Variability In Tacrolimus Trough Levels Research Articles

Butyryl chitosan: Synthesis, characterization and evaluation of the sustained release performance as tacrolimus carrier

Chitosan and its water-soluble derivatives have been widely used in biomaterials, but their disadvantages have hindered their widespread application. In this study, butyryl chitosan, a liposoluble chitosan derivative, was prepared by introducing butyryl groups into chitosan molecules through an acylation reaction. The synthesis conditions were optimised, the reaction was more efficient and simpler than previously reported strategies. Two butyryl chitosan with degrees of substitution greater than two were synthesised. Chemical characterisations confirmed that the hydroxyl and primary amine groups in the backbone of chitosan were converted into amide and ester groups, respectively. The butyryl chitosan films have advantages such as high mechanical properties, long biodegradation time, proper surface charge, good cytocompatibility, and histocompatibility. Butyryl chitosan was used as carrier to prepare an implantable tacrolimus sustained release film. Characterization results showed that tacrolimus existed in an amorphous state in the release film. This work embodies an innovative formulation using tacrolimus-loaded carboxymethyl chitosan amorphous solid dispersions embedded butyryl chitosan film with added advantage of sustained release, an effective blood concentration in vivo for 11 days and a systemic exposure but lower intrapatient variability in tacrolimus trough levels. This work merits sustainable tacrolimus release use by providing application-based proofs and qualifies as a potential formulation for sustainable tacrolimus release system. We expect an improvement in terms of therapeutic compliance with positive effects on allograft outcomes.

High Intrapatient Variability in Tacrolimus Exposure Calculated Over a Long Period Is Associated With De Novo Donor-Specific Antibody Development and/or Late Rejection in Thai Kidney Transplant Patients Receiving Concomitant CYP3A4/5 Inhibitors.

High intrapatient variability in tacrolimus trough levels (Tac IPV) is associated with poor allograft outcomes. Tac IPV was previously calculated using trough levels 6-12 months after kidney transplantation (KT). Data on the accuracy of Tac IPV calculation over a longer period, the association between high Tac IPV and donor-specific antibody (DSA) development after KT in Asian patients, and the role of IPV in patients receiving concomitant cytochrome P450 (CYP)3A4/5 inhibitors (CYPinh) are limited. A retrospective review of patients who underwent KT at our center in 2005-2015, and who received Tac with mycophenolate during the first 2 years after KT was performed. IPV was calculated using Tac levels adjusted by dosage. DSA was monitored annually after KT using a Luminex microbead assay. In total, 236 patients were enrolled. CYPinh were prescribed to 189 patients (80.1%): 145 (61.4%), 31 (13.1%), and 13 (5.5%) received diltiazem, fluconazole, and ketoconazole, respectively. Mean IPV calculated from adjusted Tac levels for 6-12 months (IPV6-12) and 6-24 months (IPV6-24) after KT were 20.64% ± 11.68% and 23.53% ± 10.39%, respectively. Twenty-six patients (11%) showed late rejection and/or DSA occurrence, and had significantly higher IPV6-24 (29.42% ± 13.78%) than others (22.77% ± 9.64%; P = 0.02). There was no difference in IPV6-12 (24.31% ± 14.98% versus 20.17% ± 10.90%; P = 0.18). IPV6-12 and IPV6-24 were comparable in patients who did and did not receive CYPinh. When using mean IPV6-24 as a cutoff, patients with higher IPV6-24 had a higher probability of developing DSA and/or late rejection (P = 0.048). Tac IPV6-24 was higher and more significantly associated with DSA development and/or late rejection than Tac IPV6-12, independent of Tac trough level. This is the first study to demonstrate the impact of high IPV on DSA development in Asian patients, and that Tac IPV is comparable between patients with and without CYPinh.

The Impact of Intrapatient Tacrolimus Trough Level Variability over 2 Years Post Transplant on the Long-Term Allograft Outcomes in Kidney Transplant Recipients

The Impact of Intrapatient Tacrolimus Trough Level Variability over 2 Years Post Transplant on the Long-Term Allograft Outcomes in Kidney Transplant Recipients

Accuracy and concordance of measurement methods to assess non-adherence after renal transplantation - a prospective study

BackgroundNon-adherence (NA) to immunosuppressants (IS) among renal transplant recipients (RTRs) is associated with higher risk of allograft rejection, graft loss, and mortality. A precise measurement of NA is indispensable, although its prevalence differs greatly depending on the respective measurement methods. The objective of this study was to assess the accuracy and concordance of different measurement methods of NA in patients after renal transplantation.Design and methodsThis was a single-center prospective observational study. At baseline (T0), NA was measured via physicians’ estimates (PE), self-reports (SR), and tacrolimus trough level variability (CV%) in 78 RTRs. A Visual Analogue Scale (VAS, 0–100%) was applied both for SR and PE. In addition, we used BAASIS© for SR and a 5-point Likert scale for PE. NA was measured prospectively via electronic monitoring (EM, VAICA©) during a three month period. Meanwhile, all participants received phone calls in a two week interval (T1-T6) during which SRs were given.ResultsSeventy-eight RTRs participated in our study. At t0, NA rates of 6.4%, 28.6%, and 15.4% were found for PE, SR, and CV%, respectively. No correlation was found between these methods. During the study, the percentages of self-reported and electronically monitored adherence remained high, with a minimum mean of 91.2% for the strictest adherence measure (Timing Adherence ±30 min). Our results revealed a moderate to high association between SR and EM. In contrast to PE and CV%, SR significantly predicted electronically monitored adherence. Overall, a decreasing effect of electronically monitored adherence was found for both taking and timing adherence (±2 h, ±30 min) over the course of the study.DiscussionThe moderate to high concordance of SR and EM suggests that both methods measure NA equally accurately. SR seems to be a method that can adequately depict electronically monitored NA and may represent a good and economical instrument to assess NA in clinical practice. The increased adherence at the beginning of the study and its subsequent decrease suggests an intervention effect. Surveillance of IS intake via EM with intermittent phone calls could improve adherence on a short-term basis. To establish long-term effects, further research is necessary.

Tacrolimus Trough Variability- Predictors and Outcomes in Pediatric Heart Transplantation

Tacrolimus is a narrow therapeutic index drug, requiring consistent levels to maximize solid organ transplant success while reducing adverse effects. High tacrolimus trough level variability (TTLV) is a significant predictor of late rejection in both kidney and liver transplant. We sought to describe the prevalence of high TTLV in our pediatric heart transplant (HT) population, and identify whether this variability is associated with patient specific factors and poor outcomes. Single center, retrospective study of HT patients from 1/2002 - 12/2018. Multi-organ recipients and retransplants were excluded. Records were reviewed for demographics, tacrolimus trough levels (TTLs) and outcomes (rejection, coronary vasculopathy, need for re-transplantation, death). Variability was calculated as the TTL standard deviation (SD) using each patient's TTLs from 1 year post-HT to last follow-up. High TTLV was defined as SD ≥3. Statistical analysis included Kruskal-Wallis, Chi-squared, and Wilcoxon rank sum testing. A total of 119 patients were included (male, 57%) with pre-HT diagnoses of congenital heart disease (57%) and cardiomyopathy (42%). The median age at HT was 2.7 yrs (IQR 0.8, 12.2) with a follow-up time post HT of 5.7 yrs (IQR 3.3, 9.9). A total of 6,344 TTLs were included, with a median of 33 TTLs/pt (IQR 14, 76). The median SD for the entire cohort was 3.1 (IQR 2.3, 4.0) with 55% of the population having a SD ≥3. Levels obtained from 1-5 yrs of age were found to have significantly greater variability (median SD 3.1 [IQR 2.4, 4.1]; p-value< 0.01) than 6-12 yrs (SD 2.5) and 12+ yrs (SD 2.5). After dichotomizing patients for higher variability (SD ≥ 3), there were no significant associations with patient specific factors including: sex, pre-HT diagnosis, pre-HT clinical course (acute vs chronic), age at HT, time with HT and Hollingshead Socioeconomic Score. High TTLV was associated with increased rejection treatment (74% vs 44%, p<0.01), higher frequency of coronary vasculopathy (23% vs 7%, p=0.02), and death (20% vs 6%, p=0.02). TTLV is high in pediatric HT recipients, especially in those < 5 yrs. Patients with a SD ≥3 experienced a higher frequency of poor outcomes including rejection, coronary vasculopathy and death.

Implementing a Process to Systematically Identify and Address Poor Medication Adherence in Pediatric Liver Transplant Recipients.

Objectives:Poor adherence to medication following pediatric liver transplantation remains a major challenge, with some estimates suggesting that 50% of adolescent liver transplant recipients exhibit reduced medication adherence. To date, no gold standard has emerged to address this challenge; however, system interventions are most likely to be successful. We sought to implement a system to identify and address adherence barriers in a liver transplant clinic.Methods:Using structured quality improvement methods, including multiple plan-do-study-act cycles, we developed a system to screen for patients at risk of poor adherence, identify patient- and/or parent-reported barriers to adherence, and partner with patients to overcome identified barriers. We developed a process to track key outcomes, including the variability in tacrolimus trough levels and episodes of late acute cellular rejection.Results:The practice saw a total of 85 patients over 6 months, and about half were females. Over this period, the improvement team implemented this system-level process with high reliability (>90% of patients received the bundle of interventions). The most commonly identified adherence barrier by patients and caregivers was “forgetting.” The second most commonly identified adherence barrier by patients was that the medication “gets in the way of their activities,” whereas by caregivers, it was “difficulty swallowing pills.”Discussion:We identified challenges and opportunities to screen for poor adherence and identify patient- and/or caregiver-reported barriers to immunosuppression adherence. Identifying such barriers and partnering with patients to overcome those barriers using patient-centered, barrier-specific interventions could improve long-term graft survival through improved medication adherence.

Tacrolimus variability is associated with de novo donor-specific antibody development in pediatric renal transplant recipients.

Donor-specific antibody (DSA) is a risk factor for antibody-mediated rejection and shortened graft survival. We investigated the role of intrapatient variability in tacrolimus trough levels on graft outcomes (i.e., de novo DSA, rejection, graft loss) in pediatric renal transplant recipients. This was a single-center retrospective study which included 38 pediatric renal transplant recipients. Intrapatient tacrolimus variability was defined using the coefficient of variation (CV; SD/Mean × 100) for all levels obtained after 3months post-transplant. CV cut-points of 30%, 40%, and 50% were used in the analyses. The median CV 43.1% (35.0%, 58.6%). Out of 38 patients, 19 (50%) developed de novo DSA. In the logistic regression model, after adjusting for age, rejection history, maintenance immunosuppression, and CV, for every 10% increase in tacrolimus variability, the odds of developing de novo DSA increased by 53% (p = 0.048, CI 1.0005, 1.11). Age at transplant was also an independent risk factor for DSA development; every 1year increase in age was associated with a 31% increase in the odds of developing DSA (p = 0.03, CI 1.03, 1.67). At a CV cut-point ≥ 30%, higher tacrolimus variability was associated with an increased incidence of allograft rejection (0% vs 42%, < 30 and ≥ 30% respectively, p = 0.07). As there were few graft loss events (n = 4) in our study population, an association could not be determined between tacrolimus variability and graft loss. Tacrolimus variability and age at transplant were identified as independent risk factors for de novo DSA development. There was an association between tacrolimus variability and rejection in pediatric renal transplant recipients. Adding the assessment of tacrolimus variability to current monitoring methods may be an important step towards improving graft outcomes.

Identification of Antibiotic Administration as a Potentially Novel Factor Associated With Tacrolimus Trough Variability in Kidney Transplant Recipients: A Preliminary Study.

We conducted a retrospective chart review of subjects who received kidney transplants at our institution from 2012 to 2013 and evaluated subjects who received antibiotics during the first month of transplantation (Abx Group, N = 60) and subjects who did not (No Abx Group, N = 200). We evaluated whether antibiotic administration in the Abx Group had increased tacrolimus trough concentrations and concentration over tacrolimus dosage (C/D) after antibiotic administration. We also evaluated tacrolimus variability as measured by standard deviation (SD) and coefficient of variation between the Abx Group and No Abx Group. In the Abx Group, tacrolimus trough concentration over tacrolimus dosage (C/D) increased 7 and 15 days after antibiotic administration (P = 0.001, P = 0.07, respectively, Wilcoxon signed-rank test). From postoperative day 31-45, the variability in tacrolimus trough levels in the Abx Group as measured by SD and coefficient of variation was significantly higher than the variability in the No Abx Group (P = 0.03, P = 0.02, Wilcoxon rank sum test, respectively). Our identification of antibiotic administration as a potentially new risk factor for tacrolimus trough variability suggests the need to carefully follow tacrolimus trough levels after antibiotic administration.

Late intra-patient tacrolimus trough level variability as a major problem in kidney transplantation: A Collaborative Transplant Study Report.

Intra-patient variability (IPV) of tacrolimus trough level has been associated with poor outcome after kidney transplantation. These findings were derived from single-center analyses and restricted mainly to measurements early after transplantation. We analyzed in a multicenter effort whether high IPV of tacrolimus levels at posttransplant years 1, 2, and 3 was associated with impaired clinical outcome. More than 6600 patients who received a deceased donor kidney transplant during 2000-2014 and had a functioning graft for >3years were studied. Graft survival was significantly impaired with increasing IPV (P<0.001). As compared to patients with a low IPV of <30%, the risk of graft loss during years 4-6 increased 32% in patients with an IPV of 30% to 44% and 66% in patients with an IPV of ≥45% (P=0.002 and P<0.001). About one-third of patients showed an IPV of ≥30% with substantially impaired outcome. Even in patients with good outcome during the first 3 posttransplant years, a high IPV was associated with inferior graft survival. Our data indicate that a fluctuating tacrolimus trough level at years 1, 2, and 3 posttransplant is a major problem in kidney transplantation.

Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation.

High tacrolimus trough drug level variability was found to be associated with reduced graft survival. The primary goal of this study was to find whether reduction of exposure to high tacrolimus trough level variability in patients in which previously had high variability was associated with better graft survival. All tacrolimus drug level values in patients that underwent kidney transplantation at our center between 2006 and 2015 were collected. Exposure to variability was calculated using a time-weighted coefficient of variability (TWCV). Time-dependent univariate and multivariate Cox proportional hazard models were used to analyze the primary outcome of graft survival and to determine a cutoff value for TWCV as a predictor of this outcome. A total of 878 patients were included in the study with a median follow-up of 1263 days. TWCV above 25% was significantly associated with reduced graft survival (HR3.66, 95% CI 2.3-5.8, p < 0.001). Of the 480 patients (54.7%) who had a cumulative TWCV of > 25% at a certain time during the follow-up, 110 (22.9%) later returned to a cumulative TWCV of less than 25%. Reduction of TWCV to values below 25% was associated with a hazard of graft loss that was not different from patients who had cumulative TWCV of less than 25% during the entire follow-up period (HR 1.81, 95% CI 0.71-4.62, p = 0.218 and HR 1.08, 95% CI 0.39-2.99, p = 0.780) in univariate and multivariate analyses, respectively. Monitoring TWCV can help detect the high-risk patients. Interventions intended to reduce variability on long-term graft survival may have a positive effect on graft survival.

High tacrolimus trough level variability is associated with rejections after heart transplant.

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ±3.4 ng/mL vs 12.8 ±2.4 ng/mL, P=.930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P=.04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P=.011). Mortality was associated only with cardiovascular complications (P=.018), with no effect of tacrolimus through level variability.

Sirolimus and tacrolimus coefficient of variation is associated with rejection, donor-specific antibodies, and nonadherence.

Immunosuppression medication nonadherence has been associated with donor-specific antibodies and treatment-refractory rejection. Drug-level monitoring is a practical direct marker for nonadherence, as variations indicate erratic ingestion of medication. We previously reported that high variability in tacrolimus trough levels determined by the percent coefficient of variation (CV%) and standard deviation (SD) were associated with biopsy-proven rejection. We hypothesized that the CV% and SD in patients on a sirolimus/low-dose tacrolimus regimen may associate with self-reported medication nonadherence, rejection and donor-specific antibodies. In this pilot feasibility study, we studied 37 biopsies in 23 pediatric renal transplant patients on both sirolimus and tacrolimus immunosuppression; CV%, SD, de novo donor-specific antibodies, rejection, and self-reported adherence were examined. A cut-off sirolimus CV% of 25 maximized the percentage of biopsies correctly classified as rejection (32 of 37, or 86%, p = 0.001). A cut-off tacrolimus CV% of 31 maximized the percentage of correctly classified biopsies (25 of 37, or 68%, p = 0.09). Among patients with both high sirolimus and tacrolimus CV%, 67% developed de novo donor-specific antibodies (p = 0.002) with a DQ predominance and 71% reported nonadherence (p = 0.05). In pediatric renal transplantation, sirolimus and tacrolimus CV% is a potential tool for monitoring patients at risk for allograft rejection and donor-specific antibodies secondary to medication nonadherence.

Tacrolimus trough-level variability predicts long-term allograft survival following kidney transplantation.

The purpose of this study is to investigate tacrolimus trough-level variability from 3 to 12 months following transplantation and its association with allograft survival in renal transplant recipients. In this observational cohort study, tacrolimus trough-level variability was used as the predictor of all-cause allograft failure (defined as return to dialysis) and patient survival (all-cause mortality). In total, 394 transplants were included in the analysis. Sixty-two transplants failed during the study. Tacrolimus trough-level variability across quartile groups were: Q1 median variability 12.5 %, range 4.76-15.71 % (n = 99), Q2 median variability 18.17 %, range 15.74-21.29 % (n = 96), Q3 median variability 24.63 % range 21.42-28.88 % (n = 100), Q4 median variability 36.91 %, range 28.91-81.9 % (n = 99). Higher tacrolimus trough-level variability was associated with inferior allograft survival in univariate models [hazard ratio per quartile increase (HR), 1.46, 95 % CI 1.16-1.83, p value = 0.001] and multivariate models (HR 1.36, 95 % CI 1.05-1.78, p value = 0.019). Higher tacrolimus trough-level variability was not associated with patient survival; univariate model (HR 1.25, 95 % CI 0.90-1.74, p value = 0.17), multivariate model (HR 1.25, 95 % CI 0.86-1.83, p value = 0.23). Inferior renal allograft survival was observed in recipients with higher variability in tacrolimus trough-levels.