Tacrolimus bone marrow transplantation

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

Tacrolimus is used in situations where cyclosporine has been shown to be ineffective or cannot be used because of toxicity or otherwise. It is also used in a topical preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants and in vitiligo. 

Neurological symptoms were observed in 12-25% of liver-transplant patients and in 29% of bone marrow transplant patients, but severe neurotoxicity occurred only in about 1% (18,19/21). They usually appeared within the first month of treatment, but were sometimes delayed (19). Particular attention should be paid to prompt recognition of severe neurotoxicity, because abnormalities of the white matter can occur. Patients usually improved rapidly after temporary ciclosporin withdrawal or dosage reduction, and tacrolimus has sometimes been used successfully instead (SEDA-21, 383) (18). However, recurrence of seizures and persistent electroencephalographic abnormahties were found in 46 and 70% of pediatric transplant patients respectively who had had ciclosporin acute encephalopathy and seizure syndrome and who were followed-up for 49 months (22). 

Ibrahim RB, Abella EM, Chaudrasekar PH. Tacrolimus-clarithromycin interaction in a patient receiving bone marrow transplantation. Ann Pharmacother 2002 36(12) 1971-2. 

Other cases of severe neurotoxicity have been seen during tacrolimus treatment for graft-versus-host disease after allogeneic bone marrow transplantation. 

Nieto Y, Russ P, Everson G, Bearman SI, Cagnoni PJ, Jones RB, Shpall EJ. Acute pancreatitis during immunosuppression with tacrolimus following an allogeneic umbilical cord blood transplantation. Bone Marrow Transplant 2000 26(1) 109-11. 

Riley L, Mudd L, Baize T, Herzig R. Cross-sensitivity reaction between tacrolimus and macrolide antibiotics. Bone Marrow Transplant 2000 25(8) 907-8. 

Takamatsu Y+, Bone Marrow Transplant 28(4), 421 (with tacrolimus)... 

In 1989 tacrolimus (FK 506), a second caldneurin inhibitor started its clinical journey [8]. Tacrolimus has an immunosuppressive effect approximately 100 times more potent than CsA and early clinical trials demonstrate that FK 506 was effective in reversing refractory acute rejection in renal, liver and heart transplantation. Subsequently, this drug showed to be at least as effective as CsA in the primary immunosuppression schedules for solid organ and bone marrow transplantation and, similarly to CsA, proved to be a valuable alternative in the treatment of autoimmune diseases [3,9-11]. At the moment, FK 506 is considered the only drug that can substitute CsA in primary immunosuppression schedules and it is currently used in almost 60% of liver transplantation immunosuppressive prescriptions. 

FK506 (tacrolimus), a natural product of Streptomyces tukubaensis, is a 23-membered macrolide antibiotic that contains a unique hemiketal-masked, a,P-diketo amide moiety (Fig. 1) [1]. It has a mode of action and toxicity profile similar to those of cyclosporin A (CsA), an immunosuppressive cyclic undecapeptide produced by Tolypocladium inflatum (Fig. 1), which has been used clinically for two decades to prevent rejection on transplantation of organs, such as kidney, heart, liver, and bone marrow. The use of CsA has led to a remarkable increase of survival of all organ allografts and has fueled a dramatic increase in the number of kidney, liver, cardiac, and bone marrow transplants [2]. Thus, CsA has revolutionized transplantation surgery, both in terms of efficiency and quality of life of the patient. FK506 is said to be a more potent immunosuppressant than CsA and was approved for the treatment and prevention of kidney transplant rejection. 

Clinical uses and pharmacokinetics Use of these immunosuppressants is a major factor in the success of solid organ transplantation. Cyclosporine is used in solid organ transplantation and in graft-versus-host syndrome in bone marrow transplants. Tacrolimus is used in liver and kidney transplant recipients and may be effective as rescue therapy in patients who fail standard therapy. Sirolimus is used alone or in combination with cyclosporine in kidney and heart transplantation. The agents, particularly cyclosporine, may also be effective in immune diseases, including rheumatoid arthritis, uveitis, psoriasis, asthma, and type 1 diabetes. 

Wingard JR, Nash RA, Ratanalharalhom V, Fay JW, Klein JL, Przepiorka D, Maher RM, De-vine SM, Boswell G, Bekersky I, Fitzsimmons W. Lack of interaction between tacrolimus (FK506) and methotrexate in bone marrow transplant recipients. Bone Marrow Transplant (1997) 20, 49-51. 

Leather HL, Boyette R, Wingard JR Evaluation of the pharmacdcinetic dn interaction between intravenous itraconazole and IV tacrolimus or IV cyclosporin in allogeneic bone marrow transplant patients Blood (2000) 96,390a. 

Osowski CL, Dix SP, Lin LS, Mullins RE, Geller RB, Wingaid JR Evahiaticn of the dn interaction between intravenous high-dose fluccm le and cyclosporine or tacrolimus in bone marrow transplant patients. Transplantation (1996) 61,1268-72. 

TrifUio SM, Scheetz MH, Pi J, Mehta J. Tacrolimus use in adult allogeueic stem cell trausplaut redpieuts receiving voriconazole preemptive dose modification and therapeutic drug monitoring. Bone Marrow Transplant 2010 45(8) 1352-6. 

Among the drugs that can decrease immunological competence are antiinflammatory steroids, cyclosporine, and tacrolimus. Certain of these compounds are used to prevent transplant rejection, but they simultaneously carry the risk of allowing infection to occur. The aplastic anemia caused by the bone marrow toxicity of benzene was described above. Lead and chlorinated aryl hydrocarbons such as hexachlorobenzene also can cause bone marrow suppression. 

Gondo H, Okamura C, Osaki K, Shimoda K, Asano Y, Okamura T. Acquired Pelger-Huet anomaly in association with conccxn itant tacrolimus and flucona le ther y foUowii allogenic bone marrow tran lantatioa Bene Marrow Transplant (200G) 26,1255-7. 

Tacrolimus (FK-506) is an extremely effective immunosuppressive agent, being approximately 100 times more active than cyclosporine A (Kino et al. 1987). Its mechanism of action is quite similar to that of cyclosporines. Tacrolimus binds to immunophilin FKproteinl2, and this binary complex inhibits calcineurin, which is responsible for activating the transcription of interleukin-2 (Liu et al. 1991). It was approved by FDA in 1994 for use in liver transplantation. Subsequently, its use has been extended to include bone marrow, cornea, heart, lung, and other transplants (O Fig. 9.11). 

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