tacrolimus and sirolimus

Individual sirolimus whole blood concentrations are highly variable, critically influenced by the concomitant use of cytochrome P450 (CYP) 3A inducers or inhibitors, and also modulated by food. Therapeutic drug monitoring is therefore recommended, especially at treatment start or in circumstances that can influence sirolimus exposure. In this case report, we highlight the challenge of achieving therapeutic sirolimus concentrations and present pragmatic solutions with regimen adaptions, pharmacokinetic enhancement (use of a drug-drug interaction), concentration monitoring, and subsequent modeling of population pharmacokinetics to support treatment decisions...

Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 mono-maintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex-mismatched allogeneic LT...

Renal transplant patients receive several immunosuppressive drug regimens that are potentially nephrotoxic for treatment. Serum creatinine is the standard for monitoring kidney function; however, cystatin C (Cys C) and kidney injury molecule-1 (KIM-1) have been found to indicate kidney injury earlier than serum creatinine and provide a better reflection of kidney function. Here, we assessed Cys C and KIM-1 serum levels in renal transplant patients receiving mycophenolate mofetil, tacrolimus, sirolimus, everolimus, or cyclosporine to evaluate kidney function...

BACKGROUND: Preclinical evidence suggests calcineurin inhibitors (CNIs) combat α-synuclein-induced neuronal dysfunction and motor impairments. However, whether CNIs prevent or treat Parkinson's disease (PD) in humans has never been investigated. OBJECTIVE: We seek to ascertain if prescription of CNIs is linked to a decreased prevalence of PD in a varied patient population and to glimpse into the mechanism(s) and target site through which CNIs might decrease PD prevalence...

Human adenovirus (HAdV) and cytomegalovirus (HCMV) are cause of high morbidity and mortality in patients receiving solid organ (SOT) and hematopoietic stem cell transplantations (HSCT). Immunosuppressors are universally used to prevent graft-versus-host disease (GVHD) in HSCT and graft rejection in SOT. The long-term use of these drugs is associated with a high risk of infections, but there are also evidences of their specific interference with virus infection. The antiviral activity of immunosuppressors commonly used in the clinical practice in SOT and HSCT recipients has been evaluated in vitro to determine whether their use could be associated with less risk of HAdV and HCMV infection...

The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug-microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools...

PURPOSE: To compare the safety and efficacy of a 100 microgram subconjunctival injection of liposome-encapsulated sirolimus (SCJS) to cyclosporine (CsA) or tacrolimus (CsA/T) for the treatment of keratoconjunctivitis sicca (KCS) in dogs. METHODS: Dogs with signs and symptoms of KCS were block-randomized to one of two treatment groups: Biweekly SCJS or conventional treatment (CsA/T). Schirmer tear test 1 (STT-1) scores, conjunctival hyperemia (CH) scores, corneal opacity (CO) scores, and clinical evaluation of potential side effects were recorded every 2 weeks for 14 weeks for both groups...

BACKGROUND: An erroneously high tacrolimus level was reported to a clinician. A root cause analysis investigation failed to determine the cause of the error. It was suspected that the incorrect preanalytical extraction reagent and procedure was used during testing; however, how this would affect the assayed drug concentration was unclear. Here we investigated the effect of the substitution of sirolimus, tacrolimus, and cyclosporine extraction reagents on assayed drug concentration. METHODS: Tacrolimus, sirolimus, and cyclosporine concentration were measured on the Abbott Architect i2000 analyzer...

INTRODUCTION: Kidney dysfunction is a known complication of intestinal transplantation; however, the rate of development and risk factors for chronic kidney disease (CKD) remain poorly defined. METHODS: This was a single-center retrospective review of isolated adult intestinal allograft recipients from 2011 to 2019. Patients who died or experienced graft loss within 1-year or had a prior transplant were excluded. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation at 0-, 6- and 12-months post-transplant, and multivariable linear regression was performed to identify variables associated with adjusted eGFR at 1-year...

BACKGROUND: Cardiac allograft vasculopathy (CAV) is one of the major late causes of mortality in cardiac transplant recipients beyond the first year. Given the lack of longer term data for PCI in cardiac transplant recipients, we report ten year follow up of such cardiac transplant recipients who underwent PCI at Mayo Clinic. METHODS: A retropecitve observational study was conducted that included cardiac transplant recipients who underwent PCI at the Mayo Clinic...

BACKGROUND: Exosomes are 30-150 nm nanovesicles with sophisticated nucleic acids cargo, actively secreted by all cells within human body, and found in abundance in all body fluids, including urine. These extracellular vesicles have tremendous potential for next generation diagnostics, theoretically enabling noninvasive assessment of organ and tissue function via liquid biopsy analysis. AIM: Recently, feasibility of an exosomal molecular test was demonstrated for post-organ transplant monitoring: Analysis of urine-derived exosomal mRNA cargo allowed early detection of kidney allograft rejection...

Solid organ transplant recipients face an increased risk of dyslipidemia, which contributes to cardiovascular complications. Commonly used drugs such as ciclosporin and tacrolimus can aggravate and cause dyslipidemia. Immunosuppressive drugs particularly ciclosporin and tacrolimus are also known to worsendyslipidemia in transplant recipients. Mammalian target of rapamycin (mTOR) inhibitors like sirolimus and everolimus also alter lipid metabolism. Lifestyle and dietary modifications should be encouraged. Careful consideration of immunosuppressant choices is also vital to control dyslipidemia...

BACKGROUND: The treatment of tacrolimus-induced post-transplantation diabetes mellitus (PTDM) has become a hot topic to improve the long-term survival of organ transplant patients, however whose pathogenesis has not been fully elucidated. In pancreas, the up-regulation of NF-κB has been reported to stimulate cytokine IL-1β/TNF-α secretion, inducing pancreatic injury, meanwhile other studies have reported the inhibitory effect of rapamycin on NF-κB. PURPOSE: The aim of this study was to clarify the mechanism of tacrolimus-induced pancreatic injury and to explore the potential effect from small dose of sirolimus...

BACKGROUND: Natural killer (NK) cells are enriched in the liver and are the main regulators in liver transplantation regarding rejection or tolerance, viral infection, or tumor recurrence. Immunosuppression consists of a triple drug standard regimen comprising tacrolimus (TAC) and corticosteroids (CS) with either mycophenolate mofetil (MMF) or sirolimus (SIR)/everolimus (EVE). The aim of this study was to evaluate the impact of trough levels of these regimens under clinical conditions and exposure on human NK-cell activity and function in order to better understand the antiviral and anti-tumor effects of mammalian target of rapamycin inhibitor (mTORI)...

INTRODUCTION: Many challenges remain for long-term survival of renal allografts. Once-daily sirolimus (SRL) combined with low-dose extended-release tacrolimus (LER-TAC) may improve medication adherence and reduce the potential nephrotoxicity of calcineurin inhibitors (CNI) compared with standard immunosuppression regimens, thus potentially improving long-term graft survival. METHODS: This retrospective, observational, single-center, propensity score matching (PSM) study compared conversion to SRL combined with low-dose ER-TAC and mycophenolic acid (MPA) combined with standard-dose TAC in kidney transplant recipients...

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for many malignant and non-malignant hematologic disorders. Chronic graft-versus-host (cGVHD) disease remains a significant hurdle for long-term survival in patients post allo-HCT, and it remains the leading cause of late non-relapse mortality. The risk factors for development of cGVHD include degree of human leukocyte antigen (HLA) disparity, increasing recipient age, use of peripheral blood stem cells as a source, myeloablative conditioning regimens, prior acute GVHD (aGVHD), and female donor to male recipient...

The triazole antifungal isavuconazole (ISAVU) is used for prevention and treatment of fungal infections in solid organ transplant (SOT). SOT recipients commonly need to transition from one azole to another due to breakthrough infection, toxicity, or other reasons. The purpose of our study was to evaluate the effect of ISAVU on immunosuppressant concentrations in thoracic transplant recipients when ISAVU was started de novo or transitioned from another azole. We conducted a single-center retrospective cohort study including 68 patients (51 lung, 14 heart, and 3 heart/lung transplant)...

Cyclosporine A, everolimus, sirolimus, and tacrolimus are the most commonly used immunosuppressant drugs in organ transplant and auto-immune patients. The narrow therapeutic window of these immunosuppressant drugs requires close monitoring of drug blood levels to ensure proper therapeutic response. A quick, robust high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was introduced for monitoring whole blood levels of these immunosuppressant drugs with the use of the MassTrak™ Immunosuppressant kit...

INTRODUCTION: Islet transplantation (ITx) shows promise in treating T1D, but the role of islet autoantibodies on graft survival has not been clearly elucidated. We aimed to analyze the effect of GAD65 and IA2 autoantibody status on graft survival and attainment of insulin independence in subjects with T1D who underwent ITx. METHOD: We conducted a retrospective cohort study on 47 ITx recipients from 2000 to 2018. Islet infusion was performed via intrahepatic portal (n=44) or onto the omentum via laparoscopic approach (n=3)...

BACKGROUND: The impact of different immunosuppression regimes on the health-related quality of life (HRQoL) and the severity of fatigue in liver transplant recipients is largely unknown. We investigated the impact of a sirolimus-based regimen compared with a tacrolimus (TAC)-based regimen on the HRQoL and the severity of fatigue. METHODS: In this multicenter, open-label, randomized, controlled trial, 196 patients were randomized 90 d after transplantation to (1) once daily normal-dose TAC or (2) once daily combination therapy of low-dose sirolimus and TAC...