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Review Tacrolimus: a New Agent for the Prevention of Graft-Versus-Host Disease in Hematopoietic Stem Cell Transplantation

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Review Tacrolimus: a New Agent for the Prevention of Graft-Versus-Host Disease in Hematopoietic Stem Cell Transplantation Bone Marrow Transplantation, (1998) 22, 217–225 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Review Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation P Jacobson1, J Uberti2, W Davis1 and V Ratanatharathorn2 1College of Pharmacy, University of Michigan; and 2Blood and Marrow Stem Cell Transplantation Program, Division of Hematology/Oncology, Department of Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA Summary: One of the challenges to reduce the morbidity and mortality after allogeneic bone marrow transplantation (BMT) is to Tacrolimus (FK506) is a macrolide lactone with potent improve the treatment and prevention of graft-versus-host immunosuppressive activity 100 times that of cyclosporine disease (GVHD).1 Currently, most regimens for GVHD by weight. The molecular mechanism of action is mediated prophylaxis are centered on cyclosporine as the main via an inhibition of the phosphorylase activity of calcineurin immunosuppressant given in conjunction with various by drug–immunophilin complex, resulting in the inhibition doses and schedules of methotrexate and/or methylpredni- of IL-2 gene expression. There are emerging studies now solone.2–5 Most clinical trials suggested the superiority of showing significant efficacy of tacrolimus in GVHD preven- a combination of cyclosporine and a short course of metho- tion in both related and unrelated donor transplantation. trexate over either agent alone. Yet, acute GVHD still Three multicenter randomized studies comparing tacrol- developed in 9–33% of patients who received a marrow imus to cyclosporine have been completed, one each in graft from an HLA-matched sibling donor.3,4,6–9 related and unrelated donor transplantation; the remaining Tacrolimus is a new immunosuppressive agent intro- study involved both related and unrelated donor transplan- duced into clinical trials for the prevention of acute GVHD. tation. All three studies showed a significantly lower inci- Emerging results of these trials suggest that tacrolimus has dence of grade II–IV acute GVHD in patients who received significant clinical efficacy, perhaps surpassing cyclospor- tacrolimus. One study in sibling donor transplantation ine for the prevention of acute GVHD. Nevertheless, tox- showed that patients with advanced disease who received icity associated with the use of tacrolimus can be substan- tacrolimus had a poorer survival than patients who tial. This paper will review the pharmacology of this agent, received cyclosporine, but the survival was similar in its toxicity and the clinical outcome of acute GVHD patients with non-advanced disease. The remaining two prophylaxis. studies, one in unrelated donors and the other combining both related and unrelated donors did not show any sur- vival difference between the tacrolimus and cyclosporine Mechanism of action groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allo- Tacrolimus is a 23-membered macrolide lactone discovered geneic stem cell transplantation: (1) the contribution of in 1984 from the fermentation broth of a Japanese soil sam- methotrexate in combination with tacrolimus; (2) the start- ple that contained the fungus Streptomyces tsukuba- ing i.v. dose of tacrolimus; (3) the suggested whole blood ensis.10,11 Although tacrolimus has the molecular structure level of tacrolimus and its effect on nephrotoxicity; and (4) of a macrolide, it has limited antimicrobial activity. How- whether tacrolimus should be used in patients with ever, it has a potent inhibitory activity on T cell activation advanced malignancy. Future studies using tacrolimus in in both humans and mice.12–15 The in vitro activity of tacro- combination with other immunosuppressants, and its use limus was 100 times that of cyclosporine with the inhibitory in patients with advanced malignancy will be warranted. concentrations (IC50) of 0.1 nmol/l and 10 nmol/l, respect- Keywords: allogeneic bone marrow transplantation; tacrol- ively.16 Clinically, tacrolimus has not only shown substan- imus; graft-versus-host disease; FK506; peripheral blood stem tial efficacy in the rescue of liver graft rejection,17 but also cell transplantation in the prevention of liver18, kidney19–21 and cardiac graft rejection.22,23 Despite the structural differences between tacrolimus and cyclosporine, they share similar mechanisms of action at the molecular level. Both drugs mediate their activity through binding to an immunophilin.24,25 Tacrolimus binds Correspondence: Dr V Ratanatharathorn, Associate Professor of Internal Medicine, B1–207 Cancer Center, University of Michigan Medical Center, to an immunophilin–FK binding protein-12 (FKBP12) to 1500 E Medical Center Drive, Ann Arbor, MI 48109–0914, USA form an active tacrolimus–FKBP12 complex. This complex Received 30 January 1998; accepted 30 March 1998 inhibits the phosphorylase activity of calcineurin, thus pre- Tacrolimus for the prevention of GVHD P Jacobson et al 218 Ϯ venting the translocation of NFAT (nuclear factor of acti- whole blood Vd was 1.67 1.02 l/kg after a single intra- vated T cells) into the nucleus and resulting in an inhibition venous dose of 0.02 mg/kg administered over 4 h.32 of IL-2 gene expression. Moreover, tacrolimus is capable of abrogating the conversion of precursor helper T lympho- Metabolism and elimination cytes to antigen-conditioned helper T lymphocytes in an in vivo model, whereas cyclosporine at 20-fold higher concen- Tacrolimus is extensively metabolized by the mixed func- trations failed to exert this effect.26 This differential effect tion oxidase system, primarily the cytochrome P450IIIa4 may have important biologic consequences by abrogating system in the liver, and possibly the small intestine.27,38–41 the critical step of the immunologic cascade leading to Less than 1% of an intravenous or oral dose is found in organ rejection or graft-versus-host disease. the urine.27,42 The drug undergoes demethylation, hydroxyl- ation and conjugation in the liver with most of the metab- olites, and possibly conjugates, of tacrolimus eliminated in Pharmacokinetics the bile.27,40,43 Although many metabolites exist, their immunosuppressive activity is not well characterized.27,40,44 Absorption Tacrolimus clearance determined by whole blood ELISA analysis was studied in 17 BMT patients on day 11 post- The bioavailability of tacrolimus after oral administration transplant.33 These patients received either tacrolimus 0.03 in healthy volunteers varies from 14 to 17%. However, it mg/kg by continuous intravenous infusion alone or in com- is highly variable in solid organ transplant recipients, rang- bination with methylprednisolone or methotrexate. The ing from 4 to 89% with a mean of 25%.27–30 This variability clearances were 0.075 Ϯ 0.048, 0.055 Ϯ 0.023 and in absorption is not well understood, but may be due to 0.063 Ϯ 0.032 l/h/kg, respectively, and these were not sig- incomplete absorption resulting from poor solubility in gas- nificantly different. Pharmacokinetics were also described tric fluids, admixture with food, or changes in gut motility in another 12 BMT patients who received intravenous bolus and metabolism.30,31 In liver transplant patients, food of 0.02 mg/kg over 4 h.32 The half-life and clearance were reduces the bioavailability of tacrolimus by 27 Ϯ 18.2% 18.2 Ϯ 12.1 h and 0.071 Ϯ 0.034 l/h/kg, respectively. when compared to the fasting state.30 Unlike cyclosporine, tacrolimus is not dependent on bile for absorption. The absorption of tacrolimus in orthotopic liver transplant Efficacy in bone marrow transplantation recipients is similar regardless of the clamping of the T- tube. Therefore, dosage adjustments are unnecessary in The efficacy of prophylactic tacrolimus for GVHD in bone patients with biliary obstructions.28 marrow transplantation was documented in two animal A pharmacokinetic study was conducted between days model systems. In the murine model, Blazar et al45 demon- 23 and 43 in 11 BMT recipients who received tacrolimus strated the reduction of mature T cell expansion in response as a single agent for GVHD prophylaxis.32 The whole blood to host alloantigens, resulting in a lower incidence of lethal concentration of tacrolimus peaked at 2.0 Ϯ 1.6 h with a GVHD. Tacrolimus also prevented the rejection of T cell- bioavailability of 32 Ϯ 24%. The bioavailability of tacrol- depleted marrow allografts via a similar cellular mech- imus was modified by the concomitant administration of anism. Using the canine model, long-term survival was methotrexate and methylprednisolone.33 The mean bioavail- found in five of 10 recipients of DLA-mismatched marrow ability of tacrolimus was significantly lower in the patients and buffy coat when tacrolimus was given in conjunction who received methotrexate (16 Ϯ 8%) when compared to with a short-course of methotrexate.46 patients who received either tacrolimus alone (49 Ϯ 10%) or tacrolimus in conjunction with methylprednisolone (27 Ϯ 12%). The decreased bioavailability in patients who Treatment of GVHD received methotrexate was attributed to heightened radi- Earlier reports on the use of tacrolimus in clinical bone ation-induced gastroenteritis. marrow transplantation centered on the treatment of resist- ant acute and chronic GVHD, especially in patients who Distribution were resistant to steroids. In six children with steroid-resist- ant grade III–IV acute GVHD treated with tacrolimus, Tacrolimus is highly bound to plasma proteins (75 to 99%) improvement was seen in the skin (6/6), gut (6/6) and liver including alpha-1 acid glycoprotein, albumin, lipoproteins (3/4).47 In a Japanese study,48 tacrolimus was given to 18 and globulins.30,34,35 The drug rapidly distributes from patients with acute GVHD unresponsive to cyclosporine or plasma into the red blood cells. The high affinity of tacrol- other immunosuppressants. Out of 13 evaluable patients imus for red blood cells may be due to the high intracellular with acute GVHD, seven responded.
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