A Comprehensive Mixed-Method Approach to Characterize the Source of Diurnal Tacrolimus Exposure Variability in Children: Systematic Review, Meta-analysis, and Application to an Existing Data Set.

Tacrolimus is widely reported to display diurnal variation in pharmacokinetic parameters with twice-daily dosing. However, the contribution of chronopharmacokinetics versus food intake is unclear, with even less evidence in the pediatric population. The objectives of this study were to summarize the existing literature by meta-analysis and evaluate the impact of food composition on 24-hour pharmacokinetics in pediatric kidney transplant recipients. For the meta-analysis, 10 studies involving 253 individuals were included. The pooled effect sizes demonstrated significant differences in area under the concentration-time curve from time 0 to 12 hours (standardized mean difference [SMD], 0.27; 95% confidence interval [CI], 0.03-0.52) and maximum concentration (SMD, 0.75; 95% CI, 0.35-1.15) between morning and evening dose administration. However, there was significant between-study heterogeneity that was explained by food exposure. The effect size for minimum concentration was not significantly different overall (SMD, -0.09; 95% CI, -0.27 to 0.09) or across the food exposure subgroups. A 2-compartment model with a lag time, linear clearance, and first-order absorption best characterized the tacrolimus pharmacokinetics in pediatric participants. As expected, adding the time of administration and food composition covariates reduced the unexplained within-subject variability for the first-order absorption rate constant, but only caloric composition significantly reduced variability for lag time. The available data suggest food intake is the major driver of diurnal variation in tacrolimus exposure, but the associated changes are not reflected by trough concentrations alone.

Predictive Capacity of Population Pharmacokinetic Models for the Tacrolimus Dose Requirements of Pediatric Solid Organ Transplant Recipients.

BACKGROUND: Transplant recipients require individualized tacrolimus doses to maximize graft survival. Multiple pediatric tacrolimus population pharmacokinetic (PopPK) models incorporating CYP3A5 genotype and other covariates have been developed. Identifying the optimal popPK model is necessary for clinical implementation in pediatric solid organ transplant. The primary objective was to compare the dose prediction capabilities of the developed models in pediatric kidney and heart transplant recipients. METHODS: Pediatric kidney or heart transplant recipients treated with tacrolimus and available CYP3A5 genotype data were identified. The initial weight-based tacrolimus dose and first therapeutic tacrolimus dose were collected retrospectively. Three published popPK models were used to predict the tacrolimus dose required to achieve a tacrolimus trough concentration of 10 ng/mL. Model dose predictions were compared with the initial and first therapeutic doses using Friedman test. The first therapeutic dose was plotted against the model-predicted dose. RESULTS: The median initial dose approximately 2-fold lower than the first therapeutic dose for CYP3A5 expressers. The Chen et al model provided the closest estimates to the first therapeutic dose for kidney transplant recipients; however, all 3 models tended to underpredict the observed therapeutic dose. For heart transplant recipients, Andrews et al model predicted doses that were higher than the initial dose but similar to the actual therapeutic dose. CONCLUSIONS: Weight-based tacrolimus dosing appears to underestimate the tacrolimus dose requirements. The development of a separate popPK model is necessary for heart transplant recipients. A genotype-guided strategy based on the Chen et al model provided the best estimates for doses in kidney transplant recipients and should be prospectively evaluated.

Sweet and simple as syrup: A review and guidance for use of novel antihyperglycemic agents for post-transplant diabetes mellitus and type 2 diabetes mellitus after kidney transplantation.

Uncontrolled type 2 diabetes mellitus (T2DM) and post-transplant diabetes mellitus (PTDM) increase morbidity and mortality after kidney transplantation. Conventional strategies for diabetes management in this population include metformin, sulfonylureas, meglitinides and insulin. Limitations with these agents, as well as promising new antihyperglycemic agents, create a need and opportunity to explore additional options for transplant diabetes pharmacotherapy. Novel agents including sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1RA), and dipeptidyl peptidase IV inhibitors (DPP4i) demonstrate great promise for T2DM management in the non-transplant population. Moreover, many of these agents possess renoprotective, cardiovascular, and/or weight loss benefits in addition to improved glucose control while having reduced risk of hypoglycemia compared with certain other conventional agents. This comprehensive review examines available literature evaluating the use of novel antihyperglycemic agents in kidney transplant recipients (KTR) with T2DM or PTDM. Formal grading of recommendations assessment, development, and evaluation (GRADE) system recommendations are provided to guide incorporation of these agents into post-transplant care. Available literature was evaluated to address the clinical questions of which agents provide greatest short- and long-term benefits, timing of novel antihyperglycemic therapy initiation after transplant, monitoring parameters for these antihyperglycemic agents, and concomitant antihyperglycemic agent and immunosuppression regimen management. Current experience with novel antihyperglycemic agents is primarily limited to single-center retrospective studies and case series. With ongoing use and increasing comfort, further and more robust research promises greater understanding of the role of these agents and place in therapy for kidney transplant recipients.

Evaluation of a Standardized Tacrolimus Therapeutic Drug Monitoring Protocol in Stable Kidney Transplant Recipients.

Introduction: Transplant nurse coordinators have assisted in accurately adjusting tacrolimus doses under a collaborative practice agreement for kidney transplant recipients in the early post-operative period. This study evaluated the efficiency of a standardized tacrolimus therapeutic drug monitoring (TDM) protocol in stable outpatient recipients. Design: We conducted a single-center, retrospective study of adult patients who received a kidney transplant at least 3 years ago and were taking immediate-release tacrolimus. Before September 2019, transplant coordinators consulted transplant providers for management of all tacrolimus trough levels (Pre-Arm). Under the standardized protocol, coordinators directly responded to out-of-range tacrolimus trough levels (Post-Arm). The primary outcome was the time to intervention for out-of-range levels. Secondary outcomes included adverse events, time in therapeutic range, coefficient of variation (CV), and protocol compliance. Results: Of 1712 levels (from 174 patients), 259 levels (15.1%) were out-of-range. The overall time to intervention was 13.2 hours shorter (95% CI: -26.4 to -0.1 hours; P = 0.048) in the Post-Arm. There was no rejection, graft loss, or death during the study period. The time in therapeutic range was 89.3% (17.6%) vs 89% (19.4%; P = 0.816) and CV was 19.7% (15.8%) vs 18.4 (10.7%; P = 0.358) in the Pre-Arm and Post-Arm, respectively. Within the Post-Arm, the protocol required coordinators to independently intervene on 96 out-of-range levels (65.8%), which were accurately addressed 57.5% of the time. Conclusion: Implementation of a standardized TDM protocol improved efficiency without compromising major clinical outcomes or intrapatient variability (IPV) of tacrolimus levels for stable kidney recipients in the outpatient setting.

The use of non-transplant biologics in solid organ transplant recipients: A practical review for the frontline clinician.

Biologics have become the forefront of medicine for management of autoimmune conditions, leading to improved quality of life. Many autoimmune conditions occur in solid organ transplant (SOT) recipients and persist following transplant. However, the use of biologics in this patient population is not well studied, and questions arise related to risk of infection and adjustments to induction and maintenance immunosuppression. Guidelines have been published highlighting management strategies of biologics around the time of elective surgical procedures, but this is not always feasible in urgent situations, especially with deceased donor transplantation. The aim of this review is to summarize the current literature regarding the use of these agents in solid organ transplant recipients, and specifically address induction and maintenance immunosuppression, as well as the need for alternative infective prevention strategies to create a practical reference for the frontline clinician, when faced with this complex clinical scenario.

Evaluating pharmacokinetic drug-drug interactions of direct oral anticoagulants in patients with renal dysfunction.

INTRODUCTION: Drug transporters, metabolic enzymes, and renal clearance play significant roles in the pharmacokinetics of direct oral anticoagulants (DOACs). Recommendations for DOAC drug-drug interactions (DDIs) by the product labeling are limited to selected CYP3A4 and P-glycoprotein inhibitors and lack considerations for concomitant renal dysfunction. AREAS COVERED: This review focuses on: 1) current recommendations for the management of pharmacokinetic DOAC DDIs and the evidence used to support them; 2) alterations in DOAC exposure in the setting of concomitant DDIs and mild, moderate, and severe renal impairment; 3) clinical outcomes associated with this combination; and 4) expert recommendations for the management of pharmacokinetic DOAC DDIs. English-language, full-text articles on apixaban, dabigatran, rivaroxaban, and edoxaban with a publication date up to 30 September 2021 were retrieved from PubMed. EXPERT OPINION: Given the lack of supporting clinical data, empiric dose adjustments based on pharmacokinetic data alone should be avoided. When a considerable increase in a DOAC exposure is anticipated, it may be advisable to use an alternative DOAC or anticoagulant from a different class. Future research on identification of DOAC therapeutic ranges and target patient populations is needed to inform clinical utility of DOAC level monitoring to guide the management of DDIs.

A multicenter evaluation of hepatitis B reactivation with and without antiviral prophylaxis after kidney transplantation.

BACKGROUND: Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (anti-HBc)-positive kidney transplant recipients ranges between 1.4% and 9.6%. Limited evidence is available regarding routine antiviral prophylaxis and identifiable risk factors for HBV reactivation in this population. METHODS: In this multicenter retrospective study, we evaluated the prevalence of HBV reactivation in HBsAg-negative anti-HBc-positive kidney transplant recipients who did or did not receive antiviral prophylaxis. The primary outcome assessed the prevalence of HBV reactivation, defined as a positive HBV DNA by PCR of any viral load at or above the minimal detection level. The principal safety outcomes assessed 1-year graft survival, 1-year all-cause mortality, biopsy-proven acute rejection, and antibody-mediated rejection. RESULTS: One hundred and sixty-one patients met inclusion criteria and comprised two groups, antiviral prophylaxis (n = 14) and no antiviral prophylaxis (n = 147). Of patients who did not receive prophylaxis, only five (3.4%) experienced HBV reactivation, whereas one (7.1%) patient in the prophylaxis group experienced reactivation over a median follow-up of 1103 days (p = .43). Furthermore, there were no differences with respect to all secondary outcomes. Statistical analysis demonstrated delayed graft function to be a significant factor associated with HBV reactivation. CONCLUSION: These study results suggest that the prevalence of HBV reactivation in HBsAg-negative anti-HBc-positive kidney transplant recipients is low, regardless of antiviral prophylaxis. Furthermore, there were no significant graft-related outcomes among those that did experience reactivation.

Tacrolimus time in therapeutic range and long-term outcomes in heart transplant recipients.

STUDY OBJECTIVE: Little is known about the association between tacrolimus time in therapeutic range (TTR) within the guideline-recommended targets and heart transplant (HT) patient outcomes. This study evaluated the association of early tacrolimus TTR with rejection and other clinical outcomes during an extended follow-up after HT. DESIGN: This was a single-center retrospective cohort study. SETTING: The study was conducted at Michigan Medicine (1/1/2006-12/31/2017). PATIENTS: HT recipients ≥18 years of age were included. MEASUREMENT: The primary end point was the effect of tacrolimus TTR on time to rejection over the entire follow-up period. MAIN RESULTS: A total of 137 patients were included with a median follow-up of 53 months. Based on the median TTR of 58%, the patients were divided into the low tacrolimus TTR (n = 68) and high tacrolimus TTR (n = 69) cohort. The high tacrolimus TTR was associated with a significantly lower risk of rejection compared to the low tacrolimus TTR cohort (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.41-0.98; p = 0.04). A post hoc analysis revealed associations between rejection and TTR when high and low TTR groups were created at different levels. TTR <30% was associated with a 7-fold higher risk of rejection (HR 7.56; 95% CI 1.76-37.6; p < 0.01) and TTR >75% was associated with a 77% lower risk of rejection (HR 0.23; 95% CI 0.08-0.627; p < 0.01). CONCLUSIONS: Patients in the higher tacrolimus TTR cohort had a lower risk of rejection. We observed correlations between higher risk of rejection with TTR <30% and lower risk of rejection with TTR >75%. Future studies should focus on validating the optimal TTR cutoff while also exploring a cutoff to delineate high-risk patients for which early interventions to improve tacrolimus TTR may be beneficial.

SLCO1B3 polymorphisms and clinical outcomes in kidney transplant recipients receiving mycophenolate.

Aim: Determine the influence of SLCO1B3 polymorphisms on outcomes in kidney transplant recipients. Materials & methods: We retrospectively evaluated 181 adult kidney transplant recipients receiving mycophenolate. Outcomes included treated biopsy-proven acute rejection (tBPAR), de novo donor-specific antibody (dnDSA) formation, graft survival, patient survival and mycophenolate-related adverse effects among SLCO1B3 genotypes. Results: The presence of SLCO1B3 variants was not associated with increased risk of tBPAR (HR: 1.45, 95% CI: 0.76-2.74), dnDSA (HR: 0.46, 95% CI: 0.16-1.36) or composite of tBPAR or dnDSA (HR: 1.14, 95% CI: 0.64-2.03). Graft and patient survival were reduced among variant carriers; however, inconsistent findings with the primary analysis suggest these associations were not due to genotype. Adverse effects were similar between groups. Conclusion: Presence of SLCO1B3 polymorphisms were not predictive of rejection or dnDSA in kidney transplant recipients.

Comparison of standard versus low-dose valganciclovir regimens for cytomegalovirus prophylaxis in high-risk liver transplant recipients.

PURPOSE: The purpose of this study was to compare the safety and efficacy of two valganciclovir (VGCV) institutional dosing protocols for cytomegalovirus (CMV) prophylaxis in liver transplant (LT) recipients with CMV serotype donor +/recipient- (D+/R-). METHODS: This was a single-center review of CMV D+/R- adult LT recipients who received VGCV 450 mg/day for 90 days (low-dose) or VGCV 900 mg/day for 180 days (standard-dose). The primary outcome was incidence of CMV disease at 1 year. Secondary outcomes included rates of CMV syndrome, end-organ disease, breakthrough infection, and resistance. Neutropenia, early discontinuation of VGCV, growth colony stimulating factors use (G-CSF), biopsy-proven rejection (BPAR), graft loss, and death at 1 year were analyzed. RESULTS: Ninety-six CMV D+/R- LT recipients were included. Although no difference in CMV disease was observed (low-dose 26% vs. standard-dose 23%, p = 0.71), 75% of CMV infections in the low-dose group presented with end-organ disease. Ganciclovir (GCV) resistance was observed only in the low-dose group (n = 2). Significantly more patients in the standard-dose group developed neutropenia (low-dose 10% vs 60% standard-dose, p < 0.001). In the standard-dose group, 29% required early discontinuation of VGCV (vs. 5% in the low-dose group, p < 0.001), and 20% were treated with G-CSF. Both cohorts had similar rates of BPAR, graft loss, and death at 1 year. CONCLUSIONS: VGCV 900 mg/day for 180 days had higher rates of hematologic adverse effects resulting in frequent treatment interruptions. However, the occurrence of two cases of GCV-resistant CMV disease raises concerns about routinely using low-dose VGCV prophylaxis.

Entrustable professional activities for pharmacy students: A primer for solid organ transplant preceptors.

DISCLAIMER: In an effort to expedite the publication of articles , AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: The role of a solid organ transplant pharmacist is multifaceted and translates to diverse experiential and elective learning experiences that can be provided to pharmacy learners. Here we provide a guide to integrating pharmacy students into patient care and other pharmacist activities in solid organ transplantation. SUMMARY: Thoughtful incorporation of learners into clinical practice and clinical research creates a positive learning environment for pharmacy students that can foster the development of core skills necessary for students to become "practice-ready" and "team-ready" pharmacy graduates and can equip them with valuable skills to incorporate into the specialty practice areas and careers they pursue. To help develop these educational experiences, attention to the list of core entrustable professional activities (EPAs) established by the American Association of Colleges of Pharmacy can help create a rich environment of learning with carefully cultivated tasks. Furthermore, learners can serve as transplant pharmacist extenders to assist in overall patient care and multidisciplinary involvement on the transplant team. This article serves as a "how-to" guide for applying the EPA framework to integrating pharmacy students in patient care and other pharmacist activities in solid organ transplantation and other specialty practice areas. CONCLUSION: As pharmacy preceptors design and operationalize their teaching to incorporate EPAs, they can benefit from recommendations tailored to specialty practice areas such as solid organ transplantation. Students may start and finish these experiences at different EPA levels, but continuance of training will allow them to achieve the final EPA level across the 6 EPA domains.

Impact of CYP3A5 phenotype on tacrolimus time in therapeutic range and clinical outcomes in pediatric renal and heart transplant recipients.

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 < 35%, 45.5% for expressers/TTR ≥ 35%, 38.1% for nonexpressers/TTR < 35%, and 72.9% for nonexpressers/TTR ≥ 35% (log-rank p = 0.03). A post hoc analysis of EFS identified CYP3A5 expressers had lower EFS compared to nonexpressers in patients with TTR ≥ 35% (p = 0.04) but no difference among patients with TTR < 35% (p = 0.6). CONCLUSIONS: The relationship between TTR and CYP3A5 phenotype suggests that achieving a TTR ≥ 35% during the first year may be a modifiable factor to attenuate the risk of BPAR and dnDSA.

A call for transplant stewardship: The need for expanded evidence-based evaluation of induction and biologic-based cost-saving strategies in kidney transplantation and beyond.

Rising expenditures threaten healthcare sustainability. While transplant programs are typically considered profitable, transplant medications are expensive and frequently targeted for cost savings. This review aims to summarize available literature supporting cost-containment strategies used in solid organ transplant. Despite widespread use of these tactics, we found the available evidence to be fairly low quality. Strategies mainly focus on induction, particularly rabbit antithymocyte globulin (rATG), given its significant cost and the lack of consensus surrounding dosing. While there is higher-quality evidence for high single-dose rATG, and dose-rounding protocols to reduce waste are likely low risk, more aggressive strategies, such as dosing rATG by CD3+ target-attainment or on ideal-body-weight, have less robust support and did not always attain similar efficacy outcomes. Extrapolation of induction dosing strategies to rejection treatment is not supported by any currently available literature. Cost-saving strategies for supportive therapies, such as IVIG and rituximab also have minimal literature support. Deferral of high-cost agents to the outpatient arena is associated with minimal risk and increases reimbursement, although may increase complexity and cost-burden for patients and infusion centers. The available evidence highlights the need for evaluation of unique patient-specific clinical scenarios and optimization of therapies, rather than simple blanket application of cost-saving initiatives in the transplant population.

Evaluating the Impact of CYP3A5 Genotype on Post-Transplant Healthcare Resource Utilization in Pediatric Renal and Heart Transplant Recipients Receiving Tacrolimus.

PURPOSE: CYP3A5 genotype is a significant contributor to inter-individual tacrolimus exposure and may impact the time required to achieve therapeutic concentrations and number of tacrolimus dose adjustments in transplant patients. Increased modifications to tacrolimus therapy may indicate a higher burden on healthcare resources. The purpose of this study was to evaluate whether CYP3A5 genotype was predictive of healthcare resource utilization in pediatric renal and heart transplant recipients. PATIENTS AND METHODS: Patients <18 years of age with a renal or heart transplant between 6/1/2014-12/31/2018 and tacrolimus-based immunosuppression were included. Secondary use samples were obtained for CYP3A5 genotyping. Clinical data was retrospectively collected from the electronic medical record. Healthcare resource utilization measures included the number of dose changes, number of tacrolimus concentrations, length of stay, number of clinical encounters, and total charges within the first year post-transplant. Rejection and donor-specific antibody (DSA) formation within the first year were also collected. The impact of CYP3A5 genotype was evaluated via univariate analysis for the first year and multivariable analysis at 30, 90, 180, 270, and 365 days post-transplant. RESULTS: Eighty-five subjects were included, 48 renal transplant recipients and 37 heart transplant recipients. CYP3A5 genotype was not associated with any outcomes in renal transplant, however, a CYP3A5 expresser phenotype was a predictor of more dose changes, more tacrolimus concentrations, longer length of stay, and higher total charges in heart transplant recipients. CYP3A5 genotype was not associated with rejection or DSA formation. Age and induction therapy were associated with higher total charges. CONCLUSION: CYP3A5 genotype may predict healthcare resource utilization in the first year post-transplant, although this may be mitigated by differences in tacrolimus management. Future studies should evaluate the impact of genotype-guided dosing strategies for tacrolimus on healthcare utilization resources.

Oropharyngeal candidiasis outcomes in renal transplant recipients receiving nystatin versus no antifungal prophylaxis.

OBJECTIVE: To compare the incidence of oropharyngeal candidiasis (OC), or thrush, in renal transplant recipients receiving nystatin versus no antifungal prophylaxis. METHODS: This was a single-center, retrospective, non-inferiority study of adult renal transplant recipients (RTRs) who received nystatin for 30 days for OC prophylaxis (nystatin group) or no antifungal prophylaxis therapy (No PPX group). The primary outcome was the incidence of OC within 3 months post-transplant. Secondary outcomes included time to OC occurrence and severity of OC. The pre-specified non-inferiority margin was 10%. RESULTS: The incidence of OC within 3 months post-transplant among 257 RTRs was 7.8% (10/128) in the No PPX group and 4.7% (6/129) RTRs in the nystatin group, a risk difference of 3.2% (95% CI, -2.7% to 9.1%, non-inferiority P = .04). The median time to OC was 7.5 days (IQR 6.3-34.3 days) in the nystatin group and 9.5 days (IQR 5.3-30.5 days) in the No PPX group (P = .64). Esophageal candidiasis was observed in 10% (1/10) of RTRs with OC in the No PPX group compared to 16.7% (1/6) RTRs in the nystatin group (P = 1.00). All RTRs with OC achieved symptom resolution with fluconazole and/or nystatin. Two patients in the No PPX group required readmission for decreased oral intake, and OC was diagnosed and treated during their hospital day. CONCLUSIONS: In this retrospective study of adult RTRs, the absence of antifungal prophylaxis demonstrated non-inferiority to 30-day nystatin prophylaxis at reducing the incidence of OC within 3 months of transplant. OC prophylaxis may not be warranted after renal transplant.

Increasing net immunosuppression after BK polyoma virus infection.

BACKGROUND: Reducing immunosuppression can effectively treat BK viremia (BKV) and BK nephropathy, but has been associated with increased risks for acute rejection and development of donor-specific antibodies (DSA). To date there have been no systematic evaluations of re-escalating immunosuppression in transplant patients with resolving BKV. Importantly, the safety of this approach and impact on graft survival is unclear. METHODS: We performed a single-center retrospective review of kidney transplant recipients between July 2011 and June 2013 who had immunosuppression reduction after developing BKV (plasma PCR ≥ 1000 copies/ml). Changes in immunosuppression and patient outcomes were tracked until occurrence of a complication event: biopsy-proven acute rejection (BPAR), detection of de novo DSA, or recurrent BKV. Patients were grouped according to whether or not net immunosuppression was eventually increased. RESULTS: Out of 88 patients with BKV, 44 (50%) had net immunosuppression increased while the other 44 did not. Duration of viremia, peak viremia, induction, and sensitization status were similar between the two groups. In a Kaplan-Meier analysis, increasing immunosuppression was associated with less BPAR (P = .001) and a trend toward less de novo DSA development (P = .06). Death-censored graft survival (P = .27) was not different between the two groups. In the net immunosuppression increase group, recurrent BKV occurred in 22.7% without any BKV-related graft losses. CONCLUSION: These findings support potential benefits of increasing immunosuppression in patients with low-level or resolved BKV, but prospective trials are needed to better understand such an approach.

The Clinical Conundrum of Cannabis: Current Practices and Recommendations for Transplant Clinicians: An Opinion of the Immunology/Transplantation PRN of the American College of Clinical Pharmacy.

Cannabis, or marijuana, comprises many compounds with varying effects. It has become a treatment option for chronic diseases and debilitating symptoms, and evidence suggests that it has immunomodulatory and antiinflammatory properties. Transplant centers are more frequently facing issues about cannabis, as indications and legalization expand. As of February 2020, 33 states and the District of Columbia have legalized medical cannabis, and 14 have legalized recreational cannabis. Moreover, 8 states have passed legislation prohibiting the denial of transplant listing solely based on cannabis use. Studies demonstrate the potential for significant pharmacokinetic and pharmacodynamic interactions between cannabis and immunosuppression. Additionally, safety concerns include increased risk of myocardial infarction, ischemic stroke, tachyarrhythmias, malignancy, neurocognitive deficits, psychosis, other neuropsychiatric disorders, cannabis use disorder, respiratory symptoms, and infection. A recent retrospective database study found a negative association between documented cannabis use disorder and graft survival, but little additional evidence exists evaluating this relationship. In the absence of robust clinical data, transplant centers need a clear, reasoned, and systematic approach to cannabis. The results of our national survey, unfortunately, found little consensus among institutions. As both recreational and medicinal cannabis become more ubiquitous nationwide, transplant centers will need to develop comprehensive policies to address its use.

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective.

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.

Use of direct-acting oral anticoagulants in solid organ transplantation: A systematic review.

The use of direct-acting oral anticoagulants (DOACs) has increased secondary to the mounting evidence for comparable efficacy and potentially superior safety to vitamin K antagonists (VKAs) in the general population. However, insufficient data regarding DOAC use in solid organ transplant (SOT) recipients and numerous pharmacokinetic and pharmacodynamic considerations limit their use in this highly selected patient population. A systematic review of recent clinical evidence on the safety and efficacy of DOACs compared to VKAs in SOT recipients was conducted. Additional considerations including transplant-specific strategies for DOAC reversal and common pharmacokinetic/pharmacodynamic concerns were also reviewed. Although current evidence is limited to single-center retrospective analyses, DOACs, especially apixaban, appear to be a safe and effective alternative to VKAs for SOT recipients with stable graft function and without drug-drug interactions. Reliable data on DOAC reversal at the time of transplant surgery are lacking, and clinicians should consider idarucizumab, andexanet alfa, and other non-specific reversal agents on an individual patient basis. There is no evidence supporting deviations from the Food and Drug Administration labeling recommendations for DOAC dosing in the setting of drug-drug interactions, obesity, and renal function, especially in patients on hemodialysis.

Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply.

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.