Mycophenolate Mofetil, Microemulsion Cyclosporine, and Prednisone as Primary Immunosuppression for Pediatric Liver Transplant Recipients

Transcription

1 Mycophenolate Mofetil, Microemulsion Cyclosporine, and Prednisone as Primary Immunosuppression for Pediatric Liver Transplant Recipients John F. Renz,* Jennifer Lightdale, Christine Mudge, Peter Bacchetti, Jennifer Watson, Nancy L. Ascher,* Jean C. Emond,* Philip Rosenthal, and John P. Roberts* Triple immunosuppressive therapy using mycophenolate mofetil (MMF), microemulsion cyclosporine (me-csa), and prednisone offers the potential for potent immunosuppression without intravenous drug therapy or anti T-cell antibody induction therapy. This report describes the application of an immunosuppressive protocol (CNp) using MMF, me-csa, and prednisone as primary immunosuppression for pediatric liver transplant recipients at the University of California at San Francisco. From August 1995 through December 1996, 26 children (17 boys, 9 girls) aged 1 month to 16 years (mean standard deviation, months; median, 31 months) underwent liver transplantation at our institution, receiving CNp as primary immunosuppression. Posttransplantation renal function, incidence of leukopenia, and drug tolerance within the group receiving CNp as primary immunosuppression were compared with those of 19 children who received primary immunosuppression consisting of azathioprine, oilbased gel-encapsulated cyclosporine, and prednisone with anti T-cell antibody induction therapy at the same institution from October 1993 through July No significant difference was observed between immunosuppressive protocols in serum creatinine level or incidence of leukopenia requiring medical therapy during the first year posttransplantation. Whereas gastrointestinal symptoms were observed in approximately 30% of CNp recipients during initial immunotherapy, tolerance of CNp primary immunotherapy was routinely achieved by the dose reduction of MMF. At 1 year posttransplantation, 20 children (77%) remained on CNp primary immunotherapy, 5 children (19%) were receiving tacrolimus-based immunotherapy secondary to rejection, and 1 patient (4%) converted to tacrolimus-based immunotherapy secondary to persistent gastrointestinal intolerance. In conclusion, CNp provides an alternative immunosuppressive protocol that eliminates the necessity of intravenous and induction immunosuppressive therapy with no increased incidence of posttransplantation renal dysfunction or leukopenia and is well tolerated in children. Copyright 1999 by the American Association for the Study of Liver Diseases From the *Department of Surgery, Division of Transplantation, the Department of Pediatrics, and the Department of Epidemiology and Biostatistics, University of California, San Francisco, CA. Supported in part by National Institutes of Health National Research Service Award no. DK09283 and the Association for Academic Surgery Davis and Geck Research Fellowship. Presented in abstract form at the American Association for the Study of Liver Diseases Digestive Diseases Week Meeting, Washington, DC, May 16-22, 1997, and the American Association for the Study of Liver Diseases Annual Meeting, Chicago, IL, November 5-8, Address reprint requests to John F. Renz, MD, PhD, UCSF Liver Transplant Program, 505 Parnassus Ave M896, San Francisco, CA Copyright 1999 by the American Association for the Study of Liver Diseases /99/ $3.00/0 I mmunosuppression of the pediatric liver transplant recipient is a continuing medical challenge. 1 As in adults, immunosuppression of children requires a delicate balance between infection and rejection; however, achieving such a balance is complicated by the unique metabolic and infectious processes occurring within children and must be performed in such a manner to ensure a child s greatest chance for sustained growth and development. 2 Optimization of graft function is imperative, not only for achievement of satisfactory growth and development, but for prolongation of graft life expectancy, which frequently exceeds that of adult recipients. Achieving and maintaining therapeutic cyclosporine drug levels using oil-based gel-encapsulated cyclosporine preparations (ob-csa) is difficult in pediatric transplant recipients. 3 Children, particularly those younger than 2 years of age, show highly variable absorption of oral ob-csa secondary to impaired gastrointestinal function and a 136 Liver Transplantation and Surgery, Vol 5, No 2 (March), 1999: pp

2 Pediatric Immunosuppression 137 relatively small gastrointestinal surface area, which frequently has been reduced by previous abdominal surgeries. 4,5 Cyclosporine dosing is further complicated by accelerated drug metabolism. Whitington et al 6 reported ob-csa absorption and bioavailability among pediatric liver transplant recipients to be inversely proportional to bowel length, whereas Ptachcinski et al 7 reported cyclosporine metabolism to be inversely related to age. 6,7 Difficulty in achieving early therapeutic ob-csa levels has resulted in the adoption of anti T-cell induction therapy or the use of intravenous cyclosporine as continuous infusion therapy as potential mechanisms to prevent acute cellular rejection. 2 The immunosuppressive protocol of the University of California at San Francisco (UCSF) for pediatric liver transplant recipients before August 1995 used ob-csa, azathioprine, and prednisone with anti T-cell antibody induction therapy (ACp). The introduction of microemulsion cyclosporine (me-csa) and mycophenolate mofetil (MMF) provided a unique opportunity to establish an oral immunosuppressive protocol that avoids intravenous immunosuppressive therapy or induction therapy. Me-CsA is an aqueous preparation that delivers the drug to the small bowel, the primary site of cyclosporine absorption, in a form that does not require further digestion before absorption. 8,9 Increased drug solubility within the small bowel improves bioavailability and absorption while eliminating hepatic and pancreatic functional requirements, 3 resulting in reduced intrapatient and interpatient blood-level variability. 3,10 Pharmacokinetic studies comparing me-csa and ob-csa in healthy human volunteers and stable renal transplant recipients show improved time to maximum blood level, bioavailability, area under the time-concentration curve, and lower percentage peak trough fluctuation. 10 Indeed, de novo use of me-csa in pediatric renal transplant recipients resulted in substantially reduced dosage requirements, compared with de novo use of ob-csa, from 500 to 300 mg/m 2 /d, respectively, to maintain equal drug trough levels. 11 The more predictable and consistent concentrationtime profile of me-csa offers the theoretical advantages of fewer dose adjustments to maintain a desired drug level and improved ability to predict total exposure from drug trough values. 12 The potential for renal toxicity is the same for me-csa and ob-csa; however, less clinical renal toxicity should result from the use of me-csa through more predictable drug profiles and the avoidance of intravenous cyclosporine administration. 3 MMF is a prodrug that is rapidly absorbed after oral administration and hydrolyzed by liver esterases to form mycophenolic acid, the active metabolite. 13 Mycophenolic acid is a selective, noncompetitive, and reversible inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH), which is a prerequisite for the de novo pathway of purine synthesis, on which B cells and T cells are dependent for DNA replication and cellular activation Inhibition of IMPDH and the de novo pathway results in the depletion of guanosine nucleotides and arrested replication because lymphocytes are unable to use the purine salvage pathway for nucleotide production In addition to activation of MMF to mycophenolate acid, the liver serves as the principal site of mycophenolic acid metabolism to an inactive monoglucuronide, which is principally excreted in the feces. 3 Combination cyclosporine prednisone immunosuppression using MMF versus azathioprine has been shown to reduce the incidence and severity of acute cellular rejection in renal transplant recipients in single-center as well as North American and European multicenter trials Furthermore, rejection-free graft survival was significantly improved when MMF was used for the initial treatment of acute cellular rejection versus initial treatment with steroids or OKT3. 29,30 MMF potentiates the immunosuppressive effects of cyclosporine, thereby permitting a theoretically lower total cyclosporine dose for the same immunosuppressive effect and a potentially lower total cyclosporine dosing regimen that may result in fewer long-term side effects. 3 Triple immunosuppressive therapy using MMF, me-csa, and prednisone (CNp) achieves early therapeutic drug levels without intravenous cyclosporine administration and obviates the need for antilymphocyte induction therapy in renal transplant recipients. The theoretical advantages of averting cyclosporine-induced renal toxicity from intravenous administration, using a more selective antimetabolite than azathioprine, and avoiding induction therapy led the UCSF Pediatric Liver Transplant team to adopt CNp as primary immunotherapy for all pediatric liver transplant recipients after August The purpose of this investigation is to report a single-center experience using CNp as primary immunosuppression in pediatric liver transplant recipients.

3 138 Renz et al Patients and Methods Patients and Data Collection A retrospective review of all children undergoing orthotopic liver transplantation (OLT) at UCSF from October 1993 through December 1996 was performed. Immunosuppression, clinical, and pathological data were collected for all recipients by using patient records and the UCSF National Institutes of Health Transplantation Database. Inclusion criteria for this study were age less than 18 years, primary immunosuppression consisting of either CNp or ACp, and posttransplantation survival exceeding 1 year. During the study period, 46 children underwent OLT at UCSF. From this group, 26 children (58%) received CNp primary immunosuppression, 19 children (40%) received ACp primary immunosuppression, and 1 child (2%) received tacrolimus-based primary immunosuppression. CNp was instituted as primary immunosuppression for all pediatric liver transplant recipients after August The ACp comparison group consisted of the immediate previous 19 pediatric liver transplantations performed at our institution between August 1995 and October The single patient to receive tacrolimus-based primary immunosuppression, who was excluded from this study, was the result of a parental request for tacrolimus immunotherapy based on a family history of hirsuitism. Demographic data and indications for transplantation were similar between groups and are listed in Table 1. Table 1. Pediatric Transplant Recipient Populations Group CNp ACp P No. of patients Period of transplantation 8/95-12/96 10/93-7/95 Sex Boys Girls 9 4 Age range (mo) Median age at transplantation (mo) Mean age at transplantation SD (mo) Indication for transplantation Biliary atresia 14 (53%) 10 (53%) 1 -antitrypsin deficiency 1 (4%) 1 (5%) Crigler-Najjar syndrome 2 (8%) 0 Hepatoblastoma 2 (8%) 0 Alagille syndrome 2 (8%) 0 Fulminant hepatic failure 3 (11%) 2 (11%) Ornithine transcarbamoylase 0 1 (5%) Cystic fibrosis 0 1 (5%) Neonatal hepatitis 2 (8%) 2 (11%) Histiocytosis 0 1 (5%) CPS 0 1 (5%) UNOS status (%) I II III Procedure (%) Cadaveric whole organ Living donor Reduced cadaveric 16 Split liver 4 Abbreviations: CPS, carbamoyl phosphate synthetase deficiency; UNOS, United Network for Organ Sharing. Immunosuppressive Protocols Immunosuppressive protocols and treatment of acute cellular rejection for CNp and ACp recipients are listed in Tables 2 and 3. CNp consists of me-csa (Neoral; Roche, Nutley, NJ), initially at 5 mg/kg/dose (orally twice daily), with dose adjustments to maintain daily cyclosporine trough levels of approximately 250 ng/dl by highpressure liquid chromatography; MMF (Cellcept; Roche), initially at 10 to 12.5 mg/kg/dose (orally twice daily), with adjustments to avert gastrointestinal symptoms and leukopenia; and prednisone, initially at 2 mg/kg/dose (orally once daily), with a rapid taper each 72 hours to achieve a dose of 0.3 mg/kg/dose by 30 days posttransplantation, and cessation of steroid therapy by 6 months posttransplantation. Toxicity secondary to MMF commonly manifests as gastrointestinal intolerance or leukopenia. 31 Reported gastrointestinal symptoms include nausea, loss of appetite, and diarrhea, with rare cases of pancreatitis and acute hemorrhagic gastritis. 3 Gastrointestinal symptoms are commonly amenable to simple dose reductions, as is leukopenia. 31 No cases of aplastic anemia secondary to MMF have been reported. To reduce gastric acid load and gastrointestinal complaints, recipients receive proton pump inhibitor therapy for at least the first year posttransplantation. 32 Ranitidine (Zantac; Glaxo-Wellcome, Research Triangle Park, NC), 0.8 mg/kg/dose (intravenously three times daily), is initiated at OLT with conversion to omeprazole (Prilosec; Astra Merck, Wayne, PA) or lansoprazole (Prevacid; Astra Merck), dosed by weight when the child tolerates oral medications without a nasogastric feeding tube. Living related liver transplant (LRLT) recipients receive pretransplantation me-csa (dosed as previously described) beginning 2 days before LRLT and MMF (dosed as previously described) with omeprazole or lansoprazole 1 day before LRLT. ACp primary immunosuppression consisted of ob-

4 Pediatric Immunosuppression 139 Table 2. UCSF Pediatric Liver Transplant Recipient Immunosuppressive Protocols for CNp Drug Primary Immunotherapy* Dose (mg/kg) Frequency/Route Target Levels MMF Twice daily/oral Me-CsA 5 Twice daily/oral 250 Prednisone 2 Every morning/oral Ranitidine 0.8 Every 8 hours/intravenous Treatment of Rejection Episode Histological Grading Treatment First Mild Steroid recycle Moderate Steroid recycle tacrolimus Second (or initial Mild Tacrolimus treatment failure) Moderate OKT3 Tacrolimus *LRLT recipients receive pretreatment with me-csa, 5 mg/kg orally twice daily beginning 2 days before OLT; MMF, mg/kg orally twice daily, 1 day before LRLT; and omeprazole or lansoprazole (weightadjusted dosage) 1 day before LRLT. Prednisone taper every 3 days with goal of 0.3 mg/kg/d by 30 days post-olt and elimination of steroid therapy by 6 months post-olt if rejection free. Omeprazole therapy is initiated as soon as the patient is tolerating oral medications without a nasogastric tube with the following dosing based on weight: 40 kg, 20 mg/kg twice daily; kg, 20 mg/kg every day; 20 kg, 10 mg/kg every day. Steroid recycle protocol consists of prednisolone (20 mg/kg intravenously once daily) for 3 days, followed by oral prednisone at 2 mg/kg/d with a taper as described above. Steroids will be recycled if previous rejection occurred 1 month before; if 1 month since steroid recycle, OKT3 will be included in therapy. OKT3 therapy for 7 to 10 days. CsA (Sandimmune; Sandoz, East Hanover, NJ), initially at 10 to 15 mg/kg/dose (orally twice daily), with dose adjustments to achieve daily trough levels of approximately 250 ng/dl by high-pressure liquid chromatography; azathioprine, initially at 2 mg/kg/dose (orally once daily), with adjustments to avert leukopenia; and prednisone, initially at 2 mg/kg/d (orally once daily), with a taper to achieve 0.3 mg/kg/dose by 6 months post-olt and cessation of all steroids by 1 year post-olt. In addition, all ACp recipients received induction therapy consisting of anti T-cell antibody preparation (Atgam; Upjohn, Kalamazoo, MI), 15 mg/kg/dose (intravenously once daily) for 7 days post-olt. Protocol liver biopsies are performed on all liver transplant recipients at 7 days, 14 days, and 1 year post-olt as a screen for early rejection and assessment of graft histological characteristics. Further biopsies are obtained as clinically indicated and on completion of treatment for biopsy-proven rejection. Clinical Assessment of Immunosuppression Tolerance of immunosuppressive therapy was determined by frequent clinical and laboratory evaluation. This study analyzed recipients reported symptoms, change in serum creatinine levels, and the incidence of leukopenia during the first year post- OLT as determinants of tolerance to specific immunosuppression protocols. Physical symptoms encountered among CNp recipients included nausea and vomiting, gastrointestinal upset, and diarrhea. Physical symptoms encountered among ACp recipients included fever, malaise, and pulmonary edema associated with induction therapy, as well as cyclosporine-induced neurological sequelae. To assess renal function, serum creatinine levels measured at Table 3. UCSF Pediatric Liver Transplant Recipient Immunosuppressive Protocols for ACp Drug Primary Immunotherapy Dose (mg/kg) Frequency/Route Target Levels Azathioprine 2 Every night/oral Ob-CsA Twice daily/oral 250 Prednisone* 2 Every morning/oral -Globulin 15 Every morning/ intravenous ACp Treatment of Rejection Episode Histological Grading Treatment First Mild Steroid Moderate Steroid Tacrolimus Second (or initial Mild Tacrolimus treatment failure) Moderate OKT3 Tacrolimus *Prednisone taper every 3 days with goal of 0.3 mg/kg/d by 6 months and elimination of all steroids by 1 year in the absence of rejection. Steroids will be recycled if previous rejection occurred 1 month before; if 1 month, OKT3 will be included in therapy.

5 140 Renz et al 7 days, 14 days, 6 months, and 1 year post-olt, in addition to the recipient s highest serum creatinine level measured during the first year post-olt, were compared with the recipient s serum creatinine level at OLT, with the change expressed as a percentage. The incidence of leukopenia was determined by evaluating all leukocyte blood counts performed during the first year post-olt and identifying patterns of abnormally low leukocyte counts ( 4000 white blood cells/ml) that prompted either immunosuppressive dose reduction or treatment with recombinant leukocyte growth-stimulating factor. Statistical Analysis Posttransplantation serum creatinine data were analyzed for normal distribution by the Shapiro- Wilk test of normality. Serum creatinine data did not meet the criteria of normal distribution and, therefore, the Wilcoxon rank sum test was used to compare groups. The incidence of leukopenia between CNp and ACp recipients was compared using the Wilcoxon two-sample test for unmatched pairs (normal approximation) with a two-tailed, 95% confidence interval. Results Posttransplantation Serum Creatinine Levels Between August 1995 and December 1996, 26 children received CNp as primary immunosuppression. Serum creatinine levels at 7 days, 14 days, 6 months, and 1 year post-olt were compared with the recipient s serum creatinine level at OLT. The data are listed in Table 4. In addition, the recipient s highest serum creatinine level observed during the first year posttransplantation was analyzed. CNp recipients mean serum creatinine levels at transplantation were significantly less than those of ACp recipients (P.04), perhaps reflecting the greater percentage of CNp patients who underwent transplantation earlier as United Network for Organ Sharing status II or III. However, by 1 year posttransplantation, no difference between groups with respect to serum creatinine level (P.68) was observed. Analysis of CNp recipients serum creatinine levels at transplantation versus 1 year posttransplantation showed a marginally significant increase in serum creatinine level over the first year Table 4. Serum Creatinine Levels and Episodes of Leukopenia 1 Year Post-OLT Group CNp ACp P N Follow-up Range (mo) Mean SD (mo) Median (mo) Mean serum creatinine SD (mg/dl) OLT Day Day Months Year Mean change in serum creatinine SD (%) Day Day Months Year Mean peak serum creatinine SD (%) Incidence of leukopenia Range Mean SD Median 1 1 after transplantation (P.04); however, for each patient, serum creatinine levels remained within the normal age limits at each time point within the entire posttransplantation year. Serum creatinine levels at 7 days, 14 days, 6 months, and 1 year posttransplantation were compared with serum creatinine levels at transplantation, with the difference expressed as a percentage change. CNp recipients experienced a mean standard deviation (SD) percentage increase in serum creatinine level of 46% 19%, with a median increase of 45% during the first year posttransplantation versus ACp recipients mean SD of 14% 55%, with a median increase of 0% (P.07). Analysis of the highest serum creatinine level observed during the first year posttransplantation versus the serum

6 Pediatric Immunosuppression 141 creatinine level at transplantation yielded similar results. CNp recipients peak serum creatinine levels increased a mean of 169% 176% (median, 125%) during the first year posttransplantation versus 93% 88% (median, 75%) in ACp recipients (P.07). Posttransplantation Leukopenia Episodes of leukopenia during the first year posttransplantation that resulted in either an immunosuppressive dosage reduction or administration of granulocyte colony-stimulating factor were compared between CNp and ACp recipients (Table 4). No significant difference in the incidence of leukopenia during the first year posttransplantation (P.07) was observed in either group. Drug Tolerance Gastrointestinal symptoms observed in CNp pediatric liver transplant recipients included nausea, vomiting, and diarrhea, with an overall incidence of approximately 30%. Management of clinical symptoms by simple MMF dose reduction was routinely achieved. At 1 year posttransplantation, 20 children (77%) remained on CNp primary immunotherapy, 5 children (19%) were receiving tacrolimus-based immunotherapy secondary to acute cellular rejection, and 1 patient (4%) converted to tacrolimus-based immunotherapy secondary to persistent gastrointestinal intolerance. Discussion Triple immunosuppressive therapy using MMF, me-csa, and prednisone avoids potential renal, neurological, and infectious complications associated with intravenous immunosuppressive and anti T-cell antibody induction therapy. This article describes the application of a protocol using MMF, me-csa, and prednisone as primary immunosuppression for pediatric liver transplant recipients at UCSF from August 1995 through December Comparisons of CNp recipients posttransplantation renal function, measured by serum creatinine level and incidence of leukopenia during the first year posttransplantation, was determined not to be statistically different from children receiving ob- CsA, prednisone, and azathioprine immunosuppression with anti T-cell antibody induction therapy. Gastrointestinal symptoms, a major concern with respect to the administration of MMF, were observed in approximately 30% of the children during initial immunotherapy, with clinical tolerance of CNp routinely achieved by a dose reduction of MMF concomitant with the administration of oral gastric proton pump inhibitors. Whereas this report does not reflect systemic questioning of patients and families for the presence of side effects and may underestimate the actual incidence of side effects, it does accurately report the incidence of side effects that resulted in a change of medical therapy. These data are in agreement with the incidence of gastrointestinal symptoms observed in adults. 26,28,30,31 At 1 year posttransplantation, 77% of the children remained on CNp as primary immunotherapy, with 19% converted to tacrolimusbased immunotherapy secondary to rejection, and only 1 patient (4%) converted to tacrolimus-based immunotherapy secondary to gastrointestinal intolerance of CNp. Long-term management of children receiving CNp primary immunosuppression is actively evolving. Presently, we have maintained a conservative immunosuppressive withdrawal philosophy with initial steroid reductions targeted for complete withdrawal by 6 months posttransplantation in the absence of clinical rejection. This is followed by a gradual MMF taper beginning 1 year posttransplantation without a targeted withdrawal point. Last, cyclosporine doses are maintained constant despite growth of the child, thereby gradually lowering cyclosporine trough levels as the child develops. Few data exist with respect to the conversion of children among therapies. Despite previous reports of successful conversion of stable transplant recipients from ob-csa to me-csa, we have been conservative in our conversion of children from ob-csa to me-csa in the absence of clinical rejection or contraindications and prefer to use rejection therapy as a starting point for initiation of CNp. With respect to antimetabolite therapy, we do not endorse conversion from azathioprine to MMF, but rather azathioprine taper in the absence of clinical rejection. If rejection recurs, the decision to initiate MMF therapy could then be approached. In conclusion, MMF, me-csa, and prednisone provide an alternative immunosuppressive protocol that eliminates the necessity of intravenous and induction immunosuppressive therapy with no increased incidence of posttransplantation renal dysfunction or leukopenia and is well tolerated in children.

7 142 Renz et al References 1. Kahan BD. Pharmacokinetic considerations in the therapeutic application of cyclosporine in renal transplantation. Transplant Proc 1996;28(4): McDiarmid SV. Special considerations for pediatric immunosuppression after liver transplantation. In: Busuttil RW and Klintmalm GB (eds). Transplantation of the Liver. Philadelphia: Saunders, 1996: Morris RE. New Immunosuppressive drugs. In: Busuttil RW and Klintmalm GB (eds). Transplantation of the Liver. Philadelphia: Saunders, 1996: Cooney GF, Dunn SP, Kaiser B, Kulinsky AV, Mochon M, Heifets M. Oral cyclosporine pharmacokinetics in pediatric renal and liver transplant recipients. Transplant Proc 1994;26(5): Dunn SP, Cooney GF, Kulinsky A, Falkenstein K, Pierson A, Elder CA, and Meligeni J. Absorption characteristics of a microemulsion formulation of cyclosporine in de novo pediatric liver transplant recipients. Transplantation 1995;60: Whitington PF, Emond JC, Whitington SH, Broelsch CE, Baker AL. Small-bowel length and the dose of cyclosporine in children after transplantation. N Engl J Med 1990;322(11): Ptachcinski RJ, Venkataramanan R, Burckart GJ, Hakala TR, Rosenthal P, Carpenter BJ, Taylor RJ. Cyclosporinehigh dose steroid interaction in renal transplant recipients: Assessment by HPLC. Transplant Proc 1987;19: Holt DW, Mueller EA, Kovarik JM, van Bree JB, Richard F, Kutz K. The pharmacokinetics of Sandimmun Neoral: A new formulation of cyclosporine. Transplant Proc 1994;26(5): Vonderscher J, Meinzer A. Rationale for the development of Sandimmune Neoral. Transplant Proc 1994; 26(5): Kovarik JM, Mueller EA, van Bree JB. Cyclosporine pharmacokinetics and variability from a microemulsion formulation a multicenter investigation in kidney transplant patients. Transplantation 1994;58: Bolkenkamp S. Sandimmune Neoral. Pediatr Nephrol 1995;9: Dunn SP, Cooney GF. The use of neoral in pediatric liver transplantation. Transplant Immunol Lett 1997;13: Lee W, Gu L, Miksztal A, Chu N, Leung K, Nelson PH. Bioavailability improvements of mycophenolate mofetil through amino ester derivatization. Pharm Res 1990;7: Mitchell B, Dayton JS, Turka LA, Thompson CB. IMP dehydrogenase inhibitors as immunomodulators. Ann N Y Acad Sci 1993;685: Sollinger HW. Mycophenolate mofetil. Kidney Intern 1995;52: Allison AC, Eugui EM. Inhibitors of de novo purine and pyrimidine synthesis as immunosuppressive drugs. Transplantation Proceedings 1993;25: Dayton J, Lindsten T, Thompson CB, Mitchell BS. Effects of human T lymphocyte activation on inosine monophosphate dehydrogenase expression. J Immunol 1994;152(3): Allison A, Kowalski WJ, Muller CJ, Eugui EM. Mechanisms of action of mycophenolic acid. Transplant Proc 1993;25(3 suppl 2): Kirklin JK, Bourge RC, Naftel DC, Morrow WR, Deierhoi MH, Kauffman RS, et al. Treatment of recurrent heart rejection with mycophenolate mofetil (RS-61443): Initial clinical experience. J Heart Lung Transplant 1994;13(3): Franklin T, Cook JM. Pharmacodynamics of Mycophenolate Mofetil. Biochem J 1969;113: Sollinger H, Deierhoi M, Belzer FO, Diethelm AG, Kauffman RS. RS A phase I clinical trial and pilot rescue study. Transplantation 1992;53(2): Sollinger HW. Update on preclinical and clinical experience with mycophenolate mofetil. Transplant Proc 1996; 28(6 suppl 1): Morris RE, Wang J. Comparison of the immunosuppressive effects of mycophenolic acid and the morpholinoethyl ester of mycophenolic acid (RS-61443) in recipients of heart allografts. Transplant Proc 1991;23: Taylor D, Ensley RD, Olsen SL, Dunn D, and Renlund DG. Mycophenolate mofetil (RS-61443): Preclinical, clinical, and three-year experience in heart transplantation. J Heart Lung Transplant 1994;13: Kirklin JK, Bourge RC, Naftel DC, Morrow WR, Deierhoi MH, Kauffman RS, et al. Treatment of recurrent heart rejection with mycophenolate mofetil (RS-61443): Initial clinical experience. J Heart Lung Transplant 1994;13(3): Danovitch GM. Mycophenolate mofetil in renal transplantation: Results from the U.S. randomized trials. Kidney Intern 1995;52:S European MMF Cooperative Study Group. Placebocontrolled study of mycophenolate mofetil combination with cyclosporine and corticosteroids for the prevention of acute rejection. Lancet 1995;345: Langman LJ, LeGatt DF, Halloran PF, Yatscoff RW. Pharmacodynamic assessment of mycophenolic acidinduced immunosuppression in renal transplant recipients. Transplantation 1996;62: Halloran P, Mathew T, Tomlanovitch S, Groth C, Hooftman L, Barker C. Mycophenolate mofetil in renal allograft recipients: A pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups. Transplantation 1997; 63(1): Mycophenolate Mofetil Renal Refractory Rejection Study Group: Clinical Transplantation 1996;10: Tomlanovitch SJ. Rescue therapy with mycophenolate mofetil. Mycophenolate Mofetil Renal Refractory Rejection Study Group. Transplant Proc 1996;28(6 suppl 1): Gonwa TA. Mycophenolate mofetil for maintenance therapy in kidney transplantation. Clin Transplant 1996; 10: Vanrenterghem Y. The use of mycophenolate mofetil (cellcept) in renal transplantation. Nephron 1997;76(4): Hoppu K, Jalanko H, Laine J, Holmberg C. Comparison of conventional oral cyclocporine and cyclosporine mi-

8 Pediatric Immunosuppression 143 croemulsion formulations in children with a liver transplant. Transplantation 1996;62(1): Dunn SP, Nicolette L, Falkenstein K, Pierson A. Sandimmune to neoral conversion in stable pediatric liver transplant recipients [abstract 223]. American Society of Transplant Physicians, Cooney GF, Dunn SP, Sommerauer J, Lindsay C, McDiarmid SV, Choc M, et al. Ethnic differences in cyclosporine pharmacokinetics with neoral and sandimmune in pediatric liver transplant recipients [abstract 725]. American Society of Transplant Physicians, 1997.