Tacrolimus Intrapatient Variability Research Articles

Influence of Tacrolimus Intrapatient Variability on Allograft Rejection Frequency and Survival Following Liver Transplantation.

Tacrolimus is the primary calcineurin inhibitor used in immunosuppressive regimens to prevent allograft rejection (AR) after organ transplantation. Recent studies have linked intrapatient variability (IPV) of tacrolimus with AR occurrence and reduced survival, especially in kidney transplant recipients. However, limited data are available on the impact of tacrolimus IPV on adverse outcomes after liver transplantation (LT). The aim of this study was to assess the association between tacrolimus IPV using various methodologies with acute AR and long-term patient survival after LT. All patients who underwent LT from January 2010 to July 2021 were retrospectively evaluated. Tacrolimus IPV was calculated for each patient using the mean and SD, mean absolute deviation (MAD), coefficient of variation (CV), and time in therapeutic range (TTR). These measures were then compared with AR within the first 24 months after LT and to long-term survival. Out of 234 patients, 32 (13.7%) developed AR and 183 (78.2%) survived, with a mean follow-up of 101 ± 43 months. Tacrolimus IPV, assessed by mean, SD, MAD, and CV, was 8.3 ± 2.1, 2.7 ± 1.3, 32.0% ± 11.7%, and 39.4% ± 15.4%, respectively. There was no statistically significant correlation between Tacrolimus IPV and AR or survival post-LT. In a large cohort of patients from diverse racial backgrounds, tacrolimus IPV was not associated with clinically relevant outcomes such as AR and survival after LT.

High intra-patient variability of tacrolimus within post-operative 1month predicted worse 1-year outcomes in pediatric liver transplant recipients.

The pharmacokinetics of tacrolimus (TAC) show high intra-patient variability (IPV), which is associated with poor long-term outcomes following adult liver transplantation(LT). However, this relationship remains to be confirmed in pediatric liver transplant (PLT) recipients. The present study aimed to investigate the association between TAC IPV and grafts or patient outcomes after pediatric liver transplantion. This retrospective study included 848 PLT recipients (including infants) between January, 2016, and June, 2021. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of trough concentrations in whole blood within 1month after transplantation. Patients were categorized into two groups, low IPV (CV < 45%) and high IPV (CV ≥ 45%), based on the third quartile of the CV distribution. A total of 848 patients were included in our study. The low CV group included 614 patients, with a mean TAC trough concentration of 8.59 ± 1.65ng/ml and a median CV of 32.37%. In contrast, the high CV group included 214 patients, the mean TAC trough concentration and median CV were 8.81 ± 2.00ng/ml and 54.88%, respectively. The median hospital duration was significantly higher in the high CV group (22days vs. 20days, P = 0.01). Univariate analysis was performed to evaluate the significant differences in 1-year recipient survival (P = 0.041) and 1-year graft survival (P = 0.005) between the high- and low-CV groups. Moreover, high CV (HR 2.316, 95%CI 1.026-5.231, P = 0.043) and persistent EBV viremia (HR 13.165, 95%CI 3.090-56.081, P < 0.001) were identified as independent risk factors for 1- year mortality after PLT. PLT recipients with high TAC trough concentration of CV in the first month were associated with poor 1-year outcomes. This CV calculation provides a valuable strategy to monitor TAC exposure.

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.

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. 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. 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 <6years 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. 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.

Association of high intra-patient variability in tacrolimus exposure with calcineurin inhibitor nephrotoxicity in kidney transplantation

Tacrolimus intra-patient variability (IPV) is a novel predictive marker for long-term kidney transplantation outcomes. We examined the association between IPV and calcineurin inhibitor (CNI) nephrotoxicity and the impact of pharmacogenes on CNI nephrotoxicity and IPV. Among kidney transplant recipients at our hospital between January 2013 and December 2015, the records of 80 patients who underwent 1-year protocol renal allograft biopsy and agreed to donate blood samples for genetic analysis were retrospectively reviewed. The cohort was divided into the low and high IPV groups based on a coefficient variability cutoff value (26.5%). In multivariate analysis, the IPV group was involved in determining CNI nephrotoxicity (HR 4.55; 95% CI 0.05–0.95; p = 0.043). The 5-year graft survival was superior in the low IPV group than in the high IPV group (100% vs 92.4% respectively, p = 0.044). Analysis of the time above therapeutic range (TATR) showed higher CNI nephrotoxicity in the high IPV with high TATR group than in the low IPV with low TATR group (35.7% versus 6.7%, p = 0.003). Genetic analysis discovered that CYP3A4 polymorphism (rs2837159) was associated with CNI nephrotoxicity (HR 28.23; 95% CI 2.2–355.9; p = 0.01). In conclusion, high IPV and CYP3A4 polymorphisms (rs2837159) are associated with CNI nephrotoxicity.

Impact of tacrolimus intra-patient variability in adverse outcomes after organ transplantation.

Tacrolimus (Tac) is currently the most common calcineurin-inhibitor employed in solid organ transplantation. High intra-patient variability (IPV) of Tac (Tac IPV) has been associated with an increased risk of immune-mediated rejection and poor outcomes after kidney transplantation. Few data are available concerning the impact of high Tac IPV in non-kidney transplants. However, even in kidney transplantation, there is still a controversy whether high Tac IPV is indeed detrimental in respect to graft and/or patient survival. This may be due to different methods employed to evaluate IPV and distinct time frames adopted to assess graft and patient survival in those reports published up to now in the literature. Little is also known about the influence of high Tac IPV in the development of other untoward adverse events, update of the current knowledge regarding the impact of Tac IPV in different outcomes following kidney, liver, heart, lung, and pancreas tran splantation to better evaluate its use in clinical practice.

Clinical association between tacrolimus intra-patient variability and liver transplantation outcomes in patients with and without hepatocellular carcinoma

Clinical association between tacrolimus intra-patient variability and liver transplantation outcomes in patients with and without hepatocellular carcinoma

Intrapatient Variability (IPV) and the Blood Concentration Normalized by the Dose (C/D Ratio) of Tacrolimus-Their Correlations and Effects on Long-Term Renal Allograft Function.

Tacrolimus, in combination with mycophenolate mofetil and glucocorticoids, is the basis of immunosuppressive therapy after renal transplantation. Tacrolimus intrapatient variability (IPV) and the blood concentration normalized by the dose (concentration/dose ratio, C/D ratio) both have an effect on the function of the transplanted kidney. In this study, we examined whether the metabolism rate affected IPV, whether the C/D ratio value was stable in the long-term follow-up, and whether it could be used for IPV measurements. In addition, our study population was examined for the effect of the C/D ratio and IPV on long-term renal function. The C/D ratio and IPV were examined in 170 patients at appointments held at 3, 6, 12 and 24 months after RTx. The average time post renal transplantation was 70 months. Renal function defined as creatinine concentration at the last appointment was examined. Results: the mean C/D ratio in the study group was 1.63. A negative correlation between the C/D ratio and creatinine concentration at the end of the follow-up was observed. Between the C/D ratio &lt; and ≥1.63 groups, significant differences in creatinine concentration at the last appointment were found. No relationship was identified between the mean C/D ratio and IPV. The C/D ratio values increased significantly over a longer post-transplant period (12, 24, 60 and 120 m). We did not find a correlation between the mean IPV and the creatinine concentration from the last appointment. Our study group was divided into terciles according to IPV, while no renal graft function differences were found at the same appointment. Conclusion: the C/D ratio is useful for assessing the effects of the metabolism rate of tacrolimus on the long-term renal graft function. The C/D ratio does not affect the IPV value. IPV calculated from variability of the C/D ratio does not influence transplanted kidney function. The C/D changes over time.

Comparison of Tacrolimus Intra-Patient Variability during 6-12 Months after Kidney Transplantation between CYP3A5 Expressers and Nonexpressers.

A high intra-patient variability (IPV) of tacrolimus exposure is associated with poor long-term kidney transplantation outcomes. To assess the influence of cytochrome P450 (CYP)&amp;nbsp;3A5 genetic polymorphisms on tacrolimus IPV, 188 clinically stable kidney transplant recipients, who had received an immediate-release tacrolimus-based immunosuppressive regimen, were enrolled in this retrospective cohort study. Genotyping of CYP3A5*3 (rs776746) was performed and 110 (58.5%) were identified as CYP3A5 expressers and 78 (41.5%) as nonexpressers. Whole blood tacrolimus concentrations were analyzed by chemiluminescent microparticle immunoassay. Dose-adjusted trough tacrolimus concentrations (C0/D) measured at months 6, 9, and 12 were used to determine IPV. There were no significant differences in the IPV estimated by the coefficient of variation, the IPV calculated by mean absolute deviation method, and the proportions of recipients with the IPV estimated by the coefficient of variation of 30% or more between CYP3A5 expressers and nonexpressers (p = 0.613, 0.686, and 0.954, respectively). Tacrolimus C0/D in CYP3A5 expressers was approximately half of those in nonexpressers, overall (p &lt; 0.001). In both CYP3A5 expressers and nonexpressers, tacrolimus C0/D increased gradually from month 6 to month 12 (p = 0.021). There was no evidence that the CYP3A5 polymorphisms significantly influence tacrolimus IPV during the 6 to 12 months after kidney transplantation.

Comparison of different methods to assess tacrolimus concentration intra-patient variability as potential marker of medication non-adherence.

Background and objective: Non-adherence to tacrolimus commonly manifests as low drug concentrations and/or high intra-patient variability (IPV) of concentrations across multiple measurements. We aimed to compare several methods of tacrolimus IPV calculation and evaluate how well each reflects blood concentration variation due to medication non-adherence in kidney transplant recipients. Methods: This Czech single-center retrospective longitudinal study was conducted in 2019. All outpatients ≥18 years of age, ≥3 months post-transplant, and on tacrolimus-based regimens were approached. After collecting seven consecutive tacrolimus concentrations we asked participating patients to self-report adherence to immunosuppressants (BAASIS© scale). The IPV of tacrolimus was calculated as the medication level variability index (MLVI), the coefficient of variation (CV), the time-weighted CV, and via nonlinearly modeled dose-corrected trough levels. These patient-level variables were analyzed using regression analysis. Detected nonlinearities in the dose-response curve were controlled for by adding tacrolimus dosing and its higher-order terms as covariates, along with self-reported medication adherence levels. Results: Of 243 patients using tacrolimus, 42% (n = 102) reported medication non-adherence. Non-adherence was associated with higher CVs, higher time-weighted CVs, and lower dose-corrected nonlinearly modeled trough levels; however, it was not associated with MLVIs. All of the significant operationalizations suggested a weak association that was similar across the applied methods. Discussion and conclusion: Implementation non-adherence was reflected by higher CV or time-weighted CV and by lower blood concentrations of tacrolimus. As an additional tool for identifying patients at risk for non-adherence, simple IPV calculations incorporated into medical records should be considered in everyday clinical practice.

Clinical association between tacrolimus intra-patient variability and liver transplantation outcomes in patients with and without hepatocellular carcinoma

Tacrolimus is the mainstay of immunosuppression in liver transplantation to prevent rejection. However, the clinical use of tacrolimus is complicated by its narrow therapeutic window and significant intra-patient variability (IPV). High tacrolimus IPV is associated with overexposure and adverse effects, including malignancy. The effects of tacrolimus IPV in liver transplant recipients with and without hepatocellular carcinoma (HCC) are unknown. We investigated the association between tacrolimus IPV and transplant outcomes in 636 liver transplant patients. Tacrolimus IPV was determined by calculating the coefficient of variance (CV) of outpatient tacrolimus trough levels from 3 to 12 months after transplantation. High tacrolimus IPV was defined as CV > 30%. Patients were grouped according to tacrolimus IPV and HCC status. Among 636 liver transplant patients, 349 had HCC and 287 had no HCC. Overall survival in HCC patients was significantly reduced with high tacrolimus IPV (P < 0.001), whereas survival of non-HCC patients was not associated with tacrolimus IPV. Multivariable analysis confirmed the independent association between high tacrolimus IPV and overall mortality in HCC patients (HR, 3.010; 95% CI, 1.084–4.918). HCC recurred in 59 patients (16.9%) post-transplantation. After adjusting for donor/recipient factors, immunosuppression, and tumor characteristics, high tacrolimus IPV was independently associated with an increased risk of HCC recurrence (HR, 2.196; 95% CI, 1.272–3.791). High tacrolimus IPV was associated with significantly increased risks of overall mortality and HCC recurrence in liver transplant recipients with HCC.

Insights into the Pharmacogenetics of Tacrolimus Pharmacokinetics and Pharmacodynamics.

The influence of pharmacogenetics in tacrolimus pharmacokinetics and pharmacodynamics needs further investigation, considering its potential in assisting clinicians to predict the optimal starting dosage and the need for a personalized adjustment of the dose, as well as to identify patients at a high risk of rejection, drug-related adverse effects, or poor outcomes. In the past decade, new pharmacokinetic strategies have been developed to improve personalized tacrolimus treatment. Several studies have shown that patients with tacrolimus doses C0/D < 1 ng/mL/mg may demonstrate a greater incidence of drug-related adverse events and infections. In addition, C0 tacrolimus intrapatient variability (IPV) has been identified as a potential biomarker to predict poor outcomes related to drug over- and under-exposure. With regard to tacrolimus pharmacodynamics, inconsistent genotype-phenotype relationships have been identified. The aim of this review is to provide a concise summary of currently available data regarding the influence of pharmacogenetics on the clinical outcome of patients with high intrapatient variability and/or a fast metabolizer phenotype. Moreover, the role of membrane transporters in the interindividual variability of responses to tacrolimus is critically discussed from a transporter scientist’s perspective. Indeed, the relationship between transporter polymorphisms and intracellular tacrolimus concentrations will help to elucidate the interplay between the biological mechanisms underlying genetic variations impacting drug concentrations and clinical effects.

Patterns in Tacrolimus Variability and Association with De Novo Donor-Specific Antibody Formation in Pediatric Kidney Transplant Recipients.

High tacrolimus intrapatient variability has been associated with inferior graft outcomes in patients with kidney transplants. We studied baseline patterns of tacrolimus intrapatient variability in pediatric patients with kidney transplants and examined these patterns in relation to C1q-binding de novo donor-specific antibodies. All tacrolimus levels in participants who underwent kidney-only transplantation at a single pediatric center from 2004 to 2018 (with at least 12-month follow-up, followed until 2019) were analyzed to determine baseline variability. Intrapatient variability was defined using the coefficient of variation (SD/mean ×100%) of all samples in a 6-month moving window. Routine de novo donor-specific antibody measurements were available for a subgroup of patients transplanted in 2010-2018. Cox proportional hazards models using tacrolimus intrapatient variability as a time-varying variable were used to examine the association between intrapatient variability and graft outcomes. The primary outcome of interest was C1q-binding de novo donor-specific antibody formation. Tacrolimus intrapatient variability developed a steady-state baseline of 30% at 10 months post-transplant in 426 patients with a combined 31,125 tacrolimus levels. Included in the outcomes study were 220 patients, of whom 51 developed C1q-binding de novo donor-specific antibodies. De novo donor-specific antibody formers had higher intrapatient variability, with a median of 38% (interquartile range, 28%-48%) compared with 28% (interquartile range, 20%-38%) for nondonor-specific antibody formers (P<0.001). Patients with high tacrolimus intrapatient variability (coefficient of variation >30%) had higher risk of de novo donor-specific antibody formation (hazard ratio, 5.35; 95% confidence interval, 2.45 to 11.68). Patients in the top quartile of tacrolimus intrapatient variability (coefficient of variation >41%) had the strongest association with C1q-binding de novo donor-specific antibody formation (hazard ratio, 11.81; 95% confidence interval, 4.76 to 29.27). High tacrolimus intrapatient variability was strongly associated with de novo donor-specific antibody formation.

MO999: Intra-Patient Variability of Tacrolimus in Kidney Transplant Patients: An Experience of a Kidney Disease Specialist Hospital

Abstract BACKGROUND AND AIMS The complexity of tacrolimus pharmacokinetics results in a unique tacrolimus recommendation in transplant centers and global level [1]. Intra-patient variability (IPV) of tacrolimus has become a simple and interesting marker to predict transplant outcomes in addition to minimum concentration (Cmin) monitoring [2–4]. As differences in ethnic affecting tacrolimus pharmacokinetics and patient response, we investigated a pilot study of tacrolimus IPV in our institution. METHOD The cohort study was conducted in all new kidney transplant patients receiving twice-daily tacrolimus as a standard immunosuppressive therapy. Patients were switched from twice-daily tacrolimus to other immunosuppressive agents were excluded from the study. All patients were followed-up at an outpatient clinic with routine monitoring. A one-year follow-up period was evaluated in the study. The primary outcome was the IPV of tacrolimus during the 3–12 months after transplantation. IPV of tacrolimus Cmin was calculated by [SD/(mean tacrolimus dose-normalized Cmin)] × 100.5 We categorized the IPV of tacrolimus into three levels: low (0%–10%), intermediate (11%–30%) and high IPV (&amp;gt;30%). The secondary outcomes were to assess renal function by eGFR and pre-defined factors associated with the IPV of tacrolimus. The study protocol was reviewed and approved by the Thai Clinical Trial Registry (TCTR20210519005). RESULTS There were 56 patients who underwent kidney transplantation during the study period. Of these 56 patients, 12 patients experienced late conversion from twice-daily to once-daily tacrolimus or were combined with sirolimus, and 4 patients became lost to follow-up. A total of 40 patients completed the one-year study period and were included in the analysis. The mean age of patients was 50.85 ± 11.07 years. A total of 39 patients received basiliximab, and one patient received anti-thymoglobulin as an induction therapy. Baseline characteristics are shown in Table 1. At 3–12 months after transplantation, the mean IPV of tacrolimus was 23.77% ± 11.23%. When categorized patients according to %IPV of tacrolimus, we found that most patients were in the intermediate IPV. The percentage of patients in each category was 7.5%, 65% and 27.5% of patients in low, intermediate and high IPV of tacrolimus, respectively (Fig. 1). The eGFR at discharge of patients with high IPV was significantly lower than that with low to intermediate IPV (P = .0282). For pre-defined factors associated with IPV of tacrolimus, the hemoglobin level at 3 months of patients with high IPV (11.23 ± 1.72 g/dL) was significantly lower than that of patients with low to intermediate IPV (12.54 ± 1.77, P = .0425). All patients were compliant as measured by pill counts and no difference in drug interaction between groups. Renal function remained stable and was similar between groups at one year of follow-up (52.03 ± 14.74 and 57.93 ± 16.40 mL/min/1.73 m2P = .3254 for high IPV and low to intermediate IPV, respectively). CONCLUSION Our findings showed that most patients were in low to intermediate IPV of tacrolimus. A low level of eGFR at discharge and a low level of hemoglobin in the early-post transplant period were associated with high IPV of tacrolimus. Therefore, clinicians should be cautious to monitor levels and adjust the dose of tacrolimus, especially if patients at risk of tacrolimus variability. A practical calculation of IPV provides a tremendous benefit for clinicians to individualized tacrolimus therapeutic drug monitoring. This study was a starting point and would expand for our large patient population. Clinical correlation with IPV of tacrolimus and IPV-directed interventions for Asian population are needed to improve tacrolimus using for achieving transplant outcomes.

Effects of tacrolimus intrapatient variability and CYP3A5 polymorphism on the outcomes of pediatric kidney transplantation.

The intrapatient variability (IPV) of tacrolimus (Tac) is associated with the long-term outcome of kidney transplantation. The CYP3A single-nucleotide polymorphism (SNP) may affect the IPV of Tac. We investigated the impact of IPV and genetic polymorphism in pediatric patients who received kidney transplantation. A total of 202 pediatric renal transplant recipients from 2000 to 2016 were analyzed retrospectively. The IPV was calculated between 6 and 12months after surgery. Among these patients, CYP3A5 polymorphism was analyzed in 67 patients. The group with high IPV had a significantly higher rate of de novo donor-specific human leukocyte antigen antibodies (dnDSA) development (35.7% vs. 16.7%, p=.003). The high IPV group also had a higher incidence of T-cell-mediated rejection (TCMR; p<.001). The high IPV had no significant influence on Epstein-Barr virus, cytomegalovirus, and BK virus viremia but was associated with the incidence of posttransplant lymphoproliferative disorders (p=.003). Overall, the graft survival rate was inferior in the high IPV group (p<.001). The CYP3A5 SNPs did not significantly affect the IPV of Tac. In the CYP3A5 expressor group, however, the IPV was significantly associated with the TCMR-free survival rate (p<.001). The IPV of Tac had a significant impact on dnDSA development, occurrence of acute TCMR, and graft failure in pediatric patients who received renal transplantation. CYP3A5 expressors with high IPV of Tac showed worse outcomes, while the CYP3A5 polymorphism had no impact on IPV of Tac.

High intrapatient variability of tacrolimus exposure associated with poorer outcomes in liver transplantation.

Tacrolimus (TAC) is a dose‐dependent immunosuppressor with considerable intrapatient variability (IPV) in its pharmacokinetics. The aim of this work is to ascertain the association between TAC IPV at 6 months after liver transplantation (LT) and patient outcome. This single‐center cohort study retrospectively analyzed adult patients who underwent transplantation from 2015 to 2019 who survived the first 6 months with a functioning graft. The primary end point was the patient’s probability of death and the secondary outcome was the loss of renal function between month 6 and the last follow‐up. TAC IPV was estimated by calculating the coefficient of variation (CV) of the dose‐corrected concentration (C0/D) between the third and sixth months post‐LT. Of the 140 patients who underwent LT included in the study, the low‐variability group (C0/D CV < 27%) comprised 105 patients and the high‐variability group (C0/D CV ≥ 27%) 35 patients. One‐, 3‐, and 5‐year patient survival rates were 100%, 82%, and 72% in the high‐variability group versus 100%, 97%, and 93% in the low‐variability group, respectively (p = 0.005). Moreover, significant impaired renal function was observed in the high‐variability group at 1 year (69 ± 16 ml/min/1.73 m2 vs. 78 ± 16 ml/min/1.73 m2, p = 0.004) and at 2 years post‐LT (69 ± 17 ml/min/1.73 m2 vs. 77 ± 15 ml/min/1.73 m2, p = 0.03). High C0/D CV 3–6 months remained independently associated with worse survival (hazard ratio = 3.57, 95% CI = 1.32–9.67, p = 0.012) and loss of renal function (odds ratio = 3.47, 95% CI = 1.30–9.20, p = 0.01). Therefore, high IPV between the third and sixth months appears to be an early and independent predictor of patients with poorer liver transplant outcomes.

High Tacrolimus Intrapatient Variability and Subtherapeutic Immunosuppression are Associated With Adverse Kidney Transplant Outcomes.

Kidney transplant recipients with high intrapatient variability (IPV) in tacrolimus (Tac) exposure experience more rejection and reduced graft survival. To understand the underlying pathophysiology of this association, the authors investigated whether patients with high tacrolimus IPV have a more activated immune system than patients with low IPV. In addition, exposure to tacrolimus and mycophenolic acid (MPA) was studied in relation to rejection and graft survival. At the time of patient inclusion (5-7 years post-transplantation), the frequency of donor-reactive cells was determined by enzyme-linked immunosorbent assay, and the development of donor-specific anti-Human Leukocyte Antigen antibodies (DSA) was measured by Luminex Single Antigen assay. Tacrolimus IPV was retrospectively calculated between 6 and 12 months and the exposure to tacrolimus and MPA was determined between 1 and 5 years post-transplantation. A total of 371 kidney transplant recipients were included in this study, of whom 56 developed a rejection episode after 12 months and 60 experienced graft failure after 5-7 years. No correlations were found between tacrolimus IPV or immunosuppression exposure and the number of donor-reactive cells after 5 years of transplantation. DSA were detected more often in patients with low exposure to both tacrolimus and MMF [4/21 (19%) versus 17/350 (4.9%), P = 0.04]. In this cohort, neither tacrolimus IPV nor low overall immunosuppression exposure was associated with a higher incidence of rejection. However, regression analysis showed that a higher tacrolimus IPV was associated with an increased incidence of graft failure (odds ratio = 1.03, P = 0.02). This study verifies the relationship between high tacrolimus IPV and impaired kidney allograft survival in long-term follow-up. DSA was also found to be more prevalent in patients with subtherapeutic concentrations of tacrolimus and MPA. An increased prevalence of donor-specific alloreactivity is yet to be demonstrated in patients with high IPV.

Evaluation of the Relationship between Medication Adherence and Tacrolimus Coefficient of Variation.

Introduction: High tacrolimus intrapatient variability is associated with poor outcomes following transplantation. A commonly hypothesized cause of this variability is medication non-adherence, but this has not been conclusively demonstrated. Research Question: The purpose of this study was to evaluate the relationship between medication adherence and tacrolimus intrapatient variability. Design: This was a retrospective cohort study of kidney transplant recipients. Adherence was assessed at the 12-month clinic visit as a composite of patient self-report, pharmacist assessment, and lab monitoring frequency. Tacrolimus intrapatient variability was calculated as the coefficient of variation (CV). Linear regression and receiver operating curve (ROC) analysis were used to assess the relationship between adherence and CV. Results: Nonadherence was identified in 37.5% of patients. The median CV was 27.1% for adherent patients and 29.8% for non-adherent patients (P = 0.051). In the multivariable analysis, the only significant predictor of CV was the incidence of dose changes (P = 0.002). ROC analysis demonstrated poor discriminant power with an AUC of 0.597. Discussion: The results fail to support a clinically meaningful relationship between medication adherence and tacrolimus CV. There is very little evidence at this time that adherence is the primary contributing factor to tacrolimus intrapatient variability and, by extension, that CV can be used as a surrogate for adherence.

Immunosuppression in patients with grade 3 acute-on-chronic liver failure at transplantation: A practice analysis study.

Transplantation for patients with acute-on-chronic liver failure grade 3 (ACLF3) has encouraging results with 1-year-survival of 80-90%. These patients with multiple organ failure meet the conditions for serious alterations of drug metabolism and increased toxicity. The goal of this study was to identify immunosuppression-dependent factors that affect survival. This retrospective monocentric study was conducted in patients with ACLF3 consecutively transplanted between 2007 and 2019. The primary endpoint was 1-year survival. Secondary endpoints were overall survival, treated rejection, and surgical complications. Immunosuppression was evaluated as to type of immunosuppression, post-transplant introduction timing, trough levels, and trough level intra-patient variability (IPV). One hundred patients were included. Tacrolimus IPV<40% (P=.019), absence of early tacrolimus overdose (P=.033), use of anti-IL2-receptor antibodies (P=.034), and early mycophenolic acid introduction (P=.038) predicted 1-year survival. Treated rejection was an independent predictor of survival (P=.001; HR 4.2 (CI 95%: 1.13-15.6)). Early everolimus introduction was neither associated with higher rejection rates nor with more surgical complications. Management of immunosuppression in ACLF3 critically ill patients undergoing liver transplantation is challenging. Occurrence and treatment of rejection impacts on survival. Early introduction of mTOR inhibitor seems safe and efficient in this situation.

A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients.

A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long‐term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate‐release (IR)‐tacrolimus to either extended‐release (ER)‐tacrolimus or LifeCyclePharma (LCP)‐tacrolimus. In this randomized, prospective, open‐label, cross‐over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR‐tacrolimus, were randomized for conversion to ER‐tacrolimus or LCP‐tacrolimus, and for the order in which IR‐tacrolimus and the once‐daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (%) of dose corrected predose concentrations. Ninety‐two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR‐tacrolimus (16.6%) and the combined once‐daily formulations (18.3%) were observed (% difference +1.7%, 95% confidence interval [CI] −1.1% to ‒4.5%, p = 0.24). The IPV of LCP‐tacrolimus (20.1%) was not significantly different from the IPV of ER‐tacrolimus (16.5%, % difference +3.6%, 95% CI −0.1% to 7.3%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR‐tacrolimus to either ER‐tacrolimus or LCP‐tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice‐daily (IR) tacrolimus formulations to once‐daily (modified‐release) tacrolimus formulations when the aim is to lower the IPV.

Tacrolimus Intrapatient Variability After Switching From Immediate or Prolonged-Release to Extended-Release Formulation, After an Organ Transplantation.

Background and Purpose: Several formulations of tacrolimus are available, but evidence of the benefit of changing to the most recent formulations is lacking. Tacrolimus intra-patient variability (tacrolimus IPV) is an emerging risk factor associated with poor graft outcomes after solid organ transplantations. Here, we examined the modifications of tacrolimus IPV after switching to a different formulation of tacrolimus. Experimental Approach: We identified 353 solid organ transplant recipients that were switched in our center from immediate-release (IR-tacrolimus) or prolonged-release tacrolimus (PR-tacrolimus) to extended-release, LCP-tacrolimus (LCP-tacrolimus). Among them, 54 patients underwent at least 3 available tacrolimus blood concentrations before and after the switch, allowing us to investigate tacrolimus IPV. Key Results: The switch was considered as a safe procedure since only four of the 353 patients presented a graft rejection after the switch, and no patient was hospitalized for tacrolimus overdose. The tacrolimus IPV estimated by the coefficient of variation (CV-IPV) was stable before and after the switch to LCP-tacrolimus (CV-IPV: 29.0% (IQR 25–75 (15.5; 38.5) before and 24.0% (15.8; 36.5) after the switch, p = 0.65). Conclusion and Implications: Switching from IR- or PR-tacrolimus to LCP-tacrolimus is a safe procedure. However, the CV-tacrolimus IPV was not impacted by the change of formulation.