Review of combination therapy with mTOR inhibitors and tacrolimus minimization after transplantation
Introduction
The calcineurin inhibitor (CNI) tacrolimus (TAC) (Prograf®; Astellas, Toyama City, Toyama Japan) is the mainstay of immunosuppressive therapy following solid organ transplantation given its efficacy for preventing acute rejection and improving short-term graft survival rates [1], [2]. However, treatment with TAC is associated with dose-dependent long-term renal and cardiovascular (CV) side effects, including nephrotoxicity, new-onset diabetes mellitus (NODM), hypertension, and hyperlipidemia [3], [4], [5]. Nephrotoxicity is the most significant side effect associated with TAC, occurring primarily as a result of intrarenal vasoconstriction [4]. Almost all patients will show signs of nephrotoxicity after 10 years of treatment with CNIs [6], and it is estimated that 7% to 18% of liver, lung, and heart transplant recipients progress to severe chronic renal failure by 5 years posttransplant [7]. Further, in transplant patients, nephrotoxicity associated with long-term use of CNIs has been implicated in the development of chronic allograft nephropathy [6] and end-stage renal disease [7].
Specific inhibitors of the mammalian target of rapamycin (mTOR) have potent immunosuppressive effects and are frequently used in antirejection regimens for transplant recipients [8]. Sirolimus (SRL) (Rapamune®; Pfizer Inc./Wyeth Pharmaceuticals Inc, Philadelphia, Pennsylvania) was the first mTOR inhibitor; everolimus (EVR) (Zortress®; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey) is a rapamycin derivative with increased oral bioavailability and a shorter half life [9]. mTOR is an important modulator of renal disease, and mTOR inhibitors have been shown to prevent renal graft dysfunction by reducing glomerular hypertrophy, proinflammatory and profibrotic cytokine production, interstitial inflammation, and fibroblast production, and inhibiting epithelial-to-mesenchymal transition [8]. In preclinical studies, mTOR inhibitors have also been shown to inhibit antibody production and reduce allograft rejection, resulting in improved long-term graft survival [10], [11]. mTOR inhibitors also reduce angiogenesis, which may reduce rates of new cancers and prevent cancer recurrence in patients such as those who received transplants for renal cell cancer or hepatocellular carcinoma [8], [12].
One strategy that has been studied to preserve renal function and reduce the risk of CV adverse events (AEs) in organ transplant recipients is to combine an mTOR inhibitor with TAC minimization (subclinical dosing) therapy [13], [14]. TAC and mTOR inhibitors are structurally similar and bind to FK506 binding proteins to form immunosuppressive complexes [4]. TAC binds to FKBP-12, which inhibits T-lymphocyte immune responses via blockade of the calcium-dependent signaling pathway and inhibition of interleukin-2 (IL-2) gene transcription [15]. SRL and EVR form complexes with FK506 binding proteins that inhibit mTOR, thereby inhibiting antigenic- and interleukin-stimulated activation and proliferation of T cells [8], [12]. In preclinical studies, subclinical doses of TAC used in combination with an mTOR inhibitor significantly increased inhibition of lymphocyte proliferation, expression of IL-2, and induction of transforming growth factor-β compared with clinical doses of either agent alone [16]. These synergistic effects allow for reduced TAC exposure and improved graft survival [13], [15], [16]. As reviewed elsewhere, studies in transplant recipients suggest that SRL, but not EVR, reduces the area under the blood–concentration time curve (AUC) of TAC [17], [18]. In contrast, TAC appears to have no significant effect on the pharmacokinetics of SRL or EVR [17], [19]. Because of the lack of pharmacokinetic interaction between TAC and EVR, dose adjustment is not necessary when these agents are used in combination [20].
We conducted a review of the literature on the use of immunosuppressive regimens that incorporate an mTOR inhibitor with TAC minimization therapy in solid organ transplant recipients. The findings from these reports using this regimen were evaluated and are reported here. Efficacy was evaluated in terms of graft survival and renal function. Safety analysis was based on the overall AE profile of different immunosuppressive regimens and the specific safety concerns of hypertension, dyslipidemia, NODM, proteinuria, infection, wound healing complications, and malignancy identified in these studies.
Section snippets
Methods
A PubMed search was conducted using the terms (mTOR OR sirolimus OR everolimus) AND tacrolimus AND renal AND (low OR reduced OR reduction OR minimization) AND transplant*. Results were limited to title/abstract and English-language articles published from January 1, 2003, through January 28, 2013. From this search, relevant articles presenting clinical data on the use of SRL or EVR plus TAC minimization therapy in solid organ transplant recipients were identified. TAC minimization was defined
Results
The PubMed search retrieved 212 articles, and these abstracts were screened for relevance. Review articles (n = 44), case reports or case series (n = 18), and pharmacokinetic studies (n = 6) were removed from the list. Of the remaining 144 articles, 24 articles representing 21 studies were identified that specifically evaluated SRL or EVR plus TAC minimization therapy in solid organ transplant recipients.
The relevant studies involved adult and pediatric kidney (n = 2201), heart (n = 260), lung (n = 108),
Conclusions
We identified a total of 21 relevant studies in the literature that specifically evaluated an mTOR inhibitor with TAC minimization therapy in solid organ transplant recipients. These studies comprised 2201 kidney, 260 heart, 108 lung, and 757 liver transplant recipients. Our review suggests that immunosuppressive regimens including an mTOR inhibitor (SRL or EVR) in combination with TAC minimization therapy better preserve renal function compared with standard-dose TAC, without significant
Acknowledgments
Technical assistance with editing, figure preparation, and styling of the manuscript for submission was provided by Cherie Koch, PhD, and Michael S. McNamara, MS, of Oxford PharmaGenesis Inc., and was funded by Novartis Pharmaceuticals Corporation. The authors were fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript. The opinions expressed in the manuscript are those of the
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2019, International ImmunopharmacologyCitation Excerpt :Development of adverse side effects such as wound healing failure, hyperlipidemia and oral mucositis are the main cause of SRL withdrawal followed by using an alternative protocol [13]. The concomitant use of SRL and reduced-dose of TAC, instead of using TAC or SRL alone, can ameliorate TAC associated adverse events, while preserving therapeutic efficacy and safety [2], amplifying TAC's immunosuppressive functions [14], lowering infection rates of BK virus (BKV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) and reducing malignant potential [15]. Although different clinical trials have shown that combined use of TAC/SRL decreases the acute rejection rate and increases the graft survival rate [16–18], to date, there has not been a report that aimed to study the effects of this protocol on immune cells subsets in vivo.
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