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Neoral in de novo liver transplantation: Adequate immunosuppression without intravenous cyclosporine
Neoral in De Novo Liver Transplantation: Adequate Immunosuppression Without Intravenous Cyclosporine Gary A. Levy,* Allan Rasmussen,† A. David Mayer,‡ Neville V. Jamieson,§ and Peter Neuhaus\ Absorption of cyclosporine from the traditional oral formulation Sandimmune (Novartis Pharma, Basel, Switzerland) is particularly unpredictable in the early stages after liver transplantation. The absorption of cyclosporine is influenced by liver function, postoperative paralytic ileus, and graft dysfunction. Oral absorption of cyclosporine from Sandimmune is also bile dependent; cholestasis and external biliary drainage are associated with low cyclosporine absorption. Postoperative administration of intravenous Sandimmune is therefore often necessary to obtain adequate immunosuppression, despite the increased risk of renal and neurological toxicity. A microemulsion formulation of cyclosporine, Neoral (Novartis), has been developed to overcome the problems of poor and variable absorption of cyclosporine from Sandim-
mune. Uptake of cyclosporine from Neoral is rapid and less dependent on bile secretion so that higher peak concentrations are reached and absorption is less variable than with Sandimmune. A review of several open studies in which Neoral was administered to liver transplant patients immediately after transplantation is presented. The results suggest that the use of Neoral as a primary immunosuppressive therapy provides adequate cyclosporine trough levels, minimizing or obviating the need for intravenous cyclosporine administration. In addition, Neoral appears to reduce the risk of acute rejection episodes compared with immunosuppressive regimens involving intravenous cyclosporine. Copyright r 1997 by the American Association for the Study of Liver Diseases
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transplantation both lead to poor cyclosporine absorption. As a consequence, intravenous administration of Sandimmune has become standard practice to obtain adequate blood levels early posttransplantation, despite the increased risk of renal and neurological toxicity associated with intravenous therapy.
asic immunosuppression with cyclosporine after liver transplantation was a major therapeutic development in the early 1980s. However, in the early postoperative period, attainment of adequate cyclosporine levels after oral administration of the traditional oil-based formulation of cyclosporine, Sandimmune, has been hindered by the poor and highly variable absorption of this drug.1-4 Moreover, long-term administration of Sandimmune is associated with wide intrapatient and interpatient variability in cyclosporine absorption, which is, in turn, an important risk factor for both acute and chronic rejection after organ transplantation.5-8 Cyclosporine levels achieved after the administration of Sandimmune are particularly unpredictable in the early stages after liver transplantation. The metabolism of cyclosporine is influenced by liver function, and absorption of the drug may be reduced because of postoperative paralytic ileus.1 However, perhaps the principal problem concerning enteric absorption of cyclosporine from Sandimmune is that the oil-based formulation is dependent on bile secretion into the gastrointestinal tract.1,9,10 Thus, early graft dysfunction with poor bile production and the use of external biliary drainage in patients who have undergone liver
Improved Absorption of Cyclosporine From Neoral, a Microemulsion Formulation To overcome the problems of poor and variable absorption of cyclosporine from Sandimmune, a
From the *Toronto Hospital and University of Toronto, Toronto, Ontario, Canada; †Department of Transplantation, Rigshospitalet, University of Copenhagen, Denmark; ‡Liver Unit, Queen Elizabeth Hospital, Birmingham, England; §Department of Surgery, University of Cambridge, Addenbrook’s Hospital, Cambridge, England; and \Chirurgische Klinik Rudolf Virchow, Humbold Universita¨t, Berlin, Germany. Address reprint requests to Gary A. Levy, MD, Norman Urquhart Wing, 621 University Ave, Room 10-151, Toronto, Ontario, Canada. Copyright r 1997 by the American Association for the Study of Liver Diseases 1074-3022/97/0306-0003$3.00/0
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microemulsion formulation of cyclosporine, Neoral, has been developed. This formulation incorporates cyclosporine in a microsuspension preconcentrate with a surfactant, lipophilic and hydrophilic solvents, and a hydrophilic cosolvent.4 Cyclosporine is rapidly absorbed from Neoral by the gastrointestinal tract so that blood concentrations reach a higher peak of maximum concentration (Cmax) within a shorter time to reach maximum concentration (tmax) than with Sandimmune.11 Importantly, dispersion of the microemulsion formulation within the intestinal tract does not rely on emulsification with bile salts. Cyclosporine is therefore taken up across the absorptive surface of the small intestine more uniformly from Neoral than from Sandimmune, providing a closer correlation between total exposure and trough blood levels of cyclosporine.11-13 The correlation between the minimum concentration (Cmin) and the area under the concentration-time curve (AUC) although markedly better than for Sandimmune (r2 5 .75), is still not sufficient to reflect AUC by itself. Because absorption of cyclosporine from Neoral is less dependent on bile secretion, Neoral should carry an advantage over Sandimmune in terms of drug absorption in patients with abnormal liver metabolism or postoperative paralytic ileus. The improved absorption and bioavailability of cyclosporine from the microemulsion formulation compared with the old oil-based formulation has raised the possibility of earlier conversion from intravenous to oral therapy in the early stages after liver transplantation. The need for intravenous therapy may even be eliminated. The findings of several studies support the suggestion that Neoral could be used successfully in de novo liver transplant patients. Cyclosporine absorption in established liver transplant patients with cholestasis was enhanced when conversion from the conventional formulation to the microemulsion formulation was performed.14-17 A number of other studies have shown that Neoral can also be used early after liver transplantation.18-21 However, most studies investigating the use of Neoral in de novo liver transplant patients have involved concomitant administration of intravenous cyclosporine or initiation of Neoral therapy at least 5 days after transplantation. This review presents the results of several open trials in which Neoral was administered immediately after liver transplantation to investigate whether Neoral can minimize or obviate the need for intravenous immunosuppressive therapy.
Open Trials With Neoral Two-Center German Study To investigate the use of Neoral early in the period after liver transplantation, 50 patients were recruited into an open-label, prospective trial in two centers in Germany.22 The study involved two phases. In the course of phase A, Neoral was administered twice daily to 20 patients in incremental doses of 2.5-7.5 mg/kg after a short initial course of intravenous cyclosporine. A starting dose of 7.5 mg/kg twice daily was found to be effective in maintaining sufficient blood cyclosporine levels (.150 ng/mL), as measured by high-performance liquid chromatography, in patients with external bile drainage. For patients without a T-tube, the optimal starting dose was 5 mg/kg twice daily. During phase B, Neoral was administered to 26 patients with external bile drainage and 4 patients without a T-tube at the starting doses determined in phase A. Neoral therapy was started immediately after transplantation without any intravenous immunosuppression. The daily doses of Neoral administered during the early posttransplant period in phase B varied between 6 and 7.5 mg/kg twice daily. The mean daily dose was later reduced to 2.6 mg/kg twice daily, while maintaining adequate cyclosporine trough levels. Among the patients with external bile drainage, no differences in the absorption profile of Neoral were observed between those with stable initial liver function and those with poor initial liver function. Half of the patients enrolled in phase A and 60% of those enrolled in phase B remained free from rejection episodes 3 months after transplantation. The one-year actual patient and graft survival rate in phases A and B was between 90% and 93.3%. One patient from phase B experienced chronic graft rejection. The results of this study indicate that cyclosporine from Neoral is well absorbed in patients who have undergone liver transplantation, allowing adequate therapeutic levels of cyclosporine to be maintained in the early period after transplantation. Neoral also appears to produce improvements in the rate of acute rejection episodes compared with regimens in which immunosuppression is initiated with intravenous therapy. United Kingdom Multicenter Study Thirty-one patients with end-stage chronic liver disease were recruited into an open-label study at
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six centers in the United Kingdom to investigate further whether Neoral could replace the need for intravenous cyclosporine therapy in new liver transplant recipients treated with triple immunosuppression.19,23,24 Biliary reconstruction was by ductto-duct anastomosis with T-tube in 3 patients, duct-to-duct anastomosis without T-tube in 23 patients, and Roux-en-Y anastomosis in 5 patients. Neoral oral solution was administered by nasogastric tube within 12 hours of transplantation. The dose was started at 5 mg/kg twice daily for 48 hours and then titrated to therapeutic cyclosporine levels (150-250 ng/mL) measured by a specific fluorescence polarization immunoassay. Intravenous therapy with Sandimmune could be started if no cyclosporine absorption was observed on day 1 or if trough cyclosporine levels on day 2 were inadequate. None of the patients required intravenous cyclosporine. The target minimum trough cyclosporine level of 150 ng/mL was achieved by 46% of patients within 12 hours after the start of immunosuppressive therapy with Neoral: 93% of patients within 48 hours and all patients within 60 hours. From day 2, the mean cyclosporine trough level was maintained at 150-250 ng/mL. External biliary drainage via T-tube did not affect the cyclosporine trough levels achieved. There was a progressive increase in the rate and extent of cyclosporine absorption from days 1 to 5; the time to maximum cyclosporine concentration (tmax) was about 4 hours on day 1, but by day 5, tmax was achieved within 2 hours of dosing (Fig. 1).23 The incidence of acute rejection in this study
Figure 1. Pharmacokinetic profiles showing absorption of cyclosporine from Neoral after doses on days 1 (n 5 20), 3 (n 5 19), and 5 (n 5 19) after liver transplantation. Doses started at 5 mk/kg twice daily for 48 hours and were titrated to cyclosporine levels of 150-250 ng/mL. Reprinted with permission.23 ●, Day 1; W, day 2; ●, day 3.
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was relatively low. Twelve patients (38%) had one or more acute rejection episodes (defined as courses of antirejection therapy) by week 8 after transplantation, and 1 further patient had a rejection episode by week 12. There were no steroid-resistant rejections and no graft losses resulting from acute rejection. No patients required dialysis for acute or chronic renal failure. The rate of neurological and infective complications compared favorably with other studies; infective episodes were reported by 71% of patients, whereas the most common neurological complications, confusion and headache, were each reported by 21% of patients. The interim results of this study indicate that administration of Neoral at 10 mg · kg21 · day21 immediately after liver transplantation can reliably provide therapeutic blood levels of cyclosporine (.150 ng/mL) without the need for intravenous therapy in the early postoperative period after liver transplantation. Danish Study Similar results were found in a study in Denmark evaluating the suitability of Neoral in induction therapy in de novo liver transplant patients.25 Thirty-three consecutive liver graft recipients were treated with immunosuppressive therapy with Neoral within 6 hours of transplantation. Neoral was administered by nasogastric tube until the patient was able to take normal oral medication. Therapy with azathioprine and prednisolone was also administered, initially intravenously. A pilot study of the first 8 patients showed that a Neoral dose of 5 mg/kg twice daily was necessary to obtain adequate cyclosporine trough levels. In the subsequent 25 patients, Neoral was administered at 5 mg/kg twice daily for 48 hours, after which the dose was titrated to achieve a target cyclosporine blood concentration of 250-300 ng/mL by monoclonal immunoassay for parent drug. Biliary reconstruction was by duct-to-duct anastomosis without T-tube in 21 patients and Roux-en-Y anastomosis in 4 patients. A control group was formed that consisted of 50 patients treated with induction therapy based on antithymocyte globulin (Atgam; Upjohn, Kalamazoo, MI) until cyclosporine (Sandimmune) could be taken as normal oral medication. In the patients treated with Neoral, the rate and extent of cyclosporine absorption steadily increased during the first 14 days after transplantation (Table 1).25 The mean peak cyclosporine
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Table 1. Pharmacokinetics of Cyclosporine Absorption From Neoral on Days 1, 2, and 14 After Administration of Neoral (5 mg/kg body wt)
Day
Tmax (h)
Cmax (ng/mL)
Ctrough (ng/mL)
AUC (ng · mL21 · h21)
1 2 14
5.8 6 3.1 3.1 6 1.6 1.5 6 0.8
369 6 351 679 6 312 1031 6 389
172 6 139 218 6 103 263 6 82
2997 6 2511 4984 6 1432 6598 6 1231
Abbreviations: Tmax, time to reach maximum concentration; Cmax, maximum concentration.
concentration was achieved within 6 hours on day 1, in about 3 hours on day 2, and within 1.5 hours on day 14. The mean trough level of cyclosporine was in the therapeutic range (.150 ng/mL) from day 1. The method of biliary drainage (duct-toduct or Roux-en-Y enterostomy) did not affect the cyclosporine trough levels obtained. Similarly, the method of administration of Neoral (by nasogastric tube or oral capsules) did not significantly change the trough levels obtained for a given dose. The rate of acute rejection in the first 12 weeks after transplantation was low in the patients treated with Neoral: 6 patients (24%) had an acute rejection episode compared with 26 of the control patients (52%) (P 5 .084). Graft survival at 12 weeks was 92% in the Neoral group compared with 88% in the control group. Serum creatinine levels and creatinine clearance were similar in the Neoral and control groups, indicating that the use of Neoral as immunosuppressive therapy was not associated with an increased risk of renal dysfunction. It was concluded from this study that the use of Neoral appears to be an effective way to initiate immunosuppressive therapy in de novo liver transplant patients. Canadian Study A case-control study was undertaken in Canada to assess the safety and efficacy of Neoral without intravenous cyclosporine for induction immunosuppression in patients who have undergone liver transplantation.26 The Neoral group consisted of 21 consecutive liver transplant recipients, analyzed prospectively, who received induction immunosuppression with Neoral. The control group comprised 20 consecutive patients who had undergone liver transplantation who initially were treated with intravenous cyclosporine followed by oral Sandimmune therapy when bowel function returned at 5-7 days postoperatively. Target cyclosporine trough levels in both groups were 300-450 ng/mL in the
first 2 weeks, 250-350 ng/mL in weeks 2-4, and 200-300 ng/mL in weeks 4-12 by a monoclonal radioimmunoassay (Inkstar, Stillwater, MN). Patients with an underlying diagnosis of primary sclerosing cholangitis underwent duct reconstruction with Roux-en-Y bilioenteric anastomosis, whereas all other patients underwent a primary duct-to-duct anastomosis. Anastomoses were performed over a T-tube in the control group and over an internal stent in the Neoral group. Patient and graft survival at 3 months was 96% in the Neoral group and 100% in the control group. In the Neoral group, 1 patient with a previous traumatic brain injury withdrew because of severe neurotoxicity and later died from complications related to alternative immunosuppression. Nineteen of the remaining 20 patients in the Neoral group (95%) did not require intravenous cyclosporine to achieve and maintain target trough cyclosporine levels. The initial dose of Neoral was 12-15 mg · kg21 · day21, but dose increments of up to 100% were required to achieve target trough cyclosporine levels. Patients in the control group were treated with intravenous cyclosporine for 8 6 3 days. On day 1, trough cyclosporine levels in the Neoral group (227 6 115 ng/mL) were comparable to those in the control group (293 6 118 ng/mL). However, on day 3, cyclosporine levels were higher in the Neoral group than in the control group (591 6 340 ng/mL compared with 400 6 116 ng/ mL, respectively). Dosage adjustment in the Neoral group returned cyclosporine levels to within the target range, and from day 4, there were no significant differences in cyclosporine levels between the two groups. At 3 months after transplantation, 15 patients (75%) in the Neoral group remained rejection free compared with 7 patients (35%) in the control group (P 5 .03). There was 1 case of steroidresistant rejection requiring treatment with mono-
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clonal antibodies in each group. Two patients in the Neoral group and 3 in the control group required treatment with azathioprine (administered if renal function would not tolerate target cyclosporine levels or if more than one episode of rejection occurred while within the target range of cyclosporine). Severe neurotoxicity occurred in 1 patient in the Neoral group who had a previous traumatic brain injury. No patients in the control group experienced severe neurotoxicity. Moderate neurotoxicity was observed in 4 patients in the Neoral group (20%) and 8 patients in the control group (40%). Overall, there was no identifiable difference in neurotoxicity between the groups (P 5 .32). Moderate nephrotoxicity was observed in 5 patients (25%) in the Neoral group and 9 patients (45%) in the control group, but the difference was not significantly different (P 5 .32). No dialysis was required in either group. At 1 month after transplantation, both treatment groups showed a similar increase in serum creatinine levels from baseline (P 5 .02). Within the first 3 months after transplantation, 5 patients (25%) in the Neoral group and 7 in the control group (35%) required antihypertensive therapy. In each group, there was 1 case of cytomegalovirus hepatitis that was resolved with ganciclovir therapy. There was no difference between the groups in the incidence of other infectious complications. The data presented in this study suggest that the use of Neoral without intravenous cyclosporine in liver transplant recipients is effective and may result in decreased episodes of acute rejection without increasing the level of toxicity associated with cyclosporine. Taken together, the results of these open studies clearly indicate that Neoral can be used as immunosuppressive therapy in the early period after liver transplantation without the need for intravenous therapy or antilymphocyte induction therapy. Adequate cyclosporine levels are rapidly achieved after transplantation, reflecting the improved pharmacokinetic properties of the Neoral microemulsion compared with the old Sandimmune formulation.
Acute Rejections and Safety With Neoral Intravenous cyclosporine administration is associated with renal dysfunction, epileptic seizures, and, occasionally, hypersensitivity reactions. Therefore,
because adequate trough cyclosporine levels can be achieved with Neoral administered immediately after liver transplantation, it would be expected that early immunosuppression with Neoral would be safer than regimens involving intravenous therapy. In addition to this, the use of Neoral without intravenous cyclosporine also appears to reduce the risk of acute rejection episodes compared with intravenous cyclosporine plus oral Sandimmune and intravenous cyclosporine plus Neoral. A retrospective analysis of outcome from Birmingham, England, showed that, among 36 patients who had undergone liver transplantation who were initially treated with intravenous Sandimmune by continuous infusion before switching to oral Sandimmune, 17 (48%) had a rejection episode. The incidence of rejection in 34 patients treated with intravenous Sandimmune followed by Neoral was similar (15 patients; 46%). However, the rejection rate among 18 patients treated with postoperative Neoral without intravenous Sandimmune was only 22% (4 patients). It is likely that the patients treated with continuous intravenous Sandimmune (maintained at the same blood levels normally targeted as trough levels for oral dosing) would have had much less total exposure to cyclosporine (i.e., a lower AUC) during the infusion than if they had been treated with Neoral. This might partly account for the reduced incidence of rejection in patients who were treated with only Neoral. In the open studies described in this report, immunosuppression with Neoral immediately after liver transplantation was associated with an apparent reduction in the risk of acute rejection episodes (Table 2), while not increasing the risk of serious
Table 2. Incidence of Acute Rejection in Patients Treated With Neoral Acute Rejection (%)* Study Center
Neoral
CsA
Germany A B United Kingdom Denmark Canada
50 40 38 24 25
—† —† —† 52 65
Abbreviations: A, phase A of study in Germany; B, phase B of study in Germany. *Percent rejection to 3 months’ posttransplantation. †No control group in the study.
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Table 3. Incidence of Toxic Effects in Patients Treated With Neoral Toxicity (%)* Center
Renal
Neurological
Hypertension
Sepsis
Cytomegalovirus
Germany United Kingdom Denmark Canada
23 29 16 25
58 21 22 20
50 38 34 25
16 71 —† 25
14 10 12 5
*Percent toxicity to 3 months after transplantation. †Not reported.
adverse events or renal dysfunction (Table 3). This further supports the view that the initiation of immunosuppressive therapy with Neoral is not only as safe but may also reduce the incidence of acute rejections compared with regimens involving intravenous cyclosporine, whose dose is limited by toxicity.
Conclusions and Future Studies The open studies described in this report show that adequate immunosuppression can be achieved with Neoral started immediately after liver transplantation, without the need for intravenous cyclosporine. Therapeutic cyclosporine levels are achieved early after transplantation because Neoral has a microemulsion formulation with improved and less variable absorption compared with the conventional oil-based oral formulation of cyclosporine, Sandimmune. The use of Neoral appears to decrease the risk of acute rejection, particularly compared with regimens involving intravenous cyclosporine, although this needs to be confirmed in controlled studies. In addition, Neoral does not appear to increase the risk of adverse events associated with intravenous cyclosporine, such as renal dysfunction, epileptic seizures, and hypersensitivity reactions. As part of the ongoing program of clinical trials with Neoral, a further randomized study to compare Neoral with Sandimmune is nearing completion. Other studies are being conducted to investigate the effect of Neoral on chronic rejection and patient and graft survival. The starting dose of Neoral used in most of the open studies described in this review was 10 mg · kg21 · day21. Other studies are planned using higher starting doses to determine whether the incidence of acute rejec-
tions can be further reduced without incurring excessive toxicity.
References 1. Lemaire M, Fahr A, Maurer G. Pharmacokinetics of cyclosporin: Inter- and intra-individual variations and metabolic pathways. Transplant Proc 1990;22:11101112. 2. Lindholm A. Factors influencing the pharmacokinetics of cyclosporin in man. Ther Drug Monit 1991;13:465-477. 3. Lindholm A, Welsh M, Rutzky L, Kahan BD. The adverse impact of high cyclosporin clearance rates on the incidences of acute rejection and graft loss. Transplantation 1993;55:985-993. 4. Vonderscher J, Meinzer A. Rationale for the development of Sandimmunt Neoralt. Transplant Proc 1994;26: 2925-2927. 5. Best NG, Trull AK, Tan KKC, Hue KL, Spiegelhalter DJ, Gore SM, et al. Blood cyclosporin concentrations and the short-term risk of lung rejection following heart-lung transplantation. Br J Clin Pharmacol 1992;34:513-520. 6. Lindholm A, Kahan BD. Influence of cyclosporin pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 1993;54:205-218. 7. Schroeder TJ, Sridhar N, Pesce AJ, Alexander JW, First MR. Clinical correlations of cyclosporin-specific and -nonspecific assays in stable renal transplants, acute rejection, and cyclosporin nephrotoxicity. Ther Drug Monit 1993;15:190-194. 8. Kahan BD. Neoraly addresses two limitations of existing cyclosporin formulations: Limited and variable drug absorption. In: Burke JF, Kahan BD, Pollak R, Frei U, Jamieson NV, Keown PA, eds. Neoraly: The new microemulsion formulation of cyclosporin. Cedar Knolls, NJ: World Medical, 1995:12-18. 9. Mehta MU, Venkataramanan R, Burchardt GJ, Starzl TE. Effect of bile on cyclosporin absorption in liver transplant patients. Br J Clin Pharmacol 1988;25:579581. 10. Naoumov NV, Tredger JM, Steward CM. Cyclosporin A pharmacokinetics in liver transplant recipients in relation to biliary T-tube clamping and liver dysfunction. Gut 1989;30:391-396.
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11. Holt DW, Mueller EA, Kovarik JM, van Bree JB, Kutz K. The pharmacokinetics of Sandimmunt Neoralt: A new oral formulation of cyclosporin. Transplant Proc 1994;26: 2935-2939. 12. Noble S, Markham A. Cyclosporin. A review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoralt). Drugs 1995;50:951-968. 13. Mueller EA, Kovarik JM, van Bree JB, Tetzloff W, Grevel J, Kutz K. Improved dose linearity of cyclosporin pharmacokinetics from a microemulsion formulation. Pharm Res 1994;11:301-304. 14. Atkinson PR, Grant DR, Williams SE, Howard J, Wall WJ, Stiller CR. Sandimmunt Neoralt in paediatric liver transplant recipients with malabsorption of CyA. Transplant Proc 1994;26:2953-2954. 15. Fa¨rber L, Maibu¨cher A, Gessler F, Gutzler F, Wiesinger FO, Winkler M. Favourable clinical results of Sandimmunt Neoralt in malabsorbing liver and heart transplant recipients. Transplant Proc 1994;26:2988-2993. 16. Trull AK, Tan KKC, Uttridge J, Bower T, Alexander G, Jamieson NV. Cyclosporin absorption from microemulsion formulation in a liver transplant recipient. Lancet 1993;341:433. 17. Winkler M, Ringe B, Schneider K, Maibu¨cher A, Fa¨rber L, Wietholtz H, et al. Enhanced bioavailability of cyclosporin A using a new oral formulation (Sandimmunt Optoralt) in a liver grafted patient with severe cholestasis. Transplant Int 1994;7:147. 18. Altraif I, Levy G, Grant D. Pharmacokinetic studies of Sandimmunt Neoralt vs Sandimmunt in liver transplant recipients [abs]. Hepatology 1993;18:747.
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19. Jamieson NV. De novo use of Neoralt in liver transplant recipients. In: Burke JF, Kahan BD, Pollak R, Frei U, Jamieson NV, Keown PA, eds. Neoraly: The new microemulsion formulation of cyclosporine. Cedar Knolls, NJ: World Medical, 1995:34-39. 20. Levy G, Rochon J, Freeman D, Wong PY, Banks L, Roach C, et al. Cyclosporin Neoralt in liver transplant recipients. Transplant Proc 1994;26:2949-2952. 21. Levy G, Grant D. Potential for CsA-Neoralt in organ transplantation. Transplant Proc 1994;26:2932-2934. 22. Winkler M, Haller G, Oldhafer K, Bechstein WO, Kattner A, Maibu¨cher A, et al. A new oral formulation for early oral immunosuppressive therapy in liver transplant recipients. Transplantation 1996;62:1063-1068. 23. Tredger JM, United Kingdom Neoral Pilot Study Group. Using cyclosporine Neoral immediately after liver transplantation. Ther Drug Monit 1995;17:638-641. 24. Jamieson NV, Gimson AES, Calne RY, Tredger JM, McCarthy M, Williams R, et al. Liver transplantation using neoral cyclosporin without intravenous induction therapy: A UK pilot study. In: Papastamatiou L, ed. European IHPBA Congress ‘‘Athens ’95.’’ Bologna: Monduzzi Editore, 1995:765-771. 25. Rasmussen A, Hjortrup A, Hansen BA, Heslet L, Kirkegaard P. Induction of immunosuppression by microemulsion cyclosporine in liver transplantation. Transplantation 1996;62:1031-1033. 26. Hemming AW, Greig PD, Cattral MS, Chung SW, Lilly LB, Aljumah AA, et al. Neoral without intravenous cyclosporine in liver transplantation. Transplantation 1997;29:543-548.
mune. Uptake of cyclosporine from Neoral is rapid and less dependent on bile secretion so that higher peak concentrations are reached and absorption is less variable than with Sandimmune. A review of several open studies in which Neoral was administered to liver transplant patients immediately after transplantation is presented. The results suggest that the use of Neoral as a primary immunosuppressive therapy provides adequate cyclosporine trough levels, minimizing or obviating the need for intravenous cyclosporine administration. In addition, Neoral appears to reduce the risk of acute rejection episodes compared with immunosuppressive regimens involving intravenous cyclosporine. Copyright r 1997 by the American Association for the Study of Liver Diseases
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transplantation both lead to poor cyclosporine absorption. As a consequence, intravenous administration of Sandimmune has become standard practice to obtain adequate blood levels early posttransplantation, despite the increased risk of renal and neurological toxicity associated with intravenous therapy.
asic immunosuppression with cyclosporine after liver transplantation was a major therapeutic development in the early 1980s. However, in the early postoperative period, attainment of adequate cyclosporine levels after oral administration of the traditional oil-based formulation of cyclosporine, Sandimmune, has been hindered by the poor and highly variable absorption of this drug.1-4 Moreover, long-term administration of Sandimmune is associated with wide intrapatient and interpatient variability in cyclosporine absorption, which is, in turn, an important risk factor for both acute and chronic rejection after organ transplantation.5-8 Cyclosporine levels achieved after the administration of Sandimmune are particularly unpredictable in the early stages after liver transplantation. The metabolism of cyclosporine is influenced by liver function, and absorption of the drug may be reduced because of postoperative paralytic ileus.1 However, perhaps the principal problem concerning enteric absorption of cyclosporine from Sandimmune is that the oil-based formulation is dependent on bile secretion into the gastrointestinal tract.1,9,10 Thus, early graft dysfunction with poor bile production and the use of external biliary drainage in patients who have undergone liver
Improved Absorption of Cyclosporine From Neoral, a Microemulsion Formulation To overcome the problems of poor and variable absorption of cyclosporine from Sandimmune, a
From the *Toronto Hospital and University of Toronto, Toronto, Ontario, Canada; †Department of Transplantation, Rigshospitalet, University of Copenhagen, Denmark; ‡Liver Unit, Queen Elizabeth Hospital, Birmingham, England; §Department of Surgery, University of Cambridge, Addenbrook’s Hospital, Cambridge, England; and \Chirurgische Klinik Rudolf Virchow, Humbold Universita¨t, Berlin, Germany. Address reprint requests to Gary A. Levy, MD, Norman Urquhart Wing, 621 University Ave, Room 10-151, Toronto, Ontario, Canada. Copyright r 1997 by the American Association for the Study of Liver Diseases 1074-3022/97/0306-0003$3.00/0
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microemulsion formulation of cyclosporine, Neoral, has been developed. This formulation incorporates cyclosporine in a microsuspension preconcentrate with a surfactant, lipophilic and hydrophilic solvents, and a hydrophilic cosolvent.4 Cyclosporine is rapidly absorbed from Neoral by the gastrointestinal tract so that blood concentrations reach a higher peak of maximum concentration (Cmax) within a shorter time to reach maximum concentration (tmax) than with Sandimmune.11 Importantly, dispersion of the microemulsion formulation within the intestinal tract does not rely on emulsification with bile salts. Cyclosporine is therefore taken up across the absorptive surface of the small intestine more uniformly from Neoral than from Sandimmune, providing a closer correlation between total exposure and trough blood levels of cyclosporine.11-13 The correlation between the minimum concentration (Cmin) and the area under the concentration-time curve (AUC) although markedly better than for Sandimmune (r2 5 .75), is still not sufficient to reflect AUC by itself. Because absorption of cyclosporine from Neoral is less dependent on bile secretion, Neoral should carry an advantage over Sandimmune in terms of drug absorption in patients with abnormal liver metabolism or postoperative paralytic ileus. The improved absorption and bioavailability of cyclosporine from the microemulsion formulation compared with the old oil-based formulation has raised the possibility of earlier conversion from intravenous to oral therapy in the early stages after liver transplantation. The need for intravenous therapy may even be eliminated. The findings of several studies support the suggestion that Neoral could be used successfully in de novo liver transplant patients. Cyclosporine absorption in established liver transplant patients with cholestasis was enhanced when conversion from the conventional formulation to the microemulsion formulation was performed.14-17 A number of other studies have shown that Neoral can also be used early after liver transplantation.18-21 However, most studies investigating the use of Neoral in de novo liver transplant patients have involved concomitant administration of intravenous cyclosporine or initiation of Neoral therapy at least 5 days after transplantation. This review presents the results of several open trials in which Neoral was administered immediately after liver transplantation to investigate whether Neoral can minimize or obviate the need for intravenous immunosuppressive therapy.
Open Trials With Neoral Two-Center German Study To investigate the use of Neoral early in the period after liver transplantation, 50 patients were recruited into an open-label, prospective trial in two centers in Germany.22 The study involved two phases. In the course of phase A, Neoral was administered twice daily to 20 patients in incremental doses of 2.5-7.5 mg/kg after a short initial course of intravenous cyclosporine. A starting dose of 7.5 mg/kg twice daily was found to be effective in maintaining sufficient blood cyclosporine levels (.150 ng/mL), as measured by high-performance liquid chromatography, in patients with external bile drainage. For patients without a T-tube, the optimal starting dose was 5 mg/kg twice daily. During phase B, Neoral was administered to 26 patients with external bile drainage and 4 patients without a T-tube at the starting doses determined in phase A. Neoral therapy was started immediately after transplantation without any intravenous immunosuppression. The daily doses of Neoral administered during the early posttransplant period in phase B varied between 6 and 7.5 mg/kg twice daily. The mean daily dose was later reduced to 2.6 mg/kg twice daily, while maintaining adequate cyclosporine trough levels. Among the patients with external bile drainage, no differences in the absorption profile of Neoral were observed between those with stable initial liver function and those with poor initial liver function. Half of the patients enrolled in phase A and 60% of those enrolled in phase B remained free from rejection episodes 3 months after transplantation. The one-year actual patient and graft survival rate in phases A and B was between 90% and 93.3%. One patient from phase B experienced chronic graft rejection. The results of this study indicate that cyclosporine from Neoral is well absorbed in patients who have undergone liver transplantation, allowing adequate therapeutic levels of cyclosporine to be maintained in the early period after transplantation. Neoral also appears to produce improvements in the rate of acute rejection episodes compared with regimens in which immunosuppression is initiated with intravenous therapy. United Kingdom Multicenter Study Thirty-one patients with end-stage chronic liver disease were recruited into an open-label study at
Neoral in Liver Transplantation
six centers in the United Kingdom to investigate further whether Neoral could replace the need for intravenous cyclosporine therapy in new liver transplant recipients treated with triple immunosuppression.19,23,24 Biliary reconstruction was by ductto-duct anastomosis with T-tube in 3 patients, duct-to-duct anastomosis without T-tube in 23 patients, and Roux-en-Y anastomosis in 5 patients. Neoral oral solution was administered by nasogastric tube within 12 hours of transplantation. The dose was started at 5 mg/kg twice daily for 48 hours and then titrated to therapeutic cyclosporine levels (150-250 ng/mL) measured by a specific fluorescence polarization immunoassay. Intravenous therapy with Sandimmune could be started if no cyclosporine absorption was observed on day 1 or if trough cyclosporine levels on day 2 were inadequate. None of the patients required intravenous cyclosporine. The target minimum trough cyclosporine level of 150 ng/mL was achieved by 46% of patients within 12 hours after the start of immunosuppressive therapy with Neoral: 93% of patients within 48 hours and all patients within 60 hours. From day 2, the mean cyclosporine trough level was maintained at 150-250 ng/mL. External biliary drainage via T-tube did not affect the cyclosporine trough levels achieved. There was a progressive increase in the rate and extent of cyclosporine absorption from days 1 to 5; the time to maximum cyclosporine concentration (tmax) was about 4 hours on day 1, but by day 5, tmax was achieved within 2 hours of dosing (Fig. 1).23 The incidence of acute rejection in this study
Figure 1. Pharmacokinetic profiles showing absorption of cyclosporine from Neoral after doses on days 1 (n 5 20), 3 (n 5 19), and 5 (n 5 19) after liver transplantation. Doses started at 5 mk/kg twice daily for 48 hours and were titrated to cyclosporine levels of 150-250 ng/mL. Reprinted with permission.23 ●, Day 1; W, day 2; ●, day 3.
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was relatively low. Twelve patients (38%) had one or more acute rejection episodes (defined as courses of antirejection therapy) by week 8 after transplantation, and 1 further patient had a rejection episode by week 12. There were no steroid-resistant rejections and no graft losses resulting from acute rejection. No patients required dialysis for acute or chronic renal failure. The rate of neurological and infective complications compared favorably with other studies; infective episodes were reported by 71% of patients, whereas the most common neurological complications, confusion and headache, were each reported by 21% of patients. The interim results of this study indicate that administration of Neoral at 10 mg · kg21 · day21 immediately after liver transplantation can reliably provide therapeutic blood levels of cyclosporine (.150 ng/mL) without the need for intravenous therapy in the early postoperative period after liver transplantation. Danish Study Similar results were found in a study in Denmark evaluating the suitability of Neoral in induction therapy in de novo liver transplant patients.25 Thirty-three consecutive liver graft recipients were treated with immunosuppressive therapy with Neoral within 6 hours of transplantation. Neoral was administered by nasogastric tube until the patient was able to take normal oral medication. Therapy with azathioprine and prednisolone was also administered, initially intravenously. A pilot study of the first 8 patients showed that a Neoral dose of 5 mg/kg twice daily was necessary to obtain adequate cyclosporine trough levels. In the subsequent 25 patients, Neoral was administered at 5 mg/kg twice daily for 48 hours, after which the dose was titrated to achieve a target cyclosporine blood concentration of 250-300 ng/mL by monoclonal immunoassay for parent drug. Biliary reconstruction was by duct-to-duct anastomosis without T-tube in 21 patients and Roux-en-Y anastomosis in 4 patients. A control group was formed that consisted of 50 patients treated with induction therapy based on antithymocyte globulin (Atgam; Upjohn, Kalamazoo, MI) until cyclosporine (Sandimmune) could be taken as normal oral medication. In the patients treated with Neoral, the rate and extent of cyclosporine absorption steadily increased during the first 14 days after transplantation (Table 1).25 The mean peak cyclosporine
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Table 1. Pharmacokinetics of Cyclosporine Absorption From Neoral on Days 1, 2, and 14 After Administration of Neoral (5 mg/kg body wt)
Day
Tmax (h)
Cmax (ng/mL)
Ctrough (ng/mL)
AUC (ng · mL21 · h21)
1 2 14
5.8 6 3.1 3.1 6 1.6 1.5 6 0.8
369 6 351 679 6 312 1031 6 389
172 6 139 218 6 103 263 6 82
2997 6 2511 4984 6 1432 6598 6 1231
Abbreviations: Tmax, time to reach maximum concentration; Cmax, maximum concentration.
concentration was achieved within 6 hours on day 1, in about 3 hours on day 2, and within 1.5 hours on day 14. The mean trough level of cyclosporine was in the therapeutic range (.150 ng/mL) from day 1. The method of biliary drainage (duct-toduct or Roux-en-Y enterostomy) did not affect the cyclosporine trough levels obtained. Similarly, the method of administration of Neoral (by nasogastric tube or oral capsules) did not significantly change the trough levels obtained for a given dose. The rate of acute rejection in the first 12 weeks after transplantation was low in the patients treated with Neoral: 6 patients (24%) had an acute rejection episode compared with 26 of the control patients (52%) (P 5 .084). Graft survival at 12 weeks was 92% in the Neoral group compared with 88% in the control group. Serum creatinine levels and creatinine clearance were similar in the Neoral and control groups, indicating that the use of Neoral as immunosuppressive therapy was not associated with an increased risk of renal dysfunction. It was concluded from this study that the use of Neoral appears to be an effective way to initiate immunosuppressive therapy in de novo liver transplant patients. Canadian Study A case-control study was undertaken in Canada to assess the safety and efficacy of Neoral without intravenous cyclosporine for induction immunosuppression in patients who have undergone liver transplantation.26 The Neoral group consisted of 21 consecutive liver transplant recipients, analyzed prospectively, who received induction immunosuppression with Neoral. The control group comprised 20 consecutive patients who had undergone liver transplantation who initially were treated with intravenous cyclosporine followed by oral Sandimmune therapy when bowel function returned at 5-7 days postoperatively. Target cyclosporine trough levels in both groups were 300-450 ng/mL in the
first 2 weeks, 250-350 ng/mL in weeks 2-4, and 200-300 ng/mL in weeks 4-12 by a monoclonal radioimmunoassay (Inkstar, Stillwater, MN). Patients with an underlying diagnosis of primary sclerosing cholangitis underwent duct reconstruction with Roux-en-Y bilioenteric anastomosis, whereas all other patients underwent a primary duct-to-duct anastomosis. Anastomoses were performed over a T-tube in the control group and over an internal stent in the Neoral group. Patient and graft survival at 3 months was 96% in the Neoral group and 100% in the control group. In the Neoral group, 1 patient with a previous traumatic brain injury withdrew because of severe neurotoxicity and later died from complications related to alternative immunosuppression. Nineteen of the remaining 20 patients in the Neoral group (95%) did not require intravenous cyclosporine to achieve and maintain target trough cyclosporine levels. The initial dose of Neoral was 12-15 mg · kg21 · day21, but dose increments of up to 100% were required to achieve target trough cyclosporine levels. Patients in the control group were treated with intravenous cyclosporine for 8 6 3 days. On day 1, trough cyclosporine levels in the Neoral group (227 6 115 ng/mL) were comparable to those in the control group (293 6 118 ng/mL). However, on day 3, cyclosporine levels were higher in the Neoral group than in the control group (591 6 340 ng/mL compared with 400 6 116 ng/ mL, respectively). Dosage adjustment in the Neoral group returned cyclosporine levels to within the target range, and from day 4, there were no significant differences in cyclosporine levels between the two groups. At 3 months after transplantation, 15 patients (75%) in the Neoral group remained rejection free compared with 7 patients (35%) in the control group (P 5 .03). There was 1 case of steroidresistant rejection requiring treatment with mono-
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clonal antibodies in each group. Two patients in the Neoral group and 3 in the control group required treatment with azathioprine (administered if renal function would not tolerate target cyclosporine levels or if more than one episode of rejection occurred while within the target range of cyclosporine). Severe neurotoxicity occurred in 1 patient in the Neoral group who had a previous traumatic brain injury. No patients in the control group experienced severe neurotoxicity. Moderate neurotoxicity was observed in 4 patients in the Neoral group (20%) and 8 patients in the control group (40%). Overall, there was no identifiable difference in neurotoxicity between the groups (P 5 .32). Moderate nephrotoxicity was observed in 5 patients (25%) in the Neoral group and 9 patients (45%) in the control group, but the difference was not significantly different (P 5 .32). No dialysis was required in either group. At 1 month after transplantation, both treatment groups showed a similar increase in serum creatinine levels from baseline (P 5 .02). Within the first 3 months after transplantation, 5 patients (25%) in the Neoral group and 7 in the control group (35%) required antihypertensive therapy. In each group, there was 1 case of cytomegalovirus hepatitis that was resolved with ganciclovir therapy. There was no difference between the groups in the incidence of other infectious complications. The data presented in this study suggest that the use of Neoral without intravenous cyclosporine in liver transplant recipients is effective and may result in decreased episodes of acute rejection without increasing the level of toxicity associated with cyclosporine. Taken together, the results of these open studies clearly indicate that Neoral can be used as immunosuppressive therapy in the early period after liver transplantation without the need for intravenous therapy or antilymphocyte induction therapy. Adequate cyclosporine levels are rapidly achieved after transplantation, reflecting the improved pharmacokinetic properties of the Neoral microemulsion compared with the old Sandimmune formulation.
Acute Rejections and Safety With Neoral Intravenous cyclosporine administration is associated with renal dysfunction, epileptic seizures, and, occasionally, hypersensitivity reactions. Therefore,
because adequate trough cyclosporine levels can be achieved with Neoral administered immediately after liver transplantation, it would be expected that early immunosuppression with Neoral would be safer than regimens involving intravenous therapy. In addition to this, the use of Neoral without intravenous cyclosporine also appears to reduce the risk of acute rejection episodes compared with intravenous cyclosporine plus oral Sandimmune and intravenous cyclosporine plus Neoral. A retrospective analysis of outcome from Birmingham, England, showed that, among 36 patients who had undergone liver transplantation who were initially treated with intravenous Sandimmune by continuous infusion before switching to oral Sandimmune, 17 (48%) had a rejection episode. The incidence of rejection in 34 patients treated with intravenous Sandimmune followed by Neoral was similar (15 patients; 46%). However, the rejection rate among 18 patients treated with postoperative Neoral without intravenous Sandimmune was only 22% (4 patients). It is likely that the patients treated with continuous intravenous Sandimmune (maintained at the same blood levels normally targeted as trough levels for oral dosing) would have had much less total exposure to cyclosporine (i.e., a lower AUC) during the infusion than if they had been treated with Neoral. This might partly account for the reduced incidence of rejection in patients who were treated with only Neoral. In the open studies described in this report, immunosuppression with Neoral immediately after liver transplantation was associated with an apparent reduction in the risk of acute rejection episodes (Table 2), while not increasing the risk of serious
Table 2. Incidence of Acute Rejection in Patients Treated With Neoral Acute Rejection (%)* Study Center
Neoral
CsA
Germany A B United Kingdom Denmark Canada
50 40 38 24 25
—† —† —† 52 65
Abbreviations: A, phase A of study in Germany; B, phase B of study in Germany. *Percent rejection to 3 months’ posttransplantation. †No control group in the study.
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Table 3. Incidence of Toxic Effects in Patients Treated With Neoral Toxicity (%)* Center
Renal
Neurological
Hypertension
Sepsis
Cytomegalovirus
Germany United Kingdom Denmark Canada
23 29 16 25
58 21 22 20
50 38 34 25
16 71 —† 25
14 10 12 5
*Percent toxicity to 3 months after transplantation. †Not reported.
adverse events or renal dysfunction (Table 3). This further supports the view that the initiation of immunosuppressive therapy with Neoral is not only as safe but may also reduce the incidence of acute rejections compared with regimens involving intravenous cyclosporine, whose dose is limited by toxicity.
Conclusions and Future Studies The open studies described in this report show that adequate immunosuppression can be achieved with Neoral started immediately after liver transplantation, without the need for intravenous cyclosporine. Therapeutic cyclosporine levels are achieved early after transplantation because Neoral has a microemulsion formulation with improved and less variable absorption compared with the conventional oil-based oral formulation of cyclosporine, Sandimmune. The use of Neoral appears to decrease the risk of acute rejection, particularly compared with regimens involving intravenous cyclosporine, although this needs to be confirmed in controlled studies. In addition, Neoral does not appear to increase the risk of adverse events associated with intravenous cyclosporine, such as renal dysfunction, epileptic seizures, and hypersensitivity reactions. As part of the ongoing program of clinical trials with Neoral, a further randomized study to compare Neoral with Sandimmune is nearing completion. Other studies are being conducted to investigate the effect of Neoral on chronic rejection and patient and graft survival. The starting dose of Neoral used in most of the open studies described in this review was 10 mg · kg21 · day21. Other studies are planned using higher starting doses to determine whether the incidence of acute rejec-
tions can be further reduced without incurring excessive toxicity.
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11. Holt DW, Mueller EA, Kovarik JM, van Bree JB, Kutz K. The pharmacokinetics of Sandimmunt Neoralt: A new oral formulation of cyclosporin. Transplant Proc 1994;26: 2935-2939. 12. Noble S, Markham A. Cyclosporin. A review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoralt). Drugs 1995;50:951-968. 13. Mueller EA, Kovarik JM, van Bree JB, Tetzloff W, Grevel J, Kutz K. Improved dose linearity of cyclosporin pharmacokinetics from a microemulsion formulation. Pharm Res 1994;11:301-304. 14. Atkinson PR, Grant DR, Williams SE, Howard J, Wall WJ, Stiller CR. Sandimmunt Neoralt in paediatric liver transplant recipients with malabsorption of CyA. Transplant Proc 1994;26:2953-2954. 15. Fa¨rber L, Maibu¨cher A, Gessler F, Gutzler F, Wiesinger FO, Winkler M. Favourable clinical results of Sandimmunt Neoralt in malabsorbing liver and heart transplant recipients. Transplant Proc 1994;26:2988-2993. 16. Trull AK, Tan KKC, Uttridge J, Bower T, Alexander G, Jamieson NV. Cyclosporin absorption from microemulsion formulation in a liver transplant recipient. Lancet 1993;341:433. 17. Winkler M, Ringe B, Schneider K, Maibu¨cher A, Fa¨rber L, Wietholtz H, et al. Enhanced bioavailability of cyclosporin A using a new oral formulation (Sandimmunt Optoralt) in a liver grafted patient with severe cholestasis. Transplant Int 1994;7:147. 18. Altraif I, Levy G, Grant D. Pharmacokinetic studies of Sandimmunt Neoralt vs Sandimmunt in liver transplant recipients [abs]. Hepatology 1993;18:747.
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19. Jamieson NV. De novo use of Neoralt in liver transplant recipients. In: Burke JF, Kahan BD, Pollak R, Frei U, Jamieson NV, Keown PA, eds. Neoraly: The new microemulsion formulation of cyclosporine. Cedar Knolls, NJ: World Medical, 1995:34-39. 20. Levy G, Rochon J, Freeman D, Wong PY, Banks L, Roach C, et al. Cyclosporin Neoralt in liver transplant recipients. Transplant Proc 1994;26:2949-2952. 21. Levy G, Grant D. Potential for CsA-Neoralt in organ transplantation. Transplant Proc 1994;26:2932-2934. 22. Winkler M, Haller G, Oldhafer K, Bechstein WO, Kattner A, Maibu¨cher A, et al. A new oral formulation for early oral immunosuppressive therapy in liver transplant recipients. Transplantation 1996;62:1063-1068. 23. Tredger JM, United Kingdom Neoral Pilot Study Group. Using cyclosporine Neoral immediately after liver transplantation. Ther Drug Monit 1995;17:638-641. 24. Jamieson NV, Gimson AES, Calne RY, Tredger JM, McCarthy M, Williams R, et al. Liver transplantation using neoral cyclosporin without intravenous induction therapy: A UK pilot study. In: Papastamatiou L, ed. European IHPBA Congress ‘‘Athens ’95.’’ Bologna: Monduzzi Editore, 1995:765-771. 25. Rasmussen A, Hjortrup A, Hansen BA, Heslet L, Kirkegaard P. Induction of immunosuppression by microemulsion cyclosporine in liver transplantation. Transplantation 1996;62:1031-1033. 26. Hemming AW, Greig PD, Cattral MS, Chung SW, Lilly LB, Aljumah AA, et al. Neoral without intravenous cyclosporine in liver transplantation. Transplantation 1997;29:543-548.