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The authors review the use of everolimus in long-term studies both in renal and heart transplantation. The pharmacokinetic and pharmacodynamic differences between everolimus and its parent drug, sirolimus are discussed. The improved pharmacokinetic, in particular the improved bioavailability, the reduced half-time and the reduced binding to plasma...
Contexts in source publication
Context 1
... which has greater polarity and is more hydrophilic, was developed to improve the pharmacokinetic and pharmacodynamic properties of sirolimus, especially oral bioavailability. 10 The chemical structures of everolimus and sirolimus differ by the presence of a 2-hydroxyethyl group at position 40 ( Figure 1). ...
Context 2
... Obviously, in this setting, the effects on the endothelium are greater because of the high local drug concentrations. RAD B253 56 was a prospective, multicenter, double-blind study in which 634 patients were randomized after heart transplantation into three arms to receive either everolimus 1.5 mg/day or 3 mg/day or azathioprine, in combination with cyclosporine and steroids ( Figure 10). After 12 months, the mean increase in coronary media-intima thickness among azathioprine-treated patients was more than double that observed in both the everolimus arms, and the incidence of To compare the efficacy and safety of each of two oral doses of RAD (1.5 mg/day and 3.0 mg/day with azathioprine) in de novo heart transplant recipients vasculopathy, evaluated by intravascular ultrasonography, was also significantly higher in this group, at 52.8% vs 35.7% and 30.4%. ...
Citations
... Incorporating antibacterial agents onto biomaterial surfaces is an effective strategy for preventing bacterial colonization and infections associated with complications from biomedical devices [5,6]. Everolimus, commonly used to prevent chronic rejection in organ transplants, has gained attention as a potential antibacterial coating due to its antiproliferative, antifungal, and immunosuppressive properties [7][8][9]. This compound exhibits strong binding to the FK506 binding protein-12 , resulting in the suppression of the mammalian target of rapamycin (mTOR) pathway. ...
Biomaterial-Centered Infection (BCI) is a significant issue in the implantation of medical devices, primarily caused by the formation of bacterial biofilms on the device surface. One potential solution to address this problem is the use of antibacterial coatings. This study examines the effectiveness of everolimus as an antibacterial coating agent with polydopamine (PDA) as an intermediate layer. The commonly used biomaterial for medical scaffolds, poly(lactic acid) (PLA), was coated with everolimus after being submerged in PDA for 24 hours. The coated PLA was then subjected to antibacterial analysis, including culturing Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli bacteria in Luria-Bertani broth, bacterial count tests, and disc inhibition tests. The results showed that everolimus has antibacterial properties, but its efficacy varies with different types of bacteria adhering to the biomaterial surfaces. Specifically, the everolimus coating was found to be more effective in killing Gram-positive S. aureus. The absence of inhibition zones and the lack of further growth of both Gram-positive S. aureus and Gram-negative E. coli on the samples demonstrated the controlled release of everolimus, indicating the potential of the PDA layer in holding the everolimus release to the surrounding. Therefore, the study concludes that the formation of everolimus coating on biomaterial surfaces aided by the PDA layer, have significant potential in retarding bacterial colonies on medical devices.
... 2,4 So far, EVR is the only clinically used mTOR inhibitor approved by the US Food and Drug Administration (FDA) for the oral administration and treatment of malignancies, including breast carcinoma, gastrointestinal tract-derived neuroendocrine tumors, renal cell carcinoma, and to prevent allograft rejection after heart, kidney, and liver transplantations. 1,2,5 Pharmacokinetic studies with transplant recipients obtaining EVR either with 0.75 mg/dose or 1.5 mg/dose twice a day combined with cyclosporin revealed maximal blood concentration of 11.1 ± 4.6 µg/L and 20.3 ± 8.0 µg/L, respectively, after 1 to 2 hours. 6,7 The elimination half-life amounts for 18-32 hours and steady-state is achieved between 4 and 7 days. ...
... 11,17 Therapeutic EVR trough blood levels should be targeted between 3 and 8 ng/mL, which has been shown to associate with reduced biopsy-proven acute rejection and graft loss. 5 Our data revealed that the mean EVR trough levels of the medium-dose and high-dose groups obtained 12 hours after third but right before the last EVR administration were above the therapeutic threshold of 3 ng/mL and, therefore, comparable to therapeutic treatments. 2,5 Although EVR has been systemically washed out since study day 8, the observed anti-proliferative effects even persist 5 days after the last EVR administration in the medium-dose and high-dose groups, whereas for IL-10 suppression this was just the case in the highdose group. ...
... 5 Our data revealed that the mean EVR trough levels of the medium-dose and high-dose groups obtained 12 hours after third but right before the last EVR administration were above the therapeutic threshold of 3 ng/mL and, therefore, comparable to therapeutic treatments. 2,5 Although EVR has been systemically washed out since study day 8, the observed anti-proliferative effects even persist 5 days after the last EVR administration in the medium-dose and high-dose groups, whereas for IL-10 suppression this was just the case in the highdose group. These findings suggest that higher doses of EVR induce residual immunosuppressive effects even when the drug is completely metabolized. ...
The rapamycin analogue everolimus (EVR) is a potent inhibitor of the mammalian target of rapamycin (mTOR) and clinically used to prevent allograft rejections as well as tumor growth. The pharmacokinetic and immunosuppressive efficacy of EVR have been extensively reported in patient populations and in vitro studies. However, dose-dependent ex vivo effects upon acute EVR administration in healthy volunteers are rare. Moreover, immunosuppressive drugs are associated with neuroendocrine changes and psychological disturbances. It is largely unknown so far whether and to what extend EVR affects neuroendocrine functions, mood, and anxiety in healthy individuals. Thus, in the present study, we analyzed the effects of three different clinically applied EVR doses (1.5, 2.25, and 3 mg) orally administered 4 times in a 12-hour cycle to healthy male volunteers on immunological, neuroendocrine, and psychological parameters. We observed that oral intake of medium (2.25 mg) and high doses (3 mg) of EVR efficiently suppressed T cell proliferation as well as IL-10 cytokine production in ex vivo mitogen-stimulated peripheral blood mononuclear cell. Further, acute low (1.5 mg) and medium (2.25 mg) EVR administration increased state anxiety levels accompanied by significantly elevated noradrenaline (NA) concentrations. In contrast, high-dose EVR significantly reduced plasma and saliva cortisol as well as NA levels and perceived state anxiety. Hence, these data confirm the acute immunosuppressive effects of the mTOR inhibitor EVR and provide evidence for EVR-induced alterations in neuroendocrine parameters and behavior under physiological conditions in healthy volunteers.
... Everolimus increased the amplitude of contraction, but not the frequency (Table 3). Everolimus was developed to improve the pharmacokinetic profile of sirolimus (Ganschow et al. 2014) and has been associated with ciclosporin to avoid acute rejection (Salvadori & Bertoni, 2011). In a randomized and double-blind study, EVR caused a greater incidence of diarrhoea than MMF treatment (Vítko et al. 2005). ...
Objectives:
The aim was to propose an animal model for investigating the effects of immunosuppressive monotherapy on gastrointestinal motility using a non-invasive biomagnetic technique.
Methods:
Male Wistar rats were randomly distributed into groups: Cyclosporine, Tacrolimus, Prednisone, Sirolimus, Mycophenolate Mofetil, Everolimus and Azathioprine. Each animal was treated during 14 days by gavage with dosage ranging from 1 to 20 mg Kg(-1) day(-1) considering area per volume ratio and hepatic metabolism. Gastrointestinal transit and gastric contractility measurements were evaluated by Alternating Current Biosusceptometry (ACB) before and after treatment.
Results:
The gastric emptying was faster in animals treated with Tacrolimus, Prednisone, Sirolimus and Everolimus compared to control (126.7 ± 12.7 min). There was a significant increase in frequency of contractions after Cyclosporine, Tacrolimus, Azathioprine and Sirolimus treatment compared to control (4.6 ± 0.3 cpm). Increases in amplitude of contraction were observed after treatment with Tacrolimus, Sirolimus and Everolimus compared to control (34.9 ± 6.0 dB).
Conclusion:
The results showed that our animal model was suitable for demonstrating that most immunosuppressive drugs currently in use impaired at least one gastrointestinal motility parameter. As a noninvasive technique, ACB can be proposal as useful tool to evaluate side effects of drugs in GI tract helping to understand the symptoms to improve clinical management of patients. This article is protected by copyright. All rights reserved.
... Everolimus (RAD001) is one of several semisynthetic deriva- tives of rapamycin, collectively known as rapalogs, with supe- rior pharmacokinetics and pharmacodynamics as compared with the parent compound (Maurizio Salvadori, 2011;Lamming et al., 2013). The drug is widely used in immuno- suppressive and cancer therapy as well as in drug-eluting stents (Wander et al., 2011;De Meyer et al., 2015). ...
... These properties allow everolimus to be formulated as an oral agent, while maintaining immunosuppressive and anti-neoplastic activities similar to rapamycin [18,19] . In addition, unlike rapamycin, no loading dose is required for everolimus, and the twice-daily dosing schedule enables accurate dose adjustments [20] . ...
Mammalian target of rapamycin, also known as mechanistic target of rapamycin (mTOR) is a protein kinase that belongs to the PI3K/AKT/mTOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of mTOR (mTORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immunological tolerance. In this review, we describe the mechanisms by which inhibitors of mTOR induce suppression by regulation of these pathways at different levels of the immune response. In addition, we particularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of mTOR.
... Some reactions are mild to moderate, including rash, oedema, delayed wound healing and stomatitis. However, severe adverse effects, such as proteinuria, pneumonitis, thrombocytopenia and anaemia, are not uncommon and may form a serious limitation to their use [27,117]. Many of these side effects can be related to direct effects of rapamycin and were successfully reduced following the introduction of semi-derivatives with improved pharmacokinetic profiles, such as everolimus [111]. ...
... Rapalogs are also known to induce metabolic and haemodynamic adverse effects which paradoxically contribute to atherosclerosis. Indeed, hypercholesterolaemia and hypertriglyceridaemia are widely observed in transplant patients receiving everolimus [117]. Dyslipidaemia is also observed in animal models of atherosclerosis such as ApoE -/and LDLR -/mice treated with mTORC1 inhibitors [69,71]. ...
Despite significant improvement in the management of atherosclerosis, this slowly progressing disease continues to affect countless patients around the world. Recently, the mechanistic target of rapamycin (mTOR) has been identified as a preeminent actor in the development of atherosclerosis. mTOR is a constitutively active kinase found in two different multiprotein complexes, mTORC1 and mTORC2. Pharmacological interventions with a class of macrolide immunosuppressive drugs, called rapalogs, have shown undeniable evidence of the value of mTORC1 inhibition to inhibit the development of atherosclerotic plaques in several animal models. Rapalog-eluting stents have also shown extraordinary results in humans, even though the exact mechanism for this anti-atherosclerotic effect remains elusive. Unfortunately, rapalogs are known to trigger diverse undesirable effects due to mTORC1 resistance or mTORC2 inhibition. These adverse effects include dyslipidaemia and insulin resistance, both known triggers of atherosclerosis. Several strategies such as combination therapy with statins and metformin have been suggested to oppose rapalog-mediated adverse effects. Statins and metformin are known to inhibit mTORC1 indirectly via AMPK activation and may hold the key to exploit the full potential of mTORC1 inhibition in the treatment of atherosclerosis. Intermittent regimens and dose reduction have also been proposed to improve rapalog's mTORC1 selectivity, thereby reducing mTORC2 related side effects.
... The hydroxyethyl group provides a pharmacokinetic advantage, conferring faster absorption and a shorter half-life than sirolimus. [55][56][57] Unlike sirolimus, no loading dose is required for everolimus, and the twice-daily dosing schedule allows better dose adjustments. 57 Everolimus (in combination with cyclosporine and corticosteroids) was first approved in 2003 for the prophylaxis of organ rejection in kidney and heart transplant recipients in many European countries, followed by a US Food and Drug Administration (FDA) approval for kidney transplantation in 2010. ...
... [55][56][57] Unlike sirolimus, no loading dose is required for everolimus, and the twice-daily dosing schedule allows better dose adjustments. 57 Everolimus (in combination with cyclosporine and corticosteroids) was first approved in 2003 for the prophylaxis of organ rejection in kidney and heart transplant recipients in many European countries, followed by a US Food and Drug Administration (FDA) approval for kidney transplantation in 2010. Everolimus, in combination with reduced-dose tacrolimus and steroids, is the first approval by US FDA for an immunosuppressive agent in liver transplantation for more than a decade. ...
During the last 5 decades, liver transplantation has witnessed rapid development in terms of both technical and pharmacologic advances. Since their discovery, calcineurin inhibitors (CNIs) have remained the standard of care for immunosuppression therapy in liver transplantation, improving both patient and graft survival. However, adverse events, particularly posttransplant nephrotoxicity, associated with long-term CNI use have necessitated the development of alternate treatment approaches. These include combination therapy with a CNI and the inosine monophosphate dehydrogenase inhibitor mycophenolic acid and use of mammalian target of rapamycin (mTOR) inhibitors. Everolimus, a 40-O-(2-hydroxyethyl) derivative of mTOR inhibitor sirolimus, has a distinct pharmacokinetic profile. Several studies have assessed the role of everolimus in liver transplant recipients in combination with CNI reduction or as a CNI withdrawal strategy. The efficacy of everolimus-based immunosuppressive therapy has been demonstrated in both de novo and maintenance liver transplant recipients. A pivotal study in 719 de novo liver transplant recipients formed the basis of the recent approval of everolimus in combination with steroids and reduced-dose tacrolimus in liver transplantation. In this study, everolimus introduced at 30 days posttransplantation in combination with reduced-dose tacrolimus (exposure reduced by 39%) showed comparable efficacy (composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, or death) and achieved superior renal function as early as month 1 and maintained it over 2 years versus standard exposure tacrolimus. This review provides an overview of the efficacy and safety of everolimus-based regimens in liver transplantation in the de novo and maintenance settings, as well as in special populations such as patients with hepatocellular carcinoma recurrence, hepatitis C virus-positive patients, and pediatric transplant recipients. We also provide an overview of ongoing studies and discuss potential expansion of the role for everolimus in these settings.
... The oral bioavailability of mTOR inhibitors is low (14% for SRL and 20% for EVR) [19]. SRL and EVR are both metabolized extensively by cytochrome P (CYP)-450 3A in the liver and intestines, and affected by the different activities of the drug efflux pump P-glycoprotein, which leads to the low bioavailability observed with these drugs [18,20]. ...
... With EVR, steady state is reached within 4 days with an accumulation in blood levels of 2-to 3-fold compared with the exposure after the first dose [19,25]. In de novo renal transplant recipients receiving EVR, CsA, and corticosteroids, steady-state C max , C0, and AUC showed a dose-proportional increase. ...
... Around 98% of EVR is excreted as metabolites in the bile and the remainder in the urine. EVR has an elimination half-life of approximately 30 h [19]. Prescribing information recommends EVR be administered twice daily (bid) in transplant recipients, mainly because of the CsA/EVR interaction described in the following section; however, preliminary evidence in renal transplant recipients suggests similar efficacy (e.g. ...
Mammalian target of rapamycin (mTOR)-inhibitor–containing immunosuppressive regimens have been developed as part of calcineurin inhibitor (CNI) minimization/withdrawal strategies for renal transplant recipients, with the goal of avoiding CNI-associated nephrotoxicity. This review focuses on the pharmacokinetic interactions and exposure-response relationships of mTOR inhibitors and tacrolimus (TAC), the most widely used CNI. We also discuss key randomized clinical studies that have evaluated use of this combination in renal transplantation. Pharmacokinetic studies have shown that mTOR inhibitors, everolimus (EVR) and sirolimus (SRL), have a large intra- and inter-patient variability in drug exposure, and narrow therapeutic windows (trough levels [C0] 3–8 ng/mL and 5–15 ng/mL, respectively). Consequently, routine therapeutic drug monitoring of EVR and SRL is recommended to optimize efficacy and minimize toxicity in individual patients. As there is a good correlation between C0 and area under the curve (AUC), C0 can be used as a convenient and reliable measure of mTOR drug exposure. Clinical data on the use of EVR or SRL in TAC minimization strategies in renal transplantation are limited. Available evidence suggests that treatment with EVR allows early and substantial TAC minimization when used with basiliximab induction and corticosteroids, to achieve good renal function without compromising efficacy or safety. However, data comparing this combination with other regimens are lacking. Results with SRL are more mixed. SRL in combination with reduced TAC has been shown to provide less nephrotoxicity than the SRL/standard TAC combination, with comparable efficacy and safety. However, this approach has been shown to be inferior to other regimens in terms of patient/graft survival and biopsy-proven acute rejection (vs MMF/TAC) as well as renal function (vs MMF/TAC and SRL/MMF). Further studies are needed to define the therapeutic window for TAC when used in combination with mTOR inhibitors, evaluate EVR/reduced TAC versus other regimens, assess long-term outcomes, and determine efficacy and safety in high-risk patients.
Successful organ transplantation requires immunosuppression, however current immunosuppressants have significant side effects, particularly nephrotoxicity. Mammalian target of rapamycin (mTOR) inhibitors are a class of drugs that interfere with the multifaceted mTOR pathway, limiting T-cell proliferation and the alloimmune response. There are two mTOR inhibitors that are approved for organ transplantation: sirolimus and everolimus, and these drugs are used in kidney, liver, and heart transplantation. The development and approval of these medications for transplantation have been controversial and complicated, however these medications also offer many exciting advantages for transplantation. The mTOR pathway is responsible for maintaining cellular homeostasis and it controls numerous cellular processes, thus inhibition of the mTOR pathway by mTOR inhibitors has numerous beneficial effects, including antineoplastic, antiviral, and antiproliferative activity. However, inhibiting the mTOR pathway also leads to numerous diverse adverse side effects. Managing the many side effects is the key to being able to take advantage of the potential benefits.
What is known and objective:
Azole antifungals, prescribed prophylactically to avoid severe infections in immunosuppressed organ transplant recipients, can interact with drug substrates of CYP3A4. We report serious adverse effects due to interaction between orally administered voriconazole and everolimus in a renal transplant recipient.
Case description:
Despite reduction of the dose of everolimus by a third, the blood trough concentration of everolimus increased considerably in a kidney transplant recipient upon oral administration of voriconazole. Everolimus was then discontinued. Pneumonia secondary to pulmonary aspergillosis worsened, possibly due to the excessive immunosuppression.
What is new and conclusion:
Orally administered voriconazole inhibits intestinal and hepatic cytochrome P450-3A4 activity and thereby reduces everolimus metabolism. An 80% decrease in dose or discontinuation of everolimus is required when concomitant voriconazole is introduced. Daily blood monitoring of everolimus is warranted until a steady state of concentrations is reached.
