Effectiveness, safety and population pharmacokinetics of calcineurin inhibitors in graft-versus-host disease prophylaxis

Abstract

1. Introduction

1.1. Graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation (HSCT)

Although anticancer effects are related to dose of anticancer agents, hematologic toxicities are the most common dose-limiting toxicities. HSCT is the transfusion of multipotent hematopoietic stem cell in order to recover hematopoiesis after high intensity chemotherapy. Thus high intensity conditioning regimen which includes high dose chemotherapy followed by HSCT is the only curative therapy of majority of hemato-oncologic disease. The number of HSCT increased for 10 years from 195 cases in 2004 to 529 cases in 2014.1 HSCT can be classified by sources of hematopoietic stem cells or graft types. Stem cells came collected from the peripheral blood, bone marrow, and umbilical cord blood are used in HSCT. In autologous transplantation, the patients own stem cells are used, while the stem cells come from other donor are used in allogeneic HSCT.2,3 After transfusion of allogeneic hematopoietic stem cells, immune cells especially T-cells derived from the donor recognize the recipients as foreign and attack the hosts cells. The reaction is called GvHD and GvHD is a severe complication of allogeneic HSCT. Transplantation related morbidity and mortality is related to acute GvHD, which occurs within 100 days after transplantation.4 Acute GvHD commonly attacks the liver, skin, and gastrointestinal tract and the severity of acute GvHD is scored according to signs and symptoms represented in those organs. Several risk factors of GvHD including recipient and donor characteristics, graft properties, conditioning chemotherapy and post-HSCT management were suggested. The risk for acute GvHD rises with increasing recipient age, use of unrelated donor, human leukocyte antigen (HLA) mismatch.5

1.2. Strategies for GvHD prophylaxis

Immunosuppression has been the primary pharmacologic strategy to prevent GvHD. Methotrexate has been used since the 1950s as a way of shutting down T cells through inhibition of dihydrofolate reductase and production of thymidylate and purines. The calcineurin inhibitors cyclosporine and tacrolimus inhibit T-cell proliferation

combinations with methotrexate have successfully been used since the 1970s and are the cornerstone of most prophylactic regimens.6 Alternate agents were the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil and the mammalian target of rapamycin (mTOR) inhibitor sirolimus. Furthermore given the central role of T cells in GvHD, T-cell depletion (TCD) has been studied since the 1980s as a preventative strategy. Other drugs attempt to target cytokine/chemokine-receptor interactions that appear integral to development of GvHD. Exciting new success has been reported with maraviroc, a CCR5 antagonist that blocks T-cell chemotaxis and dramatically decreased the incidence of gastrointestinal and liver GvHD.6

1.3. Calcineurin inhibitor-based GvHD prophylaxis regimens

The introduction in the 1980s of two new immunosuppressive agents, cyclosporine and tacrolimus, which prevented T-cell activation by inhibiting calcineurin, has dramatically improved allograft survival rates. Furthermore, in 1986, the first studies reporting the superior outcomes of calcineurin inhibitor (CNI)-based regimens with notable reduction in GvHD and improved survival as a result of combination therapy (such as cyclosporine plus methotrexate) compared to either agent alone, were published. CNI-based therapies have, therefore, been considered the standard-of-care for GvHD prevention. Cyclosporine was originally isolated from fungi and was noted to have immunosuppressive effects. This observation led to its use in the prevention of allograft solid organ rejection and GvHD after allogeneic HSCT. Although cyclosporine and tacrolimus are structurally distinct, their mechanisms of action are similar. Cyclosporine binds to the cytosolic protein Peptidyl prolyl cis-trans isomerase A (also known as cyclophilin), whereas tacrolimus binds to the Peptidyl-prolyl cis-trans isomerase FKBP12, and these complexes (cyclosporine–cyclophilin or tacrolimus–FKBP12) inhibit calcineurin, thereby blocking the dephosphorylation of nuclear factor of activated T cells (NFAT) and its nuclear translocation. These events prevent NFAT from exerting its transcriptional function, resulting in the inhibition of transcription of IL-2 and of other cytokines and ultimately leading to a reduced function of T-cells.7 Two multicenter, randomized, prospective trials conducted in the mid-1990s demonstrated decreased incidence of acute GvHD with the tacrolimus and methotrexate combination compared to cyclosporine and methotrexate, but overall survival was not significantly different. These findings led some centers to favour the tacrolimus and methotrexate combination. Nonetheless, a recent survey estimated a much higher proportion of centers using cyclosporine over tacrolimus-based regimens.7

2. Research Topics

CNIs have played an important role in GvHD prophylaxis and have used for a long time. However there are some unmet needs in selection of CNIs and dosing in GvHD prophylaxis. Although there have been much studies which compared the efficacy and safety between tacrolimus and cyclosporine, all of studies were conducted in adult HSCT patients. In this situation, the majority of the pediatric centers prefered cyclosporine in combination with methotrexate for GvHD prophylaxis. Thus a comparison study is needed to establish the efficacy and safety of tacrolimus in pediatric HSCT patients. The methods and results are presented in SECTION I. Second, adequate concentrations of CNIs are important to prevent GvHD and adverse drug reactions. To maintain concentrations in target range, therapeutic drug monitoring is carried out. Nevertheless, large inter- and intra-variability in pharmacokinetics interrupt maintaining adequate concentrations of CNIs. Thus a population pharmacokinetic (PopPK) studies of CNIs are needed and the methods and results are presented in SECTION II.

3. Overall Results

In SECTION I, a total of 50 pediatric HSCT patients were included. The cumulative incidence of grade II to IV acute GvHD was not significantly different between tacrolimus and cyclosporine groups (75.4% vs. 66.7%, p = 0.910). The cumulative incidence grade III to IV acute GvHD was also not significantly different between tacrolimus and cyclosporine groups (15.4% vs. 21.6%, p = 0.627) Furthermore relapse free survival and non-relapse mortality at 100 days post-transplantation was not significantly different between two groups (100% vs. 91.3%, p = 0.961 and 0% vs. 8.7%, p = 0.576). All of adverse drug reactions were reported in less than 10% of patients. In SECTION II, PopPK models of tacrolimus in pediatric HSCT patients and cyclosporine in adult HSCT patients were developed. PopPK model of tacrolimus included BSA and azole antifungals use as covariates. The final model was: CL (L/h) = 6.74 × (BSA/1.102)0.552 × 0.4 (if azole antifungals use) V (L) = 1160 × (BSA/1.102)0.503 PopPK model of cyclosporine included weight as covariates. The final model was: CL = THETA (1) × (weight/70)0.419 × EXP(ETA (1)) Both models were well validated by bootstrap and VPC.

4. Overall Conclusions

In these studies, the efficacy and safety of tacrolimus and cyclosporine were compared in pediatric HSCT patients. In conclusion the efficacy of tacrolimus was not superior to cyclosporine in pediatric patients and both CNIs had a low incidence of adverse drug reactions. In addition, tacrolimus in pediatric HSCT patients and cyclosporine in adult HSCT patients were developed. Using the models, adequate dosing of tacrolimus and cyclosporine might be possible. Finally these studies might give insight to the optimization strategies of CNIs in GvHD prophylaxis.