Search

Background: Volumetric absorptive microsampling may reduce the blood collection burden associated with therapeutic drug monitoring of immunosuppression to prevent organ transplant rejection. This work describes the development of a laboratory and analytical technique for quantifying tacrolimus and mycophenolic acid (MPA) from the Tasso-M20™ in human whole blood using bead-based impact-assisted extraction. Results: The sampled blood volume was accurate with estimated volumes within

STUDY OBJECTIVE This study investigated the effect of CYP3A5 phenotype on time in therapeutic range (TTR) of tacrolimus post-transplant in pediatric patients. DESIGN AND DATA SOURCE This retrospective study assessed medical records of pediatric kidney and heart recipients with available CYP3A5 genotype for tacrolimus dosing, troughs, and the clinical events (biopsy-proven acute rejection [BPAR] and de novo donor-specific antibodies [dnDSA]). MEASUREMENTS AND MAIN RESULTS The primary outcome, mean TTR in the first 90 days post-transplant, was 9.0% (95% CI: -16.1, -1.9) lower in CYP3A5 expressers (p = 0.014) when adjusting for time to therapeutic concentration and organ type. There was no difference between CYP3A5 phenotypes in time to the first clinical event using TTR during the first 90 days. When applying TTR over the first year, there was a significant difference in event-free survival (EFS) which was 50.0% for CYP3A5 expressers/TTR

BACKGROUND Currently, there is limited literature evaluating rATG induction dosing and incidence of opportunistic viral infections when using steroid-free maintenance immunosuppression. METHODS This single-center, retrospective, study compared high rATG (>4.5 mg/kg) versus low (

Objective: The objective was to evaluate statin utilization in the United States before and after the 2015 ADA position statement, which expanded statin therapy recommendations to include all adults 40-75 years old with diabetes. Research Design and Methods: The National Health and Nutrition Examination Survey was used to obtain a representative sample. The difference-in-differences technique determined the impact of the recommendation on the proportion of people with diabetes for whom statin therapy was newly recommended. Results: Among people with diabetes, the change in statin utilization in people without ASCVD risk factors controlling for change among people with ASCVD/risk factors was 6.6% (p=0.388). In the adjusted analysis, overt ASCVD, age, Black race, health insurance, a place for routine care, and total cholesterol were significantly associated with statin utilization (p Conclusion: The most recent change in statin recommendations had minimal impact on the proportion of patients receiving a statin.

Calcineurin inhibitors, the primary immunosuppressive therapy used to prevent alloreactivity of transplanted organs, have a narrow therapeutic index. Currently, treatment is individualized based on clinical assessment of the risk of rejection or toxicity guided by trough concentration monitoring. Advances in immune monitoring have identified potential markers that may have value in understanding calcineurin inhibitor pharmacodynamics. Integration of these markers has the potential to complement therapeutic drug monitoring. Existing pharmacokinetic–pharmacodynamic (PK–PD) data is largely limited to correlation between the biomarker and trough concentrations at single time points. Immune related gene expression currently has the most evidence supporting PK–PD integration. Novel biomarker-based approaches to pharmacodynamic monitoring including development of enhanced PK–PD models are proposed to realize the full clinical benefit.

Background Tacrolimus therapy in solid organ transplant (SOT) recipients is challenging due to its narrow therapeutic window and pharmacokinetic variability both between patients and within a single patient. Intrapatient variability (IPV) of tacrolimus trough concentrations has become a novel marker of interest for predicting transplant outcomes. The purpose of this review is to evaluate the association of tacrolimus IPV with graft and patient outcomes and identify interventions to improve IPV in SOT recipients. Methods A systematic review of the literature was performed using PubMed and Embase from database inception to September 20, 2020. Studies were eligible only if they evaluated an association between tacrolimus IPV and transplant outcomes. Both pediatric and adult studies were included. Measures of variability were limited to standard deviation, coefficient of variation, and time in therapeutic range. Results Forty-four studies met the inclusion criteria. Studies were published between 2008 and 2020 and were observational in nature. Majority of data were published in adult kidney transplant recipients and identified an association with rejection, de novo donor specific antibody (dnDSA) formation, graft loss, and patient survival. Evaluation of IPV-directed interventions was limited to small preliminary studies. Conclusions High tacrolimus IPV has been associated with poor outcomes including acute rejection, dnDSA formation, graft loss, and patient mortality in SOT recipients. Future research should prospectively explore IPV-directed interventions to improve transplant outcomes.

OBJECTIVE To evaluate statin use in the U.S. before and after the 2015 American Diabetes Association position statement, which expanded statin therapy recommendations to include all adults 40–75 years old with diabetes. RESEARCH DESIGN AND METHODS The National Health and Nutrition Examination Survey (NHANES) was used to obtain a representative sample. The difference-in-differences technique determined the impact of the recommendation on the proportion of people with diabetes for whom statin therapy was newly recommended. RESULTS Among people with diabetes, the change in statin use in people without atherosclerotic cardiovascular disease (ASCVD) risk factors, controlling for change among people with ASCVD/risk factors, was 6.6% (P = 0.388). In the adjusted analysis, overt ASCVD, age, Black race, health insurance, a place for routine care, and total cholesterol were significantly associated with statin use (P < 0.05). CONCLUSIONS The most recent change in statin recommendations had minimal impact on the proportion of patients receiving a statin.

Reduction in donor-specific antibody (DSA) has been associated with improved renal allograft survival after antibody-mediated rejection (AMR). These observations have not been separately analyzed for early and late AMR and mixed acute rejection (MAR). The purpose of this study was to evaluate long-term responses to proteasome inhibitor-based therapy for 4 rejection phenotypes and to determine factors that predict allograft survival.Retrospective cohort study evaluating renal transplant recipients with first AMR episodes treated with proteasome inhibitor-based therapy from January 2005 to July 2015.A total of 108 patients were included in the analysis. Immunodominant DSA reduction at 14 days differed significantly (early AMR 79.6%, early MAR 54.7%, late AMR 23.4%, late MAR 21.1%, P0.001). Death-censored graft survival (DCGS) differed at 3 years postrejection (early AMR 88.3% versus early MAR 77.8% versus late AMR 56.7% versus late MAR 54.9%, P = 0.02). Multivariate analysis revealed that immunodominant DSA reduction50% at 14 days was associated with improved DCGS (odds ratio, 0.12, 95% CI, 0.02-0.52, P = 0.01).In summary, significant differences exist across rejection phenotypes with respect to histological and DSA responses. The data suggest that DSA reduction may be associated with improved DCGS in both early and late AMR.

Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug-drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3-fold increase in dose-normalized tacrolimus concentrations while receiving 2000-2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA-approved CBD product. Larger studies are needed to better understand the impact of this drug-drug interaction in solid organ transplant recipients.

The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1-week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one-way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86 hours. The median CV for the entire population was 15.2% (range 4.8%-110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals.

Starting in 2015, the American Society of Transplantation Psychosocial Community of Practice, with representatives of the Transplant Pharmacy Community of Practice, convened a taskforce to develop a white paper that focused on clinically practical, evidenced-based interventions that transplant centers could implement to increase adherence to medication and behavioral recommendations in adult solid organ transplant recipients. The group focused on what centers could do in their daily routines to implement best practices to increase adherence in adult transplant recipients. We developed a list of strategies using available resources, clinically feasible methods of screening and tracking adherence, and activities that ultimately empower patients to improve their own self-management. We limited the target population to adults because they predominate the research, and because adherence issues differ in pediatric patients, given the necessary involvement of parents/guardians. We also examined broader multilevel areas for intervention including provider and transplant program practices. Ultimately, the task force aims to foster greater recognition, discussion, and solutions required for implementing practical interventions targeted at improving adherence.

The endeavor to study desensitization in kidney transplantation hasn't been matched by an effort to investigate strategies to prevent sensitization. In this study (NCT02437422), we investigated the safety, impact on sensitization and pharmacokinetics of SANGUINATE (SG), a hemoglobin-based oxygen carrier, as a potential alternative to packed red blood cells (PRBC) in transplant candidates with end-stage renal disease (ESRD). Ten ESRD subjects meeting inclusion/exclusion (I/E) criteria were planned to receive 3 weekly infusions of SG (320mg/Kg). The study was stopped after 5 subjects were enrolled and their data was analyzed after completing a follow up period of 90 days. Two subjects had elevated troponin I levels in setting of SG infusion, one of which was interpreted as a non-ST elevation myocardial infarction. All other adverse events were transient. SG pharmacokinetic analysis showed mean(sd) Cmax, Tmax, AUC and half-life of 4.39(0.69)mg/ml, 2.42(0.91)hours, 171.86(52.35)mg.hour/ml and 40.60(11.96)hours respectively. None of the subjects developed new anti-HLA antibodies following SG infusion and throughout the study period. In conclusion, SG is a potential alternative to PRBCs in ESRD patients considered for kidney transplantation as it was not associated with humoral sensitization. Larger studies in highly sensitized patients are required to further evaluate for potential safety signals. This article is protected by copyright. All rights reserved.

Background Severe obesity has been shown to limit access to renal transplantation in patients with end stage renal disease (ESRD). Laparoscopic sleeve gastrectomy (LSG) has been performed in the ESRD population to assist in achieving waitlist and transplant eligibility. Little is known about how LSG impacts the bioequivalence tacrolimus products and immunosuppression pharmacokinetics. Methods This was a prospective, open-label, single-dose, crossover, two-period pharmacokinetic (PK) study. The purpose of this study was to assess single-dose PK of immediate-release tacrolimus (IR-TAC), extended-release tacrolimus (ER-TAC), and mycophenolic acid (MPA) in adult ESRD patients post-LSG. Results Twenty-three subjects were included in the 24-hour PK assessments. The ratio of geometric means between ER-TAC and IR-TAC was 103.5% (90% CI 89.6 – 119.6%) for AUC0-24 and 92.5% (90% CI 80.4 – 106.4%) for Cmax. PK parameters were similar between ER-TAC and IR-TAC, except for Cmin (p=0.004) and Cmax (p=0.04). MPA AUC0-24 was similar when given with either ER-TAC or IR-TAC (p=0.32). Patients expressing CYP3A5*1 genotypes had lower tacrolimus AUC0-24 values versus those with CYP3A5*3/*3 (IR-TAC p