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- Noble, S. & Markham, A. Drugs (1995) 50: 924. doi:10.2165/00003495-199550050-00009
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The microemulsion-basedformulation of cyclosporin (Neoral®; referred to as the microemulsion formulation in this review) is a microemulsion preconcentrate which has been developed to overcome problems associated with the poor and unpredictable absorption of the standard oral formulation of this drug. These include marked intra- and interpatient variability in the extent of absorption, a poor correlation between trough blood concentrations of cyclosporin and total systemic exposure, and the need for regular monitoring of blood cyclosporin concentrations.
In healthy volunteers and renal or liver transplant recipients, administration of the microemulsion formulation resulted in cyclosporin absorption which was significantly faster, more extensive and more predictable than that seen with the standard oral formulation. Furthermore, measurement of whole-blood trough cyclosporin concentrations provided a better estimate of systemic drug exposure in renal transplant recipients who received the microemulsion formulation than in those who received the standard formulation. Systemic exposure of cyclosporin delivered by the new formulation appears to be relatively unaffected by food intake.
Initial data suggest that drug absorption from the microemulsion formulation is enhanced in comparison with that achieved from the standard formulation in liver transplant recipients undergoing biliary diversion or with cholestasis, although absorption from the new formulation does not appear to be completely independent of bile. Preliminary results from other groups that experience cyclosporin malabsorption from the standard formulation (patients with cystic fibrosis or diabetes, and children) are also encouraging.
Clinical trials specifically designed to investigate the relative immunosuppressive efficacy of the microemulsion formulation have not been reported; further data are required to fully establish the relationship between the more rapid and extensive absorption of cyclosporin from the microemulsion formulation and the probability of graft rejection or adverse events (including nephrotoxicity and hypertension). However, no statistically significant differences have been noted between the 2 formulations in the incidence of these events in studies to date. The incidence of rejection in new renal or liver transplant recipients treated for a minimum of 3 months was ≈31 to 50% in those receiving the microemulsion formulation and ≈24 to 56% in those receiving the standard formulation.
Thus, although confirmation of existing efficacy and tolerability data is required, the characteristic pharmacokinetic properties of the microemulsion formulation make it an attractive option for the oral delivery of cyclosporin in transplant recipients, offering more predictable and more extensive drug absorption than the standard formulation. The microemulsion formulation may be of particular benefit in patients who show poor absorption of cyclosporin from the standard oral formulation, such as liver transplant recipients with biliary diversion or cholestasis.
Overview of Pharmacodynamic Properties
Cyclosporin is an inhibitor of T cell activation and causes suppression of the cell-mediated immune response. In complex with its receptor protein (cyclophilin), cyclosporin is believed to inhibit calcineurin-mediated regulation of cytokine transcription. Thus, cyclosporin may prevent the expression of interleukin-2 and other cytokines by T helper cells, a process which is central to the immune response involved in graft rejection.
The standard oral formulation of cyclosporin (oil-based solution or soft gelatin capsules) is characterised by poor and unpredictable drug absorption. In an attempt to overcome these limitations, a new formulation of cyclosporin (Neoral®; referred to as the microemulsion formulation in this review) has been developed. This new formulation is a microemulsion preconcentrate which, on contact with gastrointestinal fluids, readily produces a microemulsion that mimics the mixed micellar phase of absorption seen with the standard oral formulation. The microemulsion system is stable, releases cyclosporin quickly, and can be diluted without causing precipitation.
In comparison with the standard formulation, delivery of cyclosporin by the microemulsion formulation results in more extensive and faster drug absorption [increased area under the whole-blood concentration versus time curve (AUC), increased maximum concentration (Cmax) and shorter time to Cmax], a more predictable relationship between trough cyclosporin concentration and systemic exposure, and reduced intra- and interindividual variability for a range of pharmacokinetic parameters. In addition, the overall systemic exposure of cyclosporin as measured by AUC does not appear to be significantly affected by food intake in patients receiving the microemulsion formulation; previous clinical experience indicates that the effects of food intake on cyclosporin absorption from the standard formulation are unpredictable.
In small numbers of liver transplant recipients with biliary diversion via an open T tube, the systemic exposure of cyclosporin from the microemulsion formulation was significantly greater than that seen with the standard formulation. However, limited data also suggest that cyclosporin absorption from the microemulsion formulation is not completely independent of bile flow.
Improvements in the rate and extent of cyclosporin absorption have also been seen with the microemulsion formulation compared with the standard formulation in other transplant groups (heart transplant recipients, patients with diabetes who have undergone kidney or simultaneous kidney and pancreas transplantation, and patients with cystic fibrosis who are candidates for heart-lung transplantation) and in patients with rheumatoid arthritis or other autoimmune disease.
Clinical Efficacy and Pharmacoeconomic Considerations
Statistically significant differences in the incidence of rejection episodes have not been observed between patients receiving the microemulsion or standard formulations in studies available to date. However, most of the relevant data come from pharmacokinetic and tolerability studies which were of short duration and/or involved relatively small numbers of patients; large, well-controlled clinical trials specifically designed to investigate immunosuppressive efficacy are still needed. The incidence of rejection in new renal or liver transplant recipients treated for a minimum of 3 months was ≈31 to 50% in those receiving the microemulsion formulation and ≈24 to 56% in those receiving the standard formulation.
Retrospective pharmacoeconomic analyses of clinical studies involving new or stable renal transplant recipients suggest that direct healthcare costs are up to 28% lower in patients receiving the microemulsion formulation than in those receiving the standard formulation over a 12-week period, although statistical analysis of these differences was not provided. Cyclosporin acquisition costs were not included in these analyses; however, the cost of the microemulsion formulation is the same as that of the standard formulation.
Information on the tolerability of the microemulsion formulation in transplant recipients has been derived primarily from studies which were of short duration and/or involved small numbers of patients. The microemulsion and standard formulations of cyclosporin appeared to be similar in terms of the type, incidence and severity of adverse events which were observed in these investigations. Renal function was stable in the majority of patients treated with the microemulsion formulation; where clinically significant nephrotoxicity (as measured by increased serum creatinine levels) was reported, the incidence was not significantly different from that seen in recipients of the standard formulation. Effects on blood pressure have been similar in the few comparative clinical trials of the microemulsion and standard formulations.
The most common adverse events in 33 new renal transplant recipients who received the microemulsion formulation (mean dosage 3.4 mg/kg/day) for 12 months were hypertrichosis (58%), gingival hyperplasia (52%) and tremor (30%). Headache, oedema, tremor, gingival hyperplasia and nausea/vomiting/epigastric pain were the most common adverse events (incidence less than 10% for each event) recorded in 373 stable renal transplant recipients who received the microemulsion formulation for 12 weeks after switching from the standard formulation.
Dosage and Administration
A 1 : 1 dose conversion from the standard formulation of cyclosporin to the microemulsion formulation has been used successfully in pharmacokinetic and clinical studies involving stable renal transplant recipients. However, definitive conversion guidelines have yet to be published and a 1 : 1 conversion may not be appropriate for other types of transplant recipients, particularly those with cyclosporin malabsorption. A 1 : 1 conversion to the microemulsion formulation in stable renal transplant recipients resulted in either similar trough cyclosporin concentrations or the need for downward dose adjustment of up to 20% to maintain clinically appropriate concentrations of cyclosporin. The mean oral dosage of the microemulsion formulation ranged from 3.4 to 15 mg/kg/day in clinical trials in renal or liver transplant recipients.