mL [fluorescence-polarization immunoassay]). They were retrospectively compared with the patients receiving transplants during 2001 (n=88) who had been monitored by C0 levels (target: 250+/-50 ng/mL). In the intention-to-treat analysis, 40 (45.4%) patients in the C0 group and 25 (28.1%) patients in the C2 group received treatment for rejection (P=0.017). The incidence of histologically verified rejection of Banff grade I or higher was 20.45% in the C0 group and 13.48% in the C2 group (P=0.235). In the per-protocol analysis, incidence of treated rejection was 24.7%, and incidence of histologically verified rejection of Banff grade I or higher was 12.35% in the C2 group (P=0.004 and 0.160, respectively, vs. C0). Mean CsA-MEF doses were 1.7 to 2 times higher in the C2 group than in the C0 group throughout follow-up (P=0.019). In the C2 group, target C2 levels were achieved on average 4 days after transplantation, and there was no significant difference in C2 levels between patients who rejected and patients who did not reject. Kidney-transplant recipients monitored by C2 levels receive significantly higher doses of CsA-MEF and have a lower incidence of early acute allograft rejection than patients monitored by C0 levels. In C2 monitored patients, C2 levels are not predictive for the incidence of early allograft rejection.

Use of cyclosporine in renal transplantation

Since 1983, cyclosporine has been the backbone of immunosuppression in clinical organ transplantation. Cyclosporine is usually used in combination with steroids and with another second-line immunosuppressant like azathioprine or mycofenolate mofetil. With these regimens, graft survival at 1 year exceeds 90% and long-term results are excellent. The main complication is renal toxicity, which is usually secondary to excessive exposure. The new microemulsion formulation of cyclosporine, introduced in recent years, has improved intestinal absorption and bioavailability and resulted in much less intrapatient variation than the older formulation. The introduction of 2-hour peak blood level monitoring, which corresponds closely to the area under the curve of the drug, allows more appropriate dosing, thus minimizing rejection owing to underexposure or toxicity owing to overexposure. As new effective immunosuppressants are currently becoming available for use in combination with cyclosporine, the transplant community can look forward to more effective and safer immunosuppression.

Experience with cyclosporine in heart transplantation

The introduction of cyclosporine as an immunosuppressant in early 1980s dramatically improved the outcome of organ transplantation. The adverse effects of nephrotoxicity and increased incidence of lymphomas were recognized with high doses of cyclosporine during the early part of that decade. This led to lower doses of cyclosporine and combination with prednisolone and azathioprine as the basis of immunosuppression in transplantation. During the second half of the 1990s, the microemulsion formulation of cyclosporine was introduced that gave superior and predictable drug absorption profiles. Therapeutic drug monitoring is considered as a tool to optimize transplantation results and minimize side effects. The nephrotoxicity associated with long-term cyclosporine therapy is recognized; we are learning to take measures to minimize it. As we enter the third decade of cyclosporine use, cyclosporine-based immunosuppressive protocols remain the most popular method in heart transplantation. Newer agents in combination with cyclosporine as the core immunosuppressant are being explored.

Therapeutic drug monitoring of cyclosporine

Therapeutic drug monitoring of cyclosporine has been established as part of the routine clinical treatment for patients after organ transplantation. The inability to define optimal dose (maximize efficacy/minimize toxicity) has been a problem related to drug monitoring of cyclosporine. The original cyclosporine formula showed high intra-patient and inter-patient variability and low bioavailability. The microemulsion formulation of cyclosporine (Neoral) was introduced to address the absorption problems related to the original cyclosporine formulation. With the introduction of Neoral, renewed interest in methods of therapeutic drug monitoring brought us from trough monitoring (C0) to levels measured 2 hours after dosing (C2). The pharmacokinetic rationale for using C2 to monitor patients receiving Neoral has demonstrated a reduced incidence of rejection in de novo patients and improvements in safety profile in both renal and hepatic transplant recipients. Monitoring C2 levels is a more precise method for optimizing cyclosporine dosing and a better way to individualize therapy. Further data are required from prospective trials to evaluate the clinical benefits of adopting C2 monitoring in cardiac and lung transplant recipients as well as in long-term maintenance patients.

Testing switchability of a new microemulsion formulation of cyclosporine

We assessed the bioavailability of cyclosporine (CyA) in the test formulation (Cap Arpimune ME) relative to the reference formulation (Cap Sandimmune Neoral) to ascertain the switchability between the two formulations in patients. The study population included 30 patients on maintenance hemodialysis awaiting renal transplantation. The study adopted a randomized open-label, two-way, two-period, two-sequence crossover design. The dose administered was 8 mg/kg/d in two divided doses for 5 days in each study period with a washout period of 1 week between the two periods. A five-point blood sampling (at 0, 1, 2, 3, and 4 hours postdose) was done on the last day of each study period for CyA level monitoring. The study measures included C max (maximum blood concentration), AUC (area under the blood CyA concentration versus time curve, 0 to 4 hours) and actual time concentrations at individual sampling times. The differences in mean values for all parameters and the least significant differences were less than 20% of reference mean. Assessment of bioequivalence using log-transformed data showed that the point estimate (ratio test: reference) for C max was 0.9717 with a 90% confidence interval (CI) of 0.88 to 1.06 and that for AUC was 1.0053 with a 90% CI of 0.90 to 1.12. The bioequivalence obtained suggests that the test formulation can replace the reference formulation in patients who require CyA therapy.

Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral) in pediatric renal transplant recipients and assessment of C2 level as a marker for absorption.

There are important differences in CsA pharmacokinetics between adult and pediatric patients, such that pharmacokinetic data can not necessarily be extrapolated from the adult to the pediatric setting. Research in adult renal transplant patients has shown that adequate cyclosporin exposure (AUC0-4) in the first week post-transplant is important for successful clinical outcome, and that cyclosporin concentration at 2 h post-dose (C2) provides the optimal single-time point marker for AUC0-4. Clinically, dose management based on C2 level results in a low incidence of acute rejection in the adult renal transplant population. The study reported here undertook pharmacokinetic profiling in de novo renal transplant patients over a period of 6 months and retrospectively assessed alternative monitoring strategies based on pharmacokinetic findings and clinical outcomes. This open-label, observational, prospective study was carried out at four UK transplant centers over a period of 6 months in pediatric de novo renal transplant recipients receiving the microemulsion formulation of cyclosporin (Neoral) according to local protocol. Twelve-hour pharmacokinetic profiles (8-16 blood samples each) were performed on days 5 and 14 and at weeks 4, 13 and 26 post-transplant. Thirty-two patients were recruited (median age 10 yr, range 3-18 yr). At 6 months, patient survival was 100% and graft survival was 91%. The incidence of clinically determined acute rejection was 41% (13 of 32). Six patients discontinued Neoral before 6 months: three due to graft loss, one due to rejection, one due to renal toxicity and one due to hypertrichosis. At all time points studied, C2 correlated more closely with AUC0-4 and with AUC0-12 than did the pre-dose cyclosporin concentration (C0, or trough). Patients achieving C2 > 1.5 microg/mL by the fifth postoperative day experienced no acute rejection in the first 6 months, compared with a 50% rejection rate among patients with C2 < 1.5 microg/mL (P < 0.05). Binary logistic regression analysis showed that C2 level >1.7 microg/mL was associated with approximately 90% probability of freedom from acute rejection. Analysis of renal function across patients grouped according to cyclosporine exposure (AUC0-4, C2) showed no adverse effects of higher/increased exposure on creatinine or GFR. C2 level provides a more reliable marker for CsA exposure than C0 in pediatric renal transplant recipients, and is more closely predictive of acute rejection risk. A C2 target of 1.7 microg/mL appears appropriate in this population during the immediate post-transplant period in order to maximize clinical benefit.

Sirolimus immunotherapy: the Albany Medical Center experience

At the Albany Medical Center, we have a long-term experience, mean follow-up of 61 months, in 31 renal transplant recipients treated with sirolimus, cyclosporine microemulsion formulation, and prednisone. In these patients the rate of acute rejection was 13%, actual patient and graft survival at 1 year was 100%, and the mean serum creatinine at 1 year was 1.3 mg/dL. Furthermore, long-term graft survival was 90%. The success of this regimen stimulated us to evaluate a subsequent sirolimus-based protocol, initiated in April, 2001, which decreased exposure to calcincurin inhibitors at 3 months posttransplant ( n = 50). At a mean follow-up of 10 months, graft survival was 96%. The rate of acute rejection was only 10% and the mean serum creatinine was 1.5 mg/dL. Furthermore, no acute rejection episodes have developed subsequent to the reduction in calcineurin inhibitor dosing at 3 months. Sirolimus is an effective immunosuppressive agent that safely allows for a reduction in calcineurin-inhibitor dosing.

Review of the proliferation inhibitor everolimus

Everolimus (Certican™) is being developed for prevention of acute and chronic rejection of solid organ transplants. A novel proliferation inhibitor, everolimus synergies with cyclosporine to prevent and reverse acute rejection in preclinical models of kidney, heart or lung transplantation. The manifestations of chronic rejection that may contribute to graft loss are also inhibited by everolimus in preclinical models. Although everolimus is metabolised by the cytochrome P450 CYP3A isoenzyme, coadministration with cyclosporine does not alter the pharmacokinetics of cyclosporine, but cyclosporine coadministration increases exposure to everolimus. Everolimus interacts with inhibitors and inducers of this system; its clearance is reduced in patients with hepatic impairment. In an immunosuppressive regimen with cyclosporine microemulsion formulation and corticosteroids, transplant recipients treated with everolimus show low rates of acute rejection and, in one heart and one renal trial, lower rates of cytomegalovirus infection. Acute rejection rates are lower than those seen with azathioprine in cardiac transplant recipients and similar to those seen with mycophenolate mofetil in renal transplant recipients. Low rates of acute rejection are maintained when everolimus is given as part of a quadruple immunosuppressive regimen with low-dose cyclosporine in renal transplant recipients, with the added benefit of better renal function compared with full-dose cyclosporine. Use of C2 monitoring to optimise cyclosporine exposure and enhance efficacy and safety of everolimus is planned in future studies. Hypertriglyceridaemia and hypercholesterolaemia have been associated with everolimus, but these effects are not dose-limiting. There is no clear upper therapeutic limit of everolimus. However, thrombocytopenia occurs at a rate of 17% at everolimus trough serum concentrations above 7.8 ng/ml in renal transplant recipients. There are limited safety data available in patients with trough concentrations > 12 ng/ml. Studies suggest everolimus targets primary causes of chronic rejection by reducing acute rejection, allowing for cyclosporine dose reduction (which may lead to improved renal function relative to full-dose cyclosporine) and by reducing cytomegalovirus infection and inhibiting vascular remodelling.

Mycofenolate mofetil–cyclosporine immunosuppression of kidney transplantation recipients with two different corticosteroid doses

MYCOFENOLATE MOFETIL (MMF)–cyclosporine corticosteroid immunosuppression in kidney-transplanted patients has been shown to provide a significant reduction in the occurrence and severity of acute rejection and a tendency toward better 1-year survival in large multicenter trials, with an acceptable adverse events profile. The corticosteroid dosing protocol remains questionable. One multicenter trial investigated the safety of steroid withdrawal with a low starting dose. A significantly higher incidence of steroid-sensitive acute rejection was found. At our institution, a single-center trial was carried out to assess the influence of high-/low-dose corticosteroid in combination with an MMF–and a cyclosporine microemulsion formulation (CsA-MOF) in kidney-transplanted recipients. In routine practice at our department, first-line treatment (steroid bolus) of acute rejection is based on clinical evidence, as in many transplantation centers; therefore, only steroid-resistant acute rejections were biopsy proven during the trial.

Intermittent short courses of cyclosporine microemulsion for the long-term management of psoriasis: A 2-year cohort study

Background: Cyclosporine is effective in psoriasis, but long-term continuous therapy may be limited by renal impairment and hypertension. Intermittent short courses of treatment should minimize side effects and improve the risk-benefit ratio. Objective: Our purpose was to assess the long-term efficacy and safety of intermittent short courses of the microemulsion formulation of cyclosporine (Neoral) in the management of chronic plaque psoriasis unresponsive to topical therapies. Methods: In a multicenter open cohort study, 76 subjects were treated intermittently over a 2-year period. Patients with chronic plaque psoriasis were treated with cyclosporine until clearance of psoriasis or for a maximum of 12 weeks. Patients were then randomized into two groups. Group A stopped cyclosporine abruptly, whereas group B had the dose reduced by 1 mg/kg per day each week until cessation, which was within 4 weeks. On relapsing, patients received further courses of cyclosporine. Intermittent treatment was continued in this way for 42 years. Results: There was no statistically significant difference in the percentage of time in remission during the 2-year period between patients randomized to stop cyclosporine abruptly (56.2%) and patients randomized to taper cyclosporine within 4 weeks (61.8%). The mean percentage of time that patients received treatment during the study was 40.5% for randomization group A, 46.2% for randomization group B, and 42.8% overall. The median time to relapse was 115.5 days after the first treatment course but became progressively shorter after multiple treatment courses. Mean blood pressure and serum creatinine levels did not show any clinically significant changes over time. Conclusions: This study indicates that intermittent short courses of cyclosporine are effective in patients with moderate to severe psoriasis for up to 2 years while improving the safety profile relative to continuous cyclosporine monotherapy.