Cyclosporin

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Abstract
Cyclosporin is a lipophilic cyclic polypeptide immunosuppressant that interferes with the activity of T cells chiefly via calcineurin inhibition. The original oil-based oral formulation of this drug (Sandimmun®)1 was characterised by high intra- and interpatient pharmacokinetic variability, with poor bioavailability in many patients; a novel microemulsion formulation (Neoral®)1 was therefore developed to circumvent these problems. Studies show increases, attributable chiefly to improved absorption in patients who absorb the drug only poorly from the original formulation, in mean systemic exposure to cyclosporin with the microemulsion, with no clinically significant differences in tolerability or drug interaction profiles. Cyclosporin microemulsion is at least as effective as the oil-based formulation in renal, liver and heart transplant recipients, with trends towards decreased incidence of acute rejection with the microemulsion formulation in some (statistically significant in a few) trials. Cyclosporin microemulsion and tacrolimus appear to have similar efficacy in preventing acute rejection episodes in most renal, pancreas-kidney, liver and heart transplant recipients. However, there are indications of superior efficacy for tacrolimus in some trials, particularly in the prevention of severe acute rejection and in Black transplant recipients. Current 12-month data also indicate equivalent efficacy of sirolimus in renal transplantation. Conversion from the oil-based to microemulsion formulation in stable renal, liver and heart transplant recipients is achievable with no change in acute rejection rates. The addition of an anti-interleukin-2 receptor monoclonal antibody and/or mycophenolate mofetil to cyclosporin microemulsion plus corticosteroids decreases rates of acute rejection; corticosteroid withdrawal without increased acute rejection rates was also achieved on the addition of these agents in some trials. Pharmacoeconomic analyses have shown savings in direct healthcare costs in kidney or liver transplantation when cyclosporin microemulsion is used in preference to the oil-based formulation, although studies incorporating indirect costs or expressing costs in terms of therapeutic outcomes are currently unavailable. Conclusions: The introduction of cyclosporin microemulsion has consolidated the place of the drug as a mainstay of therapy in all types of solid organ transplantation; research into optimisation of outcomes through more effective therapeutic monitoring in patients receiving this formulation is ongoing. Several novel immunosuppressants have been introduced in recent years: further clinical and pharmacoeconomic research will be needed to clarify the relative positioning of these agents, particularly with respect to specific patient groups. Other new drugs (basiliximab/daclizumab and mycophenolate mofetil) offer particular advantages when used in combination with cyclosporin. Cyclosporin inhibits the activation of the calcium/calmodulin-activated phospha-tase calcineurin via complex formation with cyclophilin, and thereby prevents the translocation of the transcription factor nuclear factor of activated T cells (NF-AT). The drug also inhibits activation of the transcription factor NF-κB, and T cell activation is suppressed by inhibition of interleukin-2 gene expression. In vitro study of porcine aortic endothelial cells has shown complete suppression by cyclosporin of tumour necrosis factor-a-mediated induction of class II major histocompatibility complex expression. Cyclosporin also has hypertensive effects; potential underlying mechanismsinclude effects on the sympathetic nervous system, upregulation of angiotensin II receptors in vascular smooth muscle cells, increased plasma levels of en-dothelin-1, and effects on whole blood viscosity and plasma fibrinogen levels. The original oil-based oral formulation of cyclosporin is characterised by widely varying bioavailability. The microemulsion, however, has self-emulsifying properties that enhance bioavailability and reduce pharmacokinetic variability between and within patients. Assay Methods, Pharmacokinetic Monitoring and Clinical Outcomes. Measurement of cyclosporin concentrations in whole blood by immunoassay is currently used most commonly for monitoring therapy in patients receiving the drug for immunosuppression. Trough cyclosporin concentrations have been most frequently used to direct dosage adjustment, although they have little predictive value with respect to actual systemic exposure in patients receiving the original oil-based formulation. The introduction of the microemulsion has led to new research into the therapeutic monitoring of cyclosporin therapy, with increasing emphasis on the importance of the 4-hour absorption phase that follows oral administration. Correlation has been shown between areas under curves of cyclosporin concentrations in whole blood versus time (AUCs) taken over 4 hours (abbreviated AUC) and a full 12-hour administration interval in patients undergoing renal transplantation. Other data suggest utility of 2-point sampling (at 2 and 6 hours), and a strong correlation has been shown between freedom from liver graft rejection during the first month after surgery and 6-hour AUCs (AUC6) or peak drug concentrations in blood (Cmax) in patients receiving cyclosporin microemulsion. Close correlations have been reported between drug concentrations measured in blood 2 hours post-dose and 4- or 6-hour AUCs, and there is evidence of improved overall clinical outcome with 2-hour over trough concentration monitoring. General Pharmacokinetic Properties of Cyclosporin. Cyclosporin undergoes extensive extravascular distribution, with a volume of distribution at steady state of 3 to 5 L/kg after intravenous administration. The drug is 90 to 98% bound to plasma proteins, crosses the placenta, and is distributed into human milk. Blood concentrations of cyclosporin generally decline in a biphasic manner. The initial elimination half-life is reported to average 1.2 hours, whereas the average terminal elimination half-life is reported to be 8.4 to 27 hours. The drug is metabolised extensively to at least 30 metabolites, chiefly by the hepatic cyto-chrome P450 3A enzyme system. Elimination is primarily biliary; around 6% of each dose is excreted in the urine, with 0.1 % eliminated in the urine as unchanged drug. Clearance is not affected to any significant extent by haemodialysis or renal failure. Pharmacokinetic Properties of Cyclosporin Microemulsion. In general, significant increases in mean systemic exposure of patients to cyclosporin, with attendant reductions in time to Cmax (tmax), are seen when the microemulsion is used in place of the original oil-based formulation. These overall increases are attributable predominantly to improved absorption in patients who absorb cyclosporin only poorly from the oil-based formulation, with little or no change in good absorbers. In renal transplantation, increases in AUC of up to 64% have been reported in randomised comparisons and in studies in which patients were converted from the older formulation to the microemulsion, with marked increases in drug exposure in patients previously classified as poor absorbers. Comparisons of variance data in several studies indicate significant reductions in intra- and interpatient pharmacokinetic variability relative to the oil-based formulation in patients receiving the microemulsion. Substantially increased AUCs (median 71% increase in one 6-month study in 25 patients) relative to the oil-based formulation have been reported with the microemulsion in children undergoing renal transplantation. Significant increases in AUC and Cmax, and decreases in tmax, with cyclosporin microemulsion relative to the oil-based formulation have also been reported in patients undergoing liver transplantation. In one study, no clinically relevant effect of food intake was reported in microemulsion recipients. Most notably, the Canadian NOF-11 trial in 32 children showed exposure to cyclosporin (mean 8-hour AUC) to be increased by over 200% relative to the oil-based formulation in the early post-transplant period in patients treated with the microemulsion. In general, systemic exposure to cyclosporin given as microemulsion appears greater than with the oil-based formulation when T tubes are open during the first few days after liver transplantation, although data are available to indicate that absorption of cyclosporin from the microemulsion is not fully independent of bile flow. Enhancement of absorption of cyclosporin from the microemulsion relative to the oil-based formulation has also been reported in patients receiving heart and/or lung allografts. Increases were particularly marked in patients receiving lung transplants, with an increase in mean AUC6 of just over 70% relative to the oil-based formulation after 12 months in a comparative study in 50 recipients of new allografts. Relative to adults, absorption of and systemic exposure to cyclosporin are substantially reduced in children undergoing bone marrow transplantation who receive the microemulsion. AUCs were increased significantly by GI inflammation in one study. Increased systemic exposure to cyclosporin with the microemulsion has also been reported in renal transplant recipients with diabetes mellitus. The pharmacokinetic characteristics of cyclosporin are not altered to any clinically significant extent by advanced age. Effect of Formulation on Cyclosporin Dosage. Cyclosporin dosage reductions were required to maintain required drug concentrations in whole blood after conversion from the oil-based formulation to microemulsion in 12.3 to 87.2% of patients in case series of stable renal transplant recipients. Overall reductions in mean dosage (after initial conversion on a 1: 1 basis) ranged from 4.7 to 14.7% over 8 weeks to 12 months in studies in a total of 1381 patients, and were predominantly statistically significant. Dosage reductions with the microemulsion relative to the original formulation have also been shown in randomised comparative studies, although statistical significance was not attained consistently. Reduced dosage requirements with the microemulsion have also been reported in liver and heart/lung transplant recipients. Drug Interactions. A wide variety of agents increase (e.g. erythromycin, ketoconazole) or decrease (e.g. phenytoin, phenobarbital) plasma or whole blood concentrations of cyclosporin by competitive hepatic enzyme inhibition or induction, or by other mechanisms (e.g. absorption or binding to P-glycoprotein). Some drugs (e.g. aminoglycosides) are also associated with enhancement of nephrotoxicity of cyclosporin when coadministration takes place. Recent data indicate possible enhancement by cyclosporin of the potential of HMG-CoA reductase inhibitors to induce rhabdomyolysis. Mycophenolate mofetil may increase systemic exposure to cyclosporin, but the proton pump inhibitor pantoprazole has no apparent pharmacokinetic effect when coad-ministered with the drug. Comparisons with Cyclosporin Oil-Based Formulation (Sandimmun®). The overall ranges of incidence of biopsy-confirmed acute rejection episodes in the various trials in adult de novo transplant recipients receiving cyclosporin microemulsion or the original oil-based cyclosporin formulation at trough blood concentration-controlled dosages were 25 to 44.2% versus 22 to 60.5% at 3 to 24 months for renal transplantation, 45.9 to 62.7% versus 49.2 to 59.1% at 4 to 24 months for liver transplantation, and (in a single study) 86.2 versus 84.9% at 6 months for heart transplantation. Azathioprine and corticosteroids were given concomitantly in most trials. A trend for improved efficacy in this respect, and for the incidence of more than one acute rejection episode, with the microemulsion formulation was seen in most renal transplantation trials, with a statistically significant difference at 3 months in one for both parameters. There were no significant differences in the end-point incidence of acute rejection between the formulations in adult recipients of liver transplants, but the microemulsion formulation appeared significantly superior in a small trial in children (35 vs 80%; p = 0.01) at 12 months. The incidence of severe (corticosteroid-resistant in most studies) acute rejection tended to be lower in adult patients receiving the microemulsion formulation than in those receiving the oil-based formulation (0 to 18.5% vs 10.8 to 20.0% at 4 to 24 months) in liver transplantation but not in heart transplantation (46.3 vs 45.8% at 2 years). The difference between the formulations was more apparent in children receiving liver transplants in this respect (6 vs 53% at 12 months; p = 0.004). There was a trend for fewer recipients of the microemulsion than the oil-based formulation to require antilymphocyte antibody treatment for acute rejection over the first 3 months after renal transplantation. This difference was more marked in heart transplant recipients (6.9 vs 17.7%; p = 0.002 at 24 months). Graft survival rates for the microemulsion and oil-based formulations were 91 to 96% versus 89 to 98% at 3 to 24 months in renal transplant recipients and 90 to 94.1% versus 86 to 93.8% at 4 to 24 months in liver transplant recipients. Patient survival rates for the microemulsion and oil-based formulations were 98 to 100% versus 99 to 100% in renal transplant recipients and 84.2 to 100% versus 85.9 to 94% in liver transplant recipients. Graft/patient survival rates were 88.3 versus 85.4% at 2 years in heart transplant recipients. Comparisons with Other Modified Formulations. There are preliminary indications of clinical equivalence between cyclosporin Neoral® and cyclosporins SangCya®, Consupren® and Neoplanta® in de novo renal transplant recipients. Equivalence has also been demonstrated between Neoral® and Consupren® or SangCya® in two small studies in patients with stable existing transplants who were transferred from therapy with the original oil-based formulation of cyclosporin. Available comparisons, however, are predominantly nonblind and are based on small numbers of patients only. Comparisons with Tacrolimus. The incidence of acute rejection in de novo cyclosporin microemulsion (initially 8 to 15 mg/kg/day) and tacrolimus (initially 0.1 to 0.2 mg/kg/day; both dosages concentration-controlled) recipients was 10 to 39% versus 9 to 40% at 3 to 24 months in renal transplantation, 11 versus 11% at 3 months in simultaneous pancreas-kidney transplantation, 23 to 82.5% versus 17 to 66% at 1 to 30 months in liver transplantation (p < 0.01 favouring tacrolimus in one of seven trials) and 30 versus 24% at 12 months in heart transplantation (in one trial). The incidence of severe acute rejection in cyclosporin microemulsion and tacrolimus recipients was 0 to 14% versus 0 to 7% at 3 to 24 months in most trials of renal transplantation, 6 to 25% versus 0 to 19% at 1 to 30 months in liver transplantation (p < 0.01 favouring tacrolimus in one of seven trials) and 30 versus 21% at 12 months in heart transplantation. Tacrolimus 0.3 mg/kg/day was associated with significantly lower incidences of acute (20 vs 37%; p < 0.001) and severe acute rejection (9 vs 21%; p < 0.001) than cyclosporin microemulsion 8 to 10 mg/kg/day in the largest trial in renal transplant recipients, a nonblind comparative 6-month study in 577 patients in 50 European centres. Graft survival rates in cyclosporin and tacrolimus recipients were 78 to 97% versus 83 to 100% at 3 to 24 months in renal transplantation (p < 0.05 favouring tacrolimus in one of nine trials) and 62 to 92% versus 68 to 95% at 1 to 30 months in liver transplantation (p < 0.05 favouring tacrolimus in one of seven trials). Patient survival rates in cyclosporin and tacrolimus recipients were 86 to 100% versus 90 to 100% at 3 to 24 months in renal transplantation, 67 to 98% versus 72 to 98% at 1 to 30 months in liver transplantation and 85 versus 85% at 12 months in heart transplantation. Interim 6-month data from 425 of 606 liver transplant recipients taking part in a randomised, nonblind study in the UK and Ireland indicate a lower incidence of death, retransplantation or treatment failure for immunological reasons with tacrolimus than with cyclosporin microemulsion (17 vs 28%; p = 0.01). Black recipients of renal transplants tended to do better on tacrolimus than on cyclosporin microemulsion (acute rejection 14 vs 38%, respectively; severe acute rejection 7 vs 14%, respectively). Similarly, Black recipients of heart transplants did significantly better on tacrolimus at 12 months (acute rejection episodes requiring treatment, p = 0.01; patient/graft survival, p = 0.04). Comparisons with Sirolimus. The efficacy of cyclosporin microemulsion appears similar to that of sirolimus on the basis of results from two 12-month, randomised, nonblind studies in a total of 161 patients undergoing de novo renal transplantation. Graft and patient survival rates were similar between treatments in both trials; rates of biopsy-confirmed acute rejection were also not statistically significantly different, although there was a trend in favour of cyclosporin in one study (18 vs 27.5%). Conversion to Cyclosporin Microemulsion. Conversion of stable renal, liver and heart transplantation patients from the oil-based cyclosporin formulation (Sandimmun®) to the microemulsion formulation, at an initial 1: 1 dosage ratio, appears not to affect the rate of acute rejection. Preliminary evidence suggests that conversion from tacrolimus to cyclosporin microemulsion because of adverse effects or lack of efficacy is comparatively successful in renal and liver transplant recipients. Use of Other Agents with Cyclosporin Microemulsion-Based Immuno-suppression. Incidences of presumed or biopsy-proven acute rejection were significantly decreased on the addition of mycophenolate mofetil 2 g/day to cyclosporin microemulsion plus corticosteroids in nonblind studies in 173 renal transplant recipients. The addition of mycophenolate mofetil 2 or 3 g/day to cyclosporin microemulsion (initial daily dosage 5 to 15 mg/kg/day) plus corticosteroid-based immunosuppression significantly reduced the incidence of biopsy-proven rejection or treatment failure over 1 year in a randomised, multicentre, double-blind, placebo-controlled study in 491 recipients of first or second renal allografts. A significantly lower incidence of acute rejection was reported with the addition of mycophenolate mofetil to cyclosporin microemulsion and corticosteroids than with the addition of azathioprine in a nonblind study in 57 liver transplant recipients (21.4 vs 44.8%; p < 0.05). In a double-blind study (n = 376), rates of acute and severe acute rejection at 6 months were significantly reduced in patients receiving concomitant basiliximab 20mg on days 0 and 4 of renal transplantation compared with those receiving cyclosporin microemulsion and corticosteroids alone. A similar study in 346 renal transplant recipients showed statistically significant reductions in 12-month incidences of first acute rejection, second rejection, biopsy-confirmed rejection, and rejection episodes requiring treatment with augmented immuno-suppression (other than corticosteroids) with the addition of basiliximab to cyclosporin microemulsion plus corticosteroid-based immunosuppression. Significantly reduced incidence relative to placebo of biopsy-proven acute rejection has also been noted with addition of daclizumab to cyclosporin microemulsion and corticosteroid therapy. Two multicentre placebo-controlled, double-blind trials in a total of 1295...