Tacrolimus (FK506): the pros and cons of its use as an immunosuppressant in pediatric liver transplantation

Kenneth L. Cox, MD
Deborah K. Freese, MD

Clin Invest Med 1996; 19(5): 389-92.

[résumé]

Dr. Cox is with the Divisions of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Stanford University, Palo Alto, Calif., and Dr. Freese is with the Mayo Clinic, Rochester, Minn.

Paper reprints may be obtained from: Dr. Kenneth L. Cox, Professor of Pediatrics, Pediatric Gastroenterology and Nutrition, Stanford University, 116­750 Welch Rd., Palo Alto, CA 94025; fax 415 498-5608.

Contents

Abstract

Tacrolimus (FK506) is a new immunosuppressive agent that has recently been given to recipients of liver transplants. Multicentre studies conducted in the United States and Europe have reported that tacrolimus is superior to cyclosporine in preventing allograft rejection. The absorption of tacrolimus is independent of bile, and, therefore, therapeutic blood levels are usually achieved by taking oral preparations within 72 hours of liver transplantation. Compared with the use of cyclosporine, this regimen has resulted in shorter hospital stays and reduced costs. Tacrolimus does not cause hirsutism or gingival hyperplasia, which are common disfiguring complications of cyclosporine. Serious neurological side effects, lymphoproliferative disorders and hypertrophic cardiomyopathy have recently been reported in children taking high doses of tacrolimus. When lower doses of tacrolimus are used in primary immunosuppressive therapy, the incidence of neurological side effects and lymphoproliferative disorders of tacrolimus and cyclosporine have been reported to be similar. Hence, tacrolimus is a potent immunosuppressant that has many advantages over cyclosporine but must be used cautiously, since high doses have been associated with an increased incidence of lymphoproliferative disorders and cardiomyopathy.

Résumé

Le tacrolimus (FK 506) est un nouveau médicament immunosuppresseur qui a été récemment administré aux receveurs de transplantation hépatique. Des études multi-centriques aux États-Unis et en Europe ont observé que le tacrolimus est supérieur à la cyclosporine pour la prévention du rejet des allogreffes. L'absorption du tacrolimus est indépendante de la bile; par conséquent, des niveaux sanguins thérapeutiques sont habituellement atteints par la prise orale du médicament pendant 72 heures précédant la transplantation hépatique. En comparaison avec la cyclosporine, cette approche a résulté en un séjour hospitalier plus court et une déminution des coûts. Le tacrolimus ne cause pas d'hirsutisme ou d'hyperplasie gingivale, qui compliquent fréquemment l'emploi de la cyclosporine. Des effets secondaires neurologiques sérieux, des troubles lymphoprolifératifs et une cardiomyopathie hypertrophique ont été décrits récemment chez les enfants recevant des doses élevées du tacrolimus. Avec l'emploi de doses plus faibles de tacrolimus comme agent immunosuppresseur primaire, l'incidence d'effets secondaires neurologiques et de troubles lymphoprolifératifs était similaire à la cyclosporine. Le tacrolimus est donc un immunosuppresseur puissant qui possède plusieurs avantages par rapport à la cyclosporine, mais il doit être employé avec prudence puisque des doses élevées ont été associées avec une incidence accrue de troubles lymphoprolifératifs et de cardiomyopathie.

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Introduction

Tacrolimus (Prograf, FK506) is a new, potent immunosuppressive agent with a mechanism of action similar to that of cyclosporine, also known as cyclosporin A.[1] However, tacrolimus is 10 to 100 times more potent than cyclosporine.[1] This potency has contributed to its superiority in preventing allograft rejection and has allowed most patients to be weaned off corticosteroids. In prospective, randomized, multicentre studies conducted in the United States and Europe that compared cyclosporine and tacrolimus treatment after liver transplantation, tacrolimus was significantly better than cyclosporine in reducing biopsy-confirmed acute and refractory rejection (Table 1).[2,3] In the US study, the decreased rejection rate among patients treated with tacrolimus, compared with those treated with cyclosporine, resulted in lower rates of the use of other drugs. OKT3 was given to 19% of patients treated with cyclosporine versus 36% for those treated with tacrolimus (p < 0.001), and 131 ± 61 mg/kg per day of corticosteroids were administered over 360 days for prophylaxis and treatment in the group treated with cyclosporine versus 90 ± 65 mg/kg per day in the group treated with tacrolimus (p < 0.001). In these multicentre studies, patient and graft survival rates were similar for the two immunosuppressive agents.

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Tacrolimus treatment in children

Since the European study excluded children and the US study included only 30 children taking tacrolimus and 21 taking cyclosporine, the experience with the use of tacrolimus for children in these studies is limited.[4] McDiarmid and collaborators[4] reported that the children taking tacrolimus in the US multicentre study had a lower rate of acute rejection (52% of the group taking tacrolimus v. 79% of the group taking cyclosporine), a lower rate of OKT3 use (21% of the group taking tacrolimus v. 32% of the group taking cyclosporine), and a lower mean cumulative steroid dose during the year after transplantation (2100 mg for the group taking tacrolimus v. 2600 mg for the group taking cyclosporine). The superiority of tacrolimus over cyclosporine in preventing severe rejection was reflected in the University of Pittsburgh's report that no primary graft retransplantations were performed because of graft rejection among the 203 children taking tacrolimus, whereas 16 were performed among the 241 children (6.6%) taking cyclosporine.[5] The University of Pittsburgh's liver-transplantation program also reported that more than 90% of children taking tacrolimus and only 5% of those taking cyclosporine were weaned off corticosteroids by 9 months after liver transplantation.[6] Similarly, Cox and associates[7] reported that 48% of pediatric liver-transplant recipients taking tacrolimus and 4.6% of those taking cyclosporine were weaned off corticosteroids. The ability to wean children off corticosteroids may allow better growth and reduce the risks of infections, hyperlipidemia and osteopenia with fractures. Because it leads to less steroid use, tacrolimus is associated with lower levels of total cholesterol and low-density lipoprotein than is cyclosporine.[8]

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Practical benefits of tacrolimus

Since cyclosporine is fat soluble, and, therefore, its absorption is bile dependent, patients who are given cyclosporine as primary therapy after liver transplantation require several days of intravenous treatment before adequate of oral preparations can maintain therapeutic blood levels.[1­3] In contrast, the absorption of tacrolimus is not bile dependent; therefore, it can be given orally within 24 hours of liver transplantation, and therapeutic blood levels can be maintained and intravenous administration discontinued usually within 72 hours of transplantation.[1­3] By discontinuing intravenous therapy earlier and reducing the complications of rejection, the length and cost of hospital stay after liver transplantation have been significantly lower for patients receiving tacrolimus than for those receiving cyclosporine. A study conducted by the University of Pittsburgh reported that the mean cost of liver transplantation was nearly twice as high for patients receiving cyclosporine than for those receiving tacrolimus ($244 000 v. $135 000).[9] The new microemulsion of cyclosporine (Neoral) is better absorbed than the form of cyclosporine used in these studies (Sandimmune) and may allow patients to be weaned from the intravenous cyclosporine sooner.[10]

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Side effects

Tacrolimus and cyclosporine have different side effects, which should be considered when choosing one of these drugs as the primary immunosuppressant. Hirsutism and gingival hyperplasia are common disfiguring side effects of cyclosporine and may be a factor in poor compliance in some adolescents. Since tacrolimus does not produce these side effects, children may accept this drug more easily.[4] Nakazato and associates[11] observed that hypertension occurred less often among children taking tacrolimus (40% of patients) than among those taking cyclosporine (75%). The incidence of serious neurological adverse effects (kinetic autism, expressive aphasia, seizures, confusion, psychosis, encephalopathy and persistent coma) is similar for cyclosporine and tacrolimus; these adverse effects are usually associated with intravenous preparations.[1­3] Minor neurological side effects (tremor, headache, sleep disturbances, nightmares, dysesthesia and photophobia) occur more frequently among patients taking tacrolimus than among those taking cyclosporine, but these side effects are usually resolved by reducing the dose of the drug.[2,3] Tacrolimus and cyclosporine have rarely caused hyperglycemia or diabetes mellitus in children.[4]

Tacrolimus is associated with an increased incidence of lymphoproliferative disorders, Epstein­Barr virus infections and hypertrophic cardiomyopathy.[7,12] Cox and associates[7] reported an increased incidence of Epstein­Barr virus infections and lymphoproliferative disorders in children less than 5 years of age taking tacrolimus than among those in the same age group taking cyclosporine. However, in this study, 12 of the 14 children taking tacrolimus who had Epstein­Barr virus infections and lymphoproliferative disorders had previously taken cyclosporine and had switched to tacrolimus; this suggests that overimmunosuppression may have been a factor in these conditions.

The liver-transplantation program at the University of Pittsburgh has reported that the incidence of lymphoproliferative disorders in children taking tacrolimus is 4.7%, which is similar to the incidence seen among those taking cyclosporine.[13]

Atkison and associates[12] recently reported that five children suffered hypertrophic cardiomyopathy while being treated with tacrolimus and that one child taking tacrolimus died as a result of pericardial tamponade associated with cardiac hypertrophy. Four of the five patients with cardiomyopathy had extremely high mean blood levels of tacrolimus, ranging from 26 ± 6 to 30 ± 6 ng/mL. The one child who had hypertrophic cardiomyopathy and lower tacrolimus blood levels, 11 ± 5 ng/mL, also had hypertension. Hypertension is also associated with cardiomyopathy in patients taking cyclosporine.[14] In contrast to Atkison and associates' report, Cacciarelli and coworkers[15] at Stanford University reported no cases of cardiomyopathy in 17 children who received tacrolimus after liver transplantation but maintained lower tacrolimus blood levels (15 ng/mL or less). In the Stanford program, tacrolimus has been used to treat 100 pediatric liver-transplant recipients and has not caused cardiomyopathy in any of these patients (unpublished data, 1996).

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Conclusions

Because of its benefits -- less frequent acute and chronic rejection, better absorption leading to earlier discharge from the hospital, fewer side effects and earlier weaning of most patients off corticosteroids -- tacrolimus offers many advantages over cyclosporine. Since tacrolimus is 10 to 100 times more potent than cyclosporine, caution must be taken in using this drug, and excessive doses that may lead to hypertrophic cardiomyopathy and lymphoproliferative disorders must be avoided. If, after greater experience has been accumulated with its use in low doses to treat children, tacrolimus proves to be a safe immunosuppressant and retains its advantages over cyclosporine, it will become the drug of choice for primary immunosuppression in pediatric liver transplantation.

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Acknowledgements

The publication of this article was supported in part by a grant from the Fonds de la recherche en santé du Québec. We would like to thank Fujisawa USA for its sponsorship of the invited speakers' program.

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References

  1. Peters DH, Fitton A, Plosker GL, Faulds D. Tacrolimus: a review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46(4): 746-94.
  2. The US Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK506) and cyclosporin for immunosuppression in liver transplantation. N Engl J Med 1994; 331: 1110-6.
  3. European FK506 Multicenter Liver Study Group. Randomized trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994; 344: 423-8.
  4. McDiarmid SV, Busuttil RW, Ascher NL, et al. FK506 (Tacrolimus) compared with cyclosporine for primary immunosuppression after pediatric liver transplantation: results of the US multicenter trial. Transplantation 1995; 59(4): 530-6.
  5. Todo S, Fung JJ, Starzl TE, et al. Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression. Ann Surg 1994; 220(3): 297-309.
  6. Tzakis AG, Reyes J, Todo S, et al. FK 506 versus cyclosporine in pediatric liver transplantation. Transplant Proc 1991; 23: 3010-5.
  7. Cox KL, Lawrence-Miyasaki LS, Garcia-Kennedy R, et al. An increased incidence of Epstein­Barr virus infection and lymphoproliferative disorder in young children on FK506 after liver transplantation. Transplantation 1995; 59: 524-9.
  8. Abouljoud MS, Levy MF, Klintmalm GB Hyperlipidemia after liver transplantation: long-term results of the FK506/cyclosporine a US Multicenter trial. US Multicenter Study Group. Transplant Proc 1995; 27: 1121-3.
  9. Staschak S, Wagner S, Block D, et al. A cost comparison of liver transplantation with FK 506 or CyA as the primary immunosuppressive agent. Transplant Proc 1990; 22(suppl 1): 47-9.
  10. Lin CY, Lee SF. Comparison of pharmacokinetics between CsA capsules and Sandimmune Neoral in pediatric patients. Transplant Proc 1994; 26(5): 2973-4.
  11. Nakazato P, Cox K, Concepcion W, et al. Early experience with FK 506 induction immunosuppression -- suggestion for using oral FK 506. Transplant Proc 1991; 23: 3019-21.
  12. Atkison P, Joubert G, Barron A, et al. Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients. Lancet 1995; 345: 894-6.
  13. Reyes J, Tzakis A, Green M, et al. Posttransplant lymphoproliferative disorders occurring under primary FK 506 immunosuppression. Transplant Proc 1991; 23: 3044-6.
  14. Ventura HO, Lavie CJ, Messerli FH, et al. Cardiovascular adaptation to cyclosporine-induced hypertension. J Hum Hypertens 1994; 8: 233-7.
  15. Cacciarelli TV, Esquivel CO, Cox KL, et al. Oral tacrolimus (FK506) induction therapy in pediatric orthotopic liver transplantation. Transplantation 1996; 61: 1188-92.

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| CIM: October 1996 / MCE: octobre 1996
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