Age-Related Brain Atrophy and the Positive Effects of Behavioral Enrichment in Middle-Aged Beagles.

Aging dogs serve as a valuable preclinical model for Alzheimer's disease (AD) due to their natural age-related development of ß-amyloid (Aß) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that the frontal lobe showed accelerated atrophy with age, while the caudate nucleus remained relatively stable. Remarkably, the hippocampus increased in volume in all dogs. None of these changes were influenced by tacrolimus or Q134R treatment. Our results suggest that behavioral enrichment can prevent atrophy and increase the volume of the hippocampus but does not prevent aging-associated prefrontal cortex atrophy.

Tacrolimus Personalized Therapy based on CYP3A5 Genotype in Chinese Patients with Idiopathic Inflammatory Myopathies.

OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous and life-threatening group of diseases, especially anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+ DM) is reportedly strongly associated with high mortality rate. Tacrolimus (TAC) provides an excellent therapeutic option, but the trough concentration (Cmin) -outcome relationship remains unexplored. This study was undertaken to identify optimal Cmin and individualized dose based on CYP3A5 genotype for IIM patients. METHODS: 134 IIM patients with 467 Cmin were enrolled. We examined the relationship between TAC Cmin and relapses. The receiver operating characteristic analysis was used to confirm the optimal Cmin. Analyses of factors influencing Cmin were conducted. The dose requirement based on CYP3A5 genotype was confirmed. RESULTS: TAC Cmin is strongly associated with relapses. The optimal cutoff values were 5.30, 5.85, 4.85 and 5.35 ng/ml for acute, subacute, chronic and all phase IIM patients (p = 0.001, 0.013, 0.002, and < 0.001, respectively), as well as 5.35, 5.85, 5.55 and 5.85 ng/ml for acute, subacute, chronic and all phase MDA5+ DM patients (p = 0.007, 0.001, 0.036, and < 0.001, respectively). CYP3A5 genotype was one of the significant factors influencing TAC Cmin. CYP3A5 expressers required 0.059 mg/kg/d to attain the target Cmin, while nonexpressers required 0.046 mg/kg/d (p = 0.019). CONCLUSION: TAC treatment may elicit favorable outcome in patients with IIM and MDA5+ DM when Cmin exceeded 5.35 and 5.85 ng/ml, which is crucial to lower relapse rate. The individualized dose based on the CYP3A5 genotype provides a reference for TAC personalized therapy in IIM.

Anti-inflammatory and antioxidative actions of tacrolimus (FK506) on human microglial HMC3 cell line.

Microglial cells are indispensable for the normal development and functioning of neurons in the central nervous system, where they play a crucial role in maintaining brain homeostasis by surveilling the microenvironment for signs of injury or stress and responding accordingly. However, in neurodegenerative diseases, the density and phenotypes of microglial cells undergo changes, leading to chronic activation and inflammation. Shifting the focus from neurons to microglia in drug discovery for neurodegenerative diseases has become an important therapeutic target. This study was aimed to investigate the potential of Tacrolimus (FK506) an FDA-approved calcineurin inhibitor, to modulate the pathology of neurodegenerative diseases through anti-inflammatory and antioxidative effects on microglial activation. The human microglia clone 3 (HMC3) cells were exposed to 1 µg/mL LPS in the presence and absence of doses of FK506. Survival rates of cells were determined using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) method. Morphological evaluation of cells showed that FK506 restored the normal morphology of activated microglia. Furthermore, FK506 treatment increases the total antioxidant capacity and reduces the total oxidative capacity, indicating its potential antioxidant effects. Data from ELISA and RT-PCR analyses showed that LPS abolished its promoting effects on the release of proinflammatory IL-1ß and IL-6 cytokines in HMC3 cells, reflecting the anti-inflammatory effect of FK506. These findings support the idea that FK506 could be a promising therapeutic agent for neurodegenerative diseases by modulating microglial activation and reducing inflammation and oxidative stress.

Clinical effects of tacrolimus blood concentrations early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. METHODS: We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. RESULTS: Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (P = 0.03) and lower nonrelapse mortality (P = 0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (P = 0.04) and high (P < 0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (P = 0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (P = 0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (P = 0.05) and significantly lower (P = 0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (P = 0.03 and P < 0.01, respectively), not treated with anti-thymocyte globulin (P = 0.02 and P = 0.02, respectively), and receiving three stMTX doses (P = 0.03 and P = 0.02, respectively). CONCLUSIONS: The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.

Glycyrrhizic acid improves tacrolimus-induced renal injury by regulating autophagy.

Tacrolimus (TAC)-induced renal injury is detrimental to long-term kidney function, but a treatment medication is not available. Glycyrrhizic acid (GA) is an active ingredient in licorice widely used to treat kidney disease. Thus, this study explored the mechanisms of renoprotection by GA on TAC-induced renal injury. C57BL/6 mice were subjected daily to TAC or a combination of TAC and GA for 4 weeks, and then renal function, histopathology, and autophagy were assessed to examine the effect of GA on a renal injury. Next, Human kidney proximal tubular epithelial (HK-2) cells were pretreated with GA for 2 h and then treated with TAC for 24 h. The effect of GA on TAC-induced HK-2 cell injury was assessed by measuring cell viability, apoptosis, autophagy, and lysosomes. Mice exposed to TAC and treated with GA had significantly greater improvements in renal function and tubulointerstitial fibrosis in comparison to mice not treated with GA. In addition, fibrosis-related protein expression, including α-smooth muscle actin and fibronectin, decreased after GA treatment. GA treatment also relieved autophagic clearance in TAC-induced renal injury. Several in vitro studies found that TAC inhibited cell viability, autophagy, lysosomal acidification, and promoted apoptosis. However, these results were less pronounced with GA pretreatment. In addition, bafilomycin A1 (which inhibits lysosomal function) reduced the protective effect of GA, indicating that lysosomal function plays an important role in this effect. Our data suggest that GA improves lysosomal function and regulates autophagy to protect against TAC-induced renal injury.

Membranous nephropathy treatment standard.

Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN has evolved, with the identification of specific autoantibodies against novel podocyte antigens and the unraveling of intricate pathogenic pathways. Although the anti-CD20 monoclonal antibody rituximab is favored as part of the initial therapy in MN, a subgroup of MN patients may be resistant to rituximab necessitating the use of alternative agents such as cytotoxic therapies. In addition, newer agents such as novel anti-CD20 monoclonal antibodies, therapies targeting the CD38-positive plasma cells and anti-complement therapy are being studied in patients who are resistant to traditional treatment strategies. This manuscript furnishes a review of the novel developments in the pathophysiology of MN including the identification of target antigens and current treatment standards for MN, concentrating on evidenced-based interventions designed to attain remission and to prevent disease progression.

Comparison of efficacy of continuous mycophenolate mofetil with sequential cyclophosphamide and tacrolimus as maintenance therapy for lupus nephritis.

OBJECTIVES: To evaluate the renal response to mycophenolate mofetil (MMF) as maintenance therapy for lupus nephritis (LN) in Japanese patients, we compared the efficacy of MMF and the sequential use of monthly intravenous cyclophosphamide (IVCY) followed by tacrolimus (TAC). METHODS: We examined 14 patients with LN who were treated with continuous MMF as induction and maintenance therapies (MMF group) and 10 patients with LN who received monthly IVCY as induction therapy followed by maintenance therapy with TAC (IVCY-TAC group). We assessed the therapeutic effects of each treatment regimen on renal manifestations and serological findings over a 36-month period after treatment initiation. RESULTS: Mean urine protein-to-creatinine ratios in the MMF and IVCY-TAC groups significantly decreased from 2.75 to 0.11 g/gCr and from 3.26 to 0.22 g/gCr, respectively. Significant improvements in serum immunological variables (serum complement C3 or C4 levels and the anti-double-stranded DNA antibody titer) and reductions in the SLE disease activity index and daily prednisolone dosages were observed in both groups during induction therapy and were maintained during maintenance therapy. Efficacy was similar between the MMF and IVCY-TAC groups. CONCLUSION: MMF has potential as an effective treatment for renal manifestations in Japanese patients throughout induction and maintenance therapies for LN, as an alternative to conventional IVCY-TAC therapy, and as a glucocorticoid-sparing agent.

Long-term renal and cardiovascular risks of tacrolimus in patients with lupus nephritis.

BACKGROUND AND HYPOTHESIS: Despite continuous advancement, treatment of lupus nephritis (LN) remains challenging. Recent guidelines now include a regimen incorporating tacrolimus as a first-line treatment option. Even though tacrolimus is effective in combination with mycophenolate and corticosteroids, concerns remain regarding long-term use, given its association with increased cardiovascular risks including nephrotoxicity, hypertension, dyslipidemia and hyperglycemia in kidney transplant recipients. However, in LN, long-term evaluations and head-to-head comparisons are lacking and thus the safety profile remains ill-defined. We hypothesized that chronic toxicity also occurs in LN patients. Therefore, this study aimed to assess long-term cardiovascular and renal outcomes of tacrolimus in LN patients. METHODS: This observational cohort study examined adult LN patients treated with tacrolimus, assessing renal outcomes, hypertension, diabetes, dyslipidemia, cardiovascular events and the Framingham risk score. The results were compared to a control group of CNI-naïve LN patients. RESULTS: Of the 219 LN patients in this study, 43 (19.6%) had tacrolimus exposure. Over a median follow-up of 7.1 years, tacrolimus use was associated with significant kidney function decline (6.8 ml/min/1.73m2, versus 0.8 in the control group). The incidence of end-stage kidney disease was similar. Cardiovascular event incidence was equally low in both groups. The 10-year risk of coronary heart disease was lower in the tacrolimus group, primarily due to age differences. HbA1c levels were higher in the tacrolimus group (37.4 mmol/mol) than in controls (33.6 mmol/mol), although the incidence of diabetes was similar. There were no differences in the occurrence of hypertension or dyslipidemia. CONCLUSIONS: Our study demonstrated that tacrolimus exposure was associated with long-term kidney function loss in LN patients. Although cardiovascular risk factors and events were similar to patients never exposed to tacrolimus, there may be an increased risk of developing diabetes. Therefore, our study supports vigilance towards renal adverse effects in LN patients treated with tacrolimus.

The effects of nirmatrelvir/ritonavir on tacrolimus levels in lung transplant recipients: A single-center study.

BACKGROUND: Lung transplant recipients (LTRs) have a higher risk of hospitalization and mortality due to COVID-19 compared with the immunocompetent population. The use of nirmatrelvir/ritonavir (NR), an effective oral treatment for COVID-19, is quite challenging due to its potent drug-drug interactions with immunosuppressants and azole antifungals. As there are few clinical reports of the use of NR in LTRs, we measured tacrolimus levels in patients receiving NR in our hospital to improve safety when prescribing NR. METHODS: In total, 48 adult LTRs who received NR between November 19, 2022, and January 19, 2023, at China-Japan Friendship Hospital were retrospectively included and followed for 20 days after initiating NR. Tacrolimus was held at least 12 h before initiating NR and re-administered based on the trough levels after completing NR treatment. All concomitant medications, drug concentrations, laboratory results, and genotypes were recorded and analyzed. RESULTS: Most patients showed stable tacrolimus trough levels despite high individual variability. Four patients exhibited supratherapeutic trough levels of tacrolimus (more than 15 ng/mL). Two patients who received 0.5 mg of tacrolimus during NR treatment had trough levels below 3.0 ng/mL. In addition, we found that in 13 patients, the trough levels were 130% of baseline after cessation of tacrolimus, and logistic regression revealed that increased trough level was significantly associated with age more than 60 years. CONCLUSIONS: NR can be safely used in LTRs with close monitoring of tacrolimus levels and appropriate dose adjustments. However, more attention should be paid to elderly patients, as NR may more severely affect their drug metabolism. Due to the limited sample size, further studies are needed to guide the optimal use of tacrolimus following treatment with NR and explore the risk factors significantly affecting the interactions between NR and tacrolimus.

Development of a predictive model for nephrotoxicity during tacrolimus treatment using machine learning methods.

AIM: When administering tacrolimus, therapeutic drug monitoring is recommended because nephrotoxicity, an adverse event, occurs at supra-therapeutic whole-blood concentrations of tacrolimus. However, some patients exhibit nephrotoxicity even at the recommended concentrations, therefore establishing a therapeutic range of tacrolimus concentration for the individual patient is necessary to avoid nephrotoxicity. This study aimed to develop a model for individualized prediction of nephrotoxicity in patients administered tacrolimus. METHODS: We collected data, such as laboratory test data at tacrolimus initiation, concomitant drugs and tacrolimus whole-blood concentration, from medical records of patients who received oral tacrolimus. Nephrotoxicity was defined as an increase in serum creatinine levels within 60 days of tacrolimus initiation. We built 13 prediction models based on different machine learning algorithms: logistic regression, support vector machine, gradient-boosting trees, random forest and neural networks. The best performing model was compared with the conventional model, which classifies patients according to the tacrolimus concentration alone. RESULTS: Data from 163 and 41 patients were used to construct models and evaluate the best performing one, respectively. Most of the patients were diagnosed with inflammatory or autoimmune diseases. The best performing model was built using a support vector machine; it showed a high F2 score of 0.750 and outperformed the conventional model (0.500). CONCLUSIONS: A machine learning model to predict nephrotoxicity in patients during tacrolimus treatment was developed using tacrolimus whole-blood concentration and other patient data. This model could potentially assist in identifying high-risk patients who require individualized target therapeutic concentrations of tacrolimus prior to treatment initiation to prevent nephrotoxicity.

Population pharmacokinetic models of tacrolimus in paediatric solid organ transplant recipients: A systematic review.

AIMS: This study aimed to provide up-to-date information on paediatric population pharmacokinetic models of tacrolimus and to identify factors influencing tacrolimus pharmacokinetic variability. METHODS: Systematic searches in the Web of Science, PubMed, Scopus, Science Direct, Cochrane, EMBASE databases and reference lists of articles were conducted from inception to March 2023. All population pharmacokinetic studies of tacrolimus using nonlinear mixed-effect modelling in paediatric solid organ transplant patients were included. RESULTS: Of the 21 studies reviewed, 62% developed from liver transplant recipients and 33% from kidney transplant recipients. Most studies used a 1-compartment model to describe tacrolimus pharmacokinetics. Body weight was a significant predictor for tacrolimus volume of distribution (Vd/F). The estimated Vd/F for 1-compartment models ranged from 20 to 1890 L, whereas the peripheral volume of distribution (Vp/F) for 2-compartment models was between 290 and 1520 L. Body weight, days post-transplant, CYP3A5 genotype or haematocrit were frequently reported as significant predictors of tacrolimus clearance. The estimated apparent clearance values range between 0.12 and 2.18 L/h/kg, with inter-individual variability from 13.5 to 110.0%. Only 29% of the studies assessed the generalizability of the models with external validation. CONCLUSION: This review highlights the potential factors, modelling approaches and validation methods that impact tacrolimus pharmacokinetics in a paediatric population. The clinician could predict tacrolimus clearance based on body weight, CYP3A5 genotype, days post-transplant or haematocrit. Further research is required to determine the relationship between pharmacogenetics and tacrolimus pharmacodynamics in paediatric patients and confirm the applicability of nonlinear kinetics in this population.

Therapeutic drug monitoring of tacrolimus after kidney transplantation: trough concentration or area under curve-based monitoring?

Measurement of pre-dose tacrolimus concentrations, also referred to as trough concentrations or C0 (in this paper the term C0 will be used), is the most frequently used parameter for therapeutic drug monitoring in patients after solid organ transplantation. C0 is relatively easy to obtain, and can be combined with other lab tests. C0 monitoring is convenient for patient and hospital staff. Adjusting the dose based on C0 assumes that the C0 has a good correlation with the overall exposure to the drug, as reflected in the area under concentration-time curve (AUC). However, C0 may not be the panacea it is suggested to be, and there are patients who may benefit from additional measurements to more precisely assess drug exposure. Especially in patients with a low C0/dose ratio, the peak tacrolimus concentrations after oral administration may be unexpectedly high, resulting in toxicity and (as has been shown already) in poor long-term graft survival. At the other extreme, patients who only need a very low dose to reach target C0 may have a low peak and also a low AUC and may be underexposed. In this paper, the limitations of C0 will be discussed, and the type of studies needed to provide the evidence for implementation of more sophisticated therapeutic drug monitoring. The paper focuses on treatment of adult kidney transplant recipients.

Removing the physician from the equation: Patient-controlled, home-based therapeutic drug self-monitoring of tacrolimus.

The dosing of tacrolimus, which forms the backbone of immunosuppressive therapy after kidney transplantation, is complex. This is due to its variable pharmacokinetics (both between and within individual patients), narrow therapeutic index, and the severe consequences of over- and underexposure, which may cause toxicity and rejection, respectively. Tacrolimus is, therefore, routinely dosed by means of therapeutic drug monitoring (TDM). TDM is performed for as long as the transplant functions and frequent and often lifelong sampling is therefore the rule. This puts a significant burden on patients and transplant professionals and is associated with high healthcare-associated costs. Furthermore, by its very nature, TDM is reactive and has no predictive power. Finally, the current practice of TDM does not foresee in an active role for patients themselves. Rather, the physician or pharmacist prescribes the next tacrolimus dose after obtaining the concentration measurement test results. In this article, we propose a strategy of patient-controlled, home-based, self-TDM of the immunosuppressant tacrolimus after transplantation. We argue that with the combined use of population tacrolimus pharmacokinetic models, home-based sampling by means of dried blood spotting and implementation of telemedicine, this may become a feasible approach in the near future.

Steroid-tacrolimus drug-drug interaction and the effect of CYP3A genotypes.

AIMS: Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug-drug interactions (DDI). Steroids induce CYP3A genes to increase tacrolimus clearance, but the effect is variable. We hypothesized that the extent of the steroid-tacrolimus DDI differs by CYP3A4/5 genotypes. METHODS: Kidney transplant recipients (n = 2462) were classified by the number of loss of function alleles (LOF) (CYP3A5*3, *6 and *7 and CYP3A4*22) and steroid use at each tacrolimus trough in the first 6 months post-transplant. A population pharmacokinetic analysis was performed by nonlinear mixed-effect modelling (NONMEM) and stepwise covariate modelling to define significant covariates affecting tacrolimus clearance. A stochastic simulation was performed and translated into a Shiny application with the mrgsolve and Shiny packages in R. RESULTS: Steroids were associated with modestly higher (3%-11.8%) tacrolimus clearance. Patients with 0-LOF alleles receiving steroids showed the greatest increase (11.8%) in clearance compared to no steroids, whereas those with 2-LOFs had a negligible increase (2.6%) in the presence of steroids. Steroid use increased tacrolimus clearance by 5% and 10.3% in patients with 1-LOF and 3/4-LOFs, respectively. CONCLUSIONS: Steroids increase the clearance of tacrolimus but vary slightly by CYP3A genotype. This is important in individuals of African ancestry who are more likely to carry no LOF alleles, may more commonly receive steroid treatment, and will need higher tacrolimus doses.

Risk factors for renal dysfunction after isolated intestinal transplantation.

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. Independent variables included age, ethnicity, BMI, history of diabetes/hypertension, vasopressor use, TPN and stoma days, urinary or bloodstream infections, intravenous contrast exposure, rejection, concomitant immunosuppression, and time above the therapeutic range of tacrolimus. Variables with a p < .1 in univariate analysis were considered for multivariable modeling. RESULTS: Thirty-three patients were included with a mean age of 43.9 ± 13.0. A mean 42.3% decline in eGFR was observed at 1-year post-transplant, with 15.2% of patients developing new stage 4/5 CKD. Factors associated with a greater decline in adjusted eGFR in the univariate model included increasing age, decreased BMI, stoma days, and vasopressor use. In the adjusted multivariable model patient age (ß = -.77, p < .01) and stoma days (ß = -.06, p < .01) remained significant. Tacrolimus and sirolimus exposure were not associated with decline in eGFR at 1 year. CONCLUSIONS: Renal dysfunction is common following intestinal transplantation. The need for stoma creation should be carefully considered, and reversal should be performed when feasible for renal protection.

Effects of WuZhi preparations on tacrolimus in pediatric and adult patients carrying the CYP3A5*1 allele of heart transplant during the early period after transplantation.

AIM: Wuzhi preparations (WZP) are commonly administrated with tacrolimus (TAC) in China to improve the liver function and increase the exposure of TAC. This study aims to investigate the effects of WZP on TAC in pediatric heart transplantation (HTx) patients carrying the CYP3A5*1 allele during the early period after transplantation and also make a comparison with these effects in adult recipients. METHODS: A total of 81 recipients with CYP3A5*1 allele were included and divided into the pediatric group (n = 29) and adult group (n = 52). The changes in TAC dose-corrected trough blood concentrations (C0 /D), dose requirement as well as intra-patient variability(IPV) of C0 /D after co-therapy with WZP were evaluated. RESULTS: The TAC C0 /D was significantly increased 1.7 and 1.8 times after co-administration of WZP in the pediatric and adult groups, respectively. We further analyzed the pediatric patients, found that no statistical difference was observed in TAC C0 /D before and after co-therapy with WZP in children <6 years old. The changes of C0 /D increased with the dose of the active ingredient (Schisantherin A) in adult patients, but not in pediatric patients. TAC IPV was reduced by 10.5% in pediatric patients and 4.8% in adult patients when co-administrated with WZP. Furthermore, after taking WZP, the AST and TB were dramatically lowered in pediatric recipients. CONCLUSION: Our study is the first attempt to demonstrate the effects of WZP on TAC in pediatric HTx recipients. By comparing these effects to those observed in adult recipients, valuable insights can be gained regarding the efficacy and potential benefits of WZP in the pediatric population.

Immune outcomes of lung transplant recipients with different cytochrome P450 3A5 phenotypes after discontinuation of voriconazole antifungal prophylaxis.

INTRODUCTION: Tacrolimus forms the backbone of immunosuppression regimens in lung transplant recipients (LTRs). It is extensively metabolized by cytochrome P450 (CYP) 3A5 enzymes, of which polymorphisms can significantly affect tacrolimus dose requirements. It is unknown how coadministration of tacrolimus with voriconazole, a potent CYP3A5 inhibitor, affects rejection rates or empiric dose adjustments needed after voriconazole discontinuation. METHODS: This retrospective cohort study compares LTRs with poor (PR) versus intermediate/extensive (IE) CYP3A5 metabolizer phenotypes. The primary endpoint is cumulative immune outcomes within three months of voriconazole discontinuation; secondary endpoints include change in tacrolimus dose-to-concentration ratios after voriconazole discontinuation. RESULTS: Thirty-four patients underwent full analysis: 13 IE and 21 PR metabolizers. A higher proportion of IE metabolizers were African American (46.2% vs. 9.5%, p = .03). There was no significant difference in composite immune outcomes, though there was a proportionally higher frequency of new donor-specific antibody development in PR metabolizers (14.3% vs 7.7%, p = .56). Both groups required approximately 2.5 to 3-fold tacrolimus dose increases post-voriconazole discontinuation to re-attain therapeutic levels. CONCLUSION: This novel investigation sheds light on how CYP3A5 phenotype could be used to guide tacrolimus dosing, with the goal of preventing both toxicity and organ rejection.

Early outcomes associated with de novo once-daily extended-release versus twice-daily immediate-release tacrolimus in a predominantly African American kidney transplant population: A single-center observational study.

INTRODUCTION: The purpose of this study was to compare early outcomes of de novo LCPT (once-daily extended-release tacrolimus) to IR TAC (twice-daily immediate-release tacrolimus) in a predominantly African American (AA) adult kidney transplant population. METHODS: This is a single center, retrospective cohort study. Patients were divided into two cohorts: IR TAC (administered between January 1, 2017, and January 31, 2019) and LCPT (administered between February 1, 2019, and May 31, 2020). Primary endpoints were changes in tacrolimus trough levels (ng/mL) and estimated glomerular filtration rate up to 12 months post-transplantation. Clinical endpoints included graft survival, delayed graft function, biopsy-proven rejection, CMV viremia, and BK. A propensity score weighted generalized linear mixed effects model was used for analysis. RESULTS: The rate of change in tacrolimus levels was significantly higher in the LCPT cohort compared to the IR TAC cohort at 14 days post-discharge (.2455 ng/mL per day vs. .1073 ng/mL, respectively; p < .001). Subsequently, the LCPT cohort had a slightly higher rate of decline (-.015 ng/mL per day vs. -.010 ng/mL with IR TAC; p = .0894) up to 12 months post-discharge. Although eGFR was similar between the two cohorts at 12 months post-transplant, the rate of increase was slower in the LCPT cohort (.1371 mL/min per day vs. .1852 mL/min per day, p = .0314). No significant differences were found in graft survival, DGF, BPAR, CMV, or BK infection. CONCLUSION: This study demonstrates that despite higher early trough levels with immediate post-transplant LCPT use, clinical outcomes are comparable to IR TAC at one-year post-transplant. Notably, LCPT use does not increase the incidence of DGF and that this formulation of CNI can be used as first line therapy post-transplant.

Successful use of tacrolimus for treatment-refractory neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome: A case series.

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is an autoimmune central nervous system disorder, primarily manifesting as a paraneoplastic sequalae to neuroblastoma, and characterized by motor disorders and behavioral disturbances. OMAS is typified by aberrant B-cell and T-cell activation. Current treatment involves immunosuppression using corticosteroids, intravenous immunoglobulin, and rituximab. However, these approaches often lead to treatment-related toxicities and symptomatic recurrences with chronic neurocognitive impairment. We treated three children with refractory neuroblastoma-associated OMAS with tacrolimus, a T-cell-targeting calcineurin inhibitor, effectively controlling symptoms within a month and enabling the discontinuation of immunosuppression with minimal side effects. Tacrolimus shows promise as a therapeutic option for refractory OMAS.

Efficacy and safety of tacrolimus in older adults with ulcerative colitis: a retrospective study.

BACKGROUND/AIMS: The prevalence of ulcerative colitis (UC) has been increasing, also in older adults. Here, we retrospectively compared the efficacy and safety of tacrolimus (TAC) in older and younger patients with UC. METHODS: We included younger (age < 65 years; n = 116) and older patients (age ≥ 65 years; n = 21) with UC who received TAC from April 2009 through December 2022(mean follow-up, 1230 ± 175 days) and achieved remission. Evaluations included age at onset, laboratory values, estimated glomerular filtration rate (eGFR), use of 5-aminosalicylic acid (5-ASA), biological experience, colonoscopy scores, remission at 1 month after treatment initiation, and adverse events. Treatment duration and renal function were assessed in patients with follow-up data (younger patients, n = 110; older patients, n = 19). RESULTS: Older patients had a higher age at onset and treatment initiation but less 5-ASA use and biological experience. Before treatment, hemoglobin, albumin, and eGFR were significantly lower in the older group and CRP was significantly higher. The remission rate was 80.1% in the younger group and 66.6% in the older group (P = 0.1862). Adverse events were similar in both groups. The older group had a shorter treatment duration and significantly less change in renal function at all time points. DISCUSSION: Rates of TAC-induced remission and adverse events were similar in older and younger adults with UC. CONCLUSION: TAC can be used safely in elderly patients with moderate to severe UC with careful monitoring.