Sirolimus Research Articles

Background/Objectives: Long-term survival among liver transplant (LT) recipients who live beyond one year has remained relatively stable over recent decades. However, reducing long-term morbidity is increasingly important, and metabolomics may enable risk-based, personalized immunosuppression. We aimed to evaluate and compare the serum metabolomic profiles of LT recipients treated with tacrolimus (TAC) versus sirolimus (SIR), to elucidate metabolic pathways associated with these regimens. Methods: Targeted metabolomic profiling of 894 metabolites was conducted on serum samples from 128 LT recipients using the Biocrates MxP® Quant 500 kit. Data were analyzed with MetaboAnalyst 6.0, and multivariate analysis was performed using Partial Least Squares-Discriminant Analysis (PLS-DA). Metabolites with Variable Importance in Projection (VIP) scores > 1.5 underwent pathway enrichment in OmicsNet, incorporating Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG)-based network analysis. Results: Eighty-seven metabolites were significantly altered between groups. Phosphatidylcholines (PCs) and ceramides were elevated in TAC-treated patients, while di- and triacylglycerols were higher in the SIR group. Pathway enrichment implicated lipid metabolism, particularly glycerophospholipid, ether lipid, and sphingolipid pathways. Network analysis identified enriched modules related to metabolic regulation and immune response. Conclusions: Divergent metabolomic profiles distinguish TAC- and SIR-treated recipients, suggesting regimen-specific impacts on lipid metabolism with potential relevance to post-transplant complications.

To determine whether sirolimus (SIR) and cyclosporine (CSP) combined with post-transplantation cyclophosphamide (PTCy), after nonmyeloablative or reduced-intensity conditioning unrelated donor hematopoietic cell transplantation (HCT), would be more effective than SIR, CSP, and mycophenolate mofetil (MMF) in reducing the risk of chronic graft-versus-host disease (cGVHD) without increasing risk of recurrent malignancy. In a Phase II trial of HLA-matched or mismatched unrelated donor mobilized blood HCT (ClinicalTrials.gov identifier: NCT03246906), adults with hematologic malignancies ineligible for myeloablative HCT were randomly assigned 1:1 to GVHD prophylaxis with SIR/CSP/PTCy (50 mg/kg once daily on days +3, +4) or SIR/CSP/MMF. The primary end point was 1-year chronic GVHD-free relapse-free survival (CRFS). One hundred forty-five patients were randomly assigned and transplanted. Median follow-up among survivors was 3.0 (range, 0.6-7.0) years. Comparing PTCy-based with non-PTCy-based immunosuppression, estimated 1-year CRFS was 73% (95% CI, 61% to 82%) versus 48% (95% CI, 36% to 59%), translating into a hazard ratio (HR) for CRFS failure of 0.46 (95% CI, 0.26 to 0.79; P = .005) for PTCy. Probabilities of acute GVHD (aGVHD) grades II-IV and III-IV, respectively, were 40% versus 42% and 6% versus 10%. One-year estimates for secondary end points were as follows: moderate-to-severe cGVHD, 3% (95% CI, 1% to 9%) versus 33% (95% CI, 22% to 44%); relapse, 15% versus 15%; progression-free survival, 75% versus 78%; survival, 86% versus 86%; and nonrelapse mortality, 10% versus 7%. The HR of ≥grade 3 infections with PTCy versus non-PTCy was 2.65 (95% CI, 1.41 to 4.97; P = .003). After HLA-matched or mismatched unrelated donor mobilized blood HCT, replacing MMF with PTCy, when used in combination with SIR and CSP, significantly reduced risk of cGVHD, without increasing risks of aGVHD or relapse. Thus, the combination of PTCy and SIR/CSP may have synergistic cGVHD-protective effects warranting further study.

Background/Objectives: Prolonged use of immunosuppressive drugs (IMDs) is correlated with increased risk of cancer in transplant patients. However, detailed side-by-side analysis of cancer risk associated with individual IMDs in the same population is not available. The aim of this study was to identify drug-specific risks of cancer for commonly used transplant IMDs. Methods: We analyzed the risk of cancer for the IMDs commonly used in transplant patients (tacrolimus (TAC), cyclosporin (CY), sirolimus (SIR), mycophenolate (MMF), and their combinations) in Texas Medicare beneficiaries between 2007 and 2018. Results: Of 7721 transplant recipients receiving an IMD of interest, 2261 developed cancer. There was an increased risk of any cancer diagnosis with the use of TAC (HR: 1.49; 95% CI: 1.25-1.78) and CY (HR: 1.51; 95% CI: 1.19-1.92), and decreased risk with use of MMF (HR: 0.77; 95% CI: 0.67-0.89). Cancer-specific models revealed increased risk of liver cancer (HR: 5.25, 95% CI: 2.03-13.61) and decreased risk of ovarian/uterine cancer (HR: 0.25, 95% CI: 0.07-0.84) with TAC; increased risk of lung cancer with CY (HR: 5.06, 95% CI: 1.47-17.41); and increased risk of lymphoma associated with SIR (HR: 2.80, 95% CI: 1.00-7.81). Conclusions: TAC increases cancer risk, and MMF decreases cancer risk. Individual cancer types also vary in risk associated with individual IMDs. This study provides new information on IMD-specific cancer risk that can guide individualized screening/treatment decisions to reduce the risk associated with specific cancers after transplantation.

Therapeutic drug monitoring (TDM) of immunosuppressive drugs (ISDs) is essential for transplant recipients. The aim of this study is to establish an LC-MS/MS method to determine mycophenolic acid (MPA) and its metabolite, cyclosporin A (CsA), tacrolimus (TAC) and sirolimus (SRL) levels in whole blood and plasma simultaneously. Whole blood and plasma samples were treated with protein precipitation. After centrifugation, the supernatant was eluted through Agilent Eclipse XDB-C18 (3.5μm, 2.1mm × 100mm) column by water (2mmol/L ammonium formate) and methanol through a gradient method. The ISDs in renal allograft recipients were compared with TDM results. The methods established were linear within a range of 0.204-51μg/mL for MPA, 2.0-500μg/mL for MPAG, 4-1,000ng/mL for CsA, 0.2-50ng/mL for TAC and 0.2-50ng/mL for SRL (r2 = 0.9998) in plasma and whole blood. The intra- and inter-day accuracy was in the range of 85-115%, and imprecision of all ISDs was <15%. Plasma MPA and MPAG levels can be estimated based on whole blood level: Cplasma = 1.52 × Cblood + 0.16 (r2 = 0.9168) and Cplasma = 1.58 × Cblood - 0.56 (r2 = 0.9069). The CsA (r2 = 0.9694, n = 60), TAC (r2 = 0.9426, n = 115) and SRL (r2 = 0.9484, n = 70) levels in whole blood were consistent with those obtained from the immunoassays. The LC-MS/MS method established is suitable for patients with various immunosuppressive regimens.

Incidence and risk factors for rejection after conversion from calcineurin inhibitor to sirolimus-based immunosuppression in orthotopic heart transplant recipients.

Background and ObjectiveThe purpose of this study is to investigate the status of blood concentration of sirolimus (SRL), explore the factors influencing SRL drug blood concentration, and provide guidance for the appropriate utilization of clinical medications.MethodsA single-center retrospective cohort study encompassed 1535 blood drug concentration observations obtained from 249 children from August 2018 to June 2023. Participants were categorized into four groups (A, B, C, and D) on the basis of their blood concentration levels at various time intervals. The analysis focused on identifying the factors that influenced blood concentration in the short- and long-term posttreatment. The primary endpoint was factors affecting the sirolimus blood concentration. The effect of physiopathological indicators on the corrected blood drug concentration (C/D value) was analyzed to avoid the effect of differences in the dose of SRL used in patients on SRL blood concentrations. The multiple linear regression model was used to examine the impact of factors influencing pharmacokinetics and pharmacodynamics on the C/D.ResultsAnalysis of SRL blood concentration monitoring indicated that a majority (60.43%) of patients demonstrated a trough sirolimus concentration (C0) below the level of the recommended threshold of 5 ng/mL, while approximately 17.7% of patients exceeded 15 ng/mL. The results indicated a noteworthy association between weight and body surface area (BSA) and the C/D of SRL in groups A, B, and D (P < 0.05). Additionally, aspartate transaminase (AST), alanine aminotransferase (ALT), and albumin (ALB) in group A; ALB in group B; and platelet count (PLT) in group C demonstrated a statistically significant correlation with the C/D of SRL (P < 0.05).ConclusionsClinicians should optimize medication plans by considering the child’s weight, BSA, ALT, AST, PLT, ALB, and relevant factors. These findings may serve as a valuable resource for clinicians.

Background: mTOR-Is positively influence the occurrence and course of certain tumors after solid organ transplantation. mTOR-inhibitor (mTOR-I) treatment, either alone or in combination with Calcineurininhibitors (CNIs), significantly reduces the incidence of malignancies after organ transplantation. However, there is no information on which mTOR-I, Sirolimus (SIR) or Everolimus (ERL), has a stronger anti-tumoral effect. Methods: The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 1.164 trials screened, of which 20 could be included (7465 patients). We performed a network meta-analysis to analyze the relative risk of different types of mTOR-I compared to CNI treatment on malignancies after transplantation. A minimum follow-up of 24 months was mandatory for inclusion. Results: Four different types of mTOR-I treatment were analyzed in network meta-analyses—SIR mono, ERL mono, SIR with CNI, and ERL with CNI. The average follow-up of all trials was 43.8 months. All four different mTOR-I regimes showed a significant reduced relative risk for malignancies compared to a regular CNI-treatment with the strongest effect under SIR in combination with a CNI (RR 0.23, CI 0.09–0.55, p = 0.001). This effect remained consistent for all tumor entities except non-melanoma skin cancer (RR 0.25, CI 0.07–0.90, p = 0.033). Conclusions: It is well known that an mTOR-I based treatment in transplant patients reduces the risk of tumor manifestation in comparison to CNI treatment. A combination of SIR and CNI seems to be the most potent mTOR-I therapy against malignancies.

Treatment With mTOR Inhibitors as Primary Immunosuppression After Combined Heart and Kidney Transplantation.

Sirolimus Combined Dexamethasone As the First-Line Therapy for Newly Diagnosed Adult Primary Immune Thrombocytopenia: A Multicenter, Open-Label, Prospective, Randomized Controlled Clinical Trial

Treatment with mTOR Inhibitors as primary immunosuppression after combined heart and kidney transplantation

BackgroundThe benefits of pharmacotherapy with sirolimus (SIR) in pediatric transplant recipients are well established. Traditionally, whole blood samples have been used to measure SIR concentrations. Volumetric Absorptive Microsampling (VAMS) is an alternative sampling strategy suitable for Therapeutic Drug Monitoring (TDM). In this study, we developed and validated two liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for determining SIR concentrations in whole blood (WB) and capillary whole blood samples collected using a VAMS-Mitra™ device.MethodsWe used protein precipitation during WB sample preparation and dispersive liquid-liquid microextraction (DLLME) with methyl tert-butyl ether for VAMS sample preparation to optimise the analyte extraction process. The described validation protocols were cross-validated, confirming the equivalence of the whole-blood and VAMS-based methods. Furthermore, the developed methods were evaluated in two three-level rounds of an external proficiency-testing scheme.ResultsThe analytical methods were successfully validated within the calibration range of SIR (0.5–60 ng/ml). The validation parameters met the European Medicines Agency (EMA) and the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDM&CT) acceptance criteria. No hematocrit (tested in the range of 24.3–64.1%), matrix, or carry-over effects were observed. Cross-validation confirmed the interchangeability between VAMS-LC-MS/MS and WB-LC-MS/MS methods. The developed methods were successfully implemented for SIR determination in 140 clinical samples (70 each of WB and VAMS) from pediatric renal transplant recipients, demonstrating their practicality and reliability.ConclusionThe VAMS-based method has been rigorously tested and is clinically equivalent to the reference WB-LC-MS/MS method. Additionally, clinical validation confirmed the utility of the presented methods for TDM of the SIR in the pediatric population after renal transplantation.Graphical abstract

Objectives: Sirolimus (SRL), a mammalian target of rapamycin inhibitor, has been widely used to treat patients with vascular anomalies (VAs). The objectives of this study were to summarize the routine blood SRL monitoring data for VAs children, to investigate the factors contributing to the variable blood SRL concentrations and to evaluate the efficacy and safety of SRL therapy. Methods: VAs patients with routine blood SRL monitoring from July 2017 to April 2022 at the Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University were retrospectively collected. Clinical data were obtained from the hospital information system. Results: In total, 67 children (35 females) were enrolled. The therapeutic drug monitoring data showed that the range of measured blood trough concentrations (Ctrough) was 3.6-46.8 ng/mL. At the initial measurements, only 33% of patients were in the target concentration range (10-15 ng/mL). But this proportion became 54% at the last measurements. The whole blood-Ctrough-to-daily dose (Ctrough/Dose) ratio was significantly associated with age and body weight (BW). The patients' laboratory results did not change significantly after SRL treatment. Although the incidence of adverse events was relatively high (44.8%), most of them were mild and tolerable. 70.3% patients had total responses to SRL, whereas 29.7% children exhibited stable disease or progressive disease. No significant differences were found in Ctrough between the total response group and non-response group. Conclusions: This retrospective study revealed a high variability in SRL blood concentrations in Chinese children with VAs. Of note, pediatric patients with older age and a higher BW had a lower Ctrough/Dose ratio. It is a concern whether the range of 10-15 ng/mL is feasible for Chinese children based only on our study. Further studies recruiting more patients are required to redefine the target reference range for children with VAs.

Sirolimus (SR) is a macrolide with antifungal and antitumor immunosuppressant properties, classified as a selective inhibitor of mammalian target of rapamycin (mTOR). In this study, an ionic in situ gel of SR (SR-SUS-ISG) was formulated using gellan gum, exhibiting stability regardless of temperature and pH variations, causing minimal irritation. Harnessing the physiological conditions of the eye, SR-SUS-ISG underwent gelation upon contact with ions, increasing drug viscosity and prolonging retention on the ocular surface. Concurrently, SR-SUS-ISG displayed favorable shear dilution properties, reducing viscosity at ambient temperature, enhancing fluidity, and facilitating convenient packaging and transport. Biocompatibility assessments on both human corneal epithelial cells and rabbit eyes demonstrated that SR-SUS-ISG could well be tolerated. Pharmacokinetic investigations in rabbit ocular aqueous humor revealed sustained release, improved corneal penetration, and enhanced bioavailability. Additionally, in a rat corneal alkali burn model, SR-SUS-ISG exhibited inhibitory effects on corneal neovascularization, associated with decreased levels of the inflammatory factors VEGF and MMPs. These findings suggested that SR-SUS-ISG held promise as an effective ocular drug delivery system.Graphical

Comparison of whole-blood sirolimus concentrations measured by EMIT-based Siemens Viva-ProE® System and LC-MS/MS in Chinese transplant patients

e15096 Background: The mTORC1 pathway, often activated by mutations in genes like TSC1, TSC2, PIK3CA, PTEN, STK11, and KEAP1, plays a pivotal role in cancer progression; in some settings, alterations in STK11 and KEAP1 may be associated with treatment resistance and poor prognosis. Despite the broad importance of the mTORC1 pathway in cancer cell growth and survival, mTOR inhibitors (mTORis) temsirolimus (TEM), sirolimus (SIRO), and everolimus (EVE) have limited clinical application in the cancer setting. nab-Sirolimus, an injectable form of albumin-bound SIRO that leverages unique transport properties of albumin known to increase tumor drug accumulation, is approved for treatment of malignant PEComa. Here, we report the antitumor activity of nab-sirolimus in comparison to other mTORis in A549 NSCLC ( KRAS G12S, STK11 Q37*, and KEAP1 G333C) xenografts, and the correlation of antitumor activity, tumor PK profile, and mTOR pathway suppression. Methods: Athymic mice bearing subcutaneous A549 NSCLC xenografts were treated with either saline or equal weekly doses of nab-sirolimus (administered intravenously [IV]; 5 or 15 mg/kg/week), TEM (IV; 5 mg/kg/week), or SIRO or EVE (both oral; 15 mg/kg/week). Tumors were harvested at different time points after mTORi treatment and analyzed for tumor drug levels (LC-MS/MS) and mTOR pathway biomarkers (pS6 and p4EBP1) via western blot (WB). Results: In A549 xenografts, nab-sirolimus (IV) treatment resulted in significantly greater suppression of tumor growth compared with TEM (IV), SIRO (oral), and EVE (oral) (Table). Average intratumoral drug concentrations 24 hours after IV mTORi treatment were significantly higher with nab-sirolimus (420-539 ng/g) compared with TEM (TEM [parent] 34.9 ng/g; SIRO [active metabolite measured from TEM] 13.2 ng/g) and compared with 7-day steady-state concentrations for oral SIRO (17 ng/g) and EVE (10 ng/g). WB confirmed that nab-sirolimus consistently inhibited mTOR targets pS6 and p4EBP1, whereas TEM, SIRO, and EVE were less effective. Conclusions: nab-Sirolimus resulted in significantly higher intratumoral drug concentration, stronger inhibition of mTOR targets, and greater antitumor activity compared to other IV and oral mTORis in a KRAS/STK11/KEAP1 mutated NSCLC xenograft model. These results support further clinical evaluation of nab-sirolimus as a single agent or in combination with other therapeutic agents in oncology. [Table: see text]

Safety and Efficacy of Mycophenolate Mofetil Associated With Tacrolimus for Kidney-pancreas and Kidney Transplantation: A Systematic Review and Meta-Analysis of Randomized Studies

Cost-Effectiveness Analysis of Pharmacological Treatment for Adult Kidney Transplant Recipients in Colombia

Eustachian tube balloon dilatation (ETBD) has shown promising results in the treatment of ET dysfunction (ETD); however, recurrent symptoms after ETBD frequently occur in patients with refractory ETD. The excessive pressure of balloon catheter during ETBD may induce the tissue hyperplasia and fibrotic changes around the injured mucosa. Sirolimus (SRL), an antiproliferative agent, inhibits tissue proliferation. An SRL-coated balloon catheter was fabricated using an ultrasonic spray coating technique with a coating solution composed of SRL, purified shellac, and vitamin E. This study aimed to investigate effectiveness of ETBD with a SRL-coated balloon catheter to prevent tissue proliferation in the rat ET after ETBD. In 21 Sprague–Dawley rats, the left ET was randomly divided into the control (drug-free ETBD; n = 9) and the SRL (n = 9) groups. All rats were sacrificed for histological examination immediately after and at 1 and 4 weeks after ETBD. Three rats were used to represent the normal ET. The SRL-coated ETBD significantly suppressed tissue proliferation caused by mechanical injuries compared with the control group. ETBD with SRL-coated balloon catheter was effective and safe to maintain ET luminal patency without tissue proliferation at the site of mechanical injuries for 4 weeks in a rat ET model.

Infectious complications, including widespread human cytomegalovirus (CMV) disease, frequently occur after hematopoietic stem cell and solid organ transplantation due to immunosuppressive treatment causing impairment of T-cell immunity. Therefore, in-depth analysis of the impact of immunosuppressants on antiviral T cells is needed. We analyzed the impact of mTOR inhibitors sirolimus (SIR/S) and everolimus (EVR/E), calcineurin inhibitor tacrolimus (TAC/T), purine synthesis inhibitor mycophenolic acid (MPA/M), glucocorticoid prednisolone (PRE/P) and common double (T+S/E/M/P) and triple (T+S/E/M+P) combinations on antiviral T-cell functionality. T-cell activation and effector molecule production upon antigenic stimulation was impaired in presence of T+P and triple combinations. SIR, EVR and MPA exclusively inhibited T-cell proliferation, TAC inhibited activation and cytokine production and PRE inhibited various aspects of T-cell functionality including cytotoxicity. This was reflected in an in vitro infection model, where elimination of CMV-infected human fibroblasts by CMV-specific T cells was reduced in presence of PRE and all triple combinations. CMV-specific memory T cells were inhibited by TAC and PRE, which was also reflected with double (T+P) and triple combinations. EBV- and SARS-CoV-2-specific T cells were similarly affected. These results highlight the need to optimize immune monitoring to identify patients who may benefit from individually tailored immunosuppression.

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