Trough Blood Concentrations Research Articles

A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation.

Tacrolimus (Tac) is widely used to prevent rejection and graft loss in solid organ transplantation. A limiting characteristic of Tac is the high intra and interpatient variability associated with its use. Routine therapeutic drug monitoring (TDM) is necessary to facilitate Tac management and to avoid undesirable clinical outcomes. However, whole blood trough concentrations commonly utilized in TDM are not strong predictors of the detrimental clinical outcomes of interest. Recently, researchers have focused on Tac intrapatient variability (Tac IPV) as a novel marker to better assess patient risk. Higher Tac IPV has been associated with a number of mechanisms leading to shortened graft survival. Medication nonadherence (MNA) is considered to be the primary determinant of high Tac IPV and perhaps the most modifiable risk factor. An understanding of the methodology behind Tac IPV is imperative to its recognition as an important prognostic measure and integration into clinical practice. Therapeutic interventions targeting MNA and reducing Tac IPV are crucial to improving long-term graft survival.

P1779NOVEL ONCE-DAILY EXTENDED-RELEASE TACROLIMUS VERSUS TWICE -DAILY TACROLIMUS IN DE NOVO KIDNEY TRANSPLANT RECIPIENTS DURING THE EARLY POSTTRANSPLANT PERIOD

Abstract Background and Aims Both under and over-dosing of tacrolimus may compromise clinical outcomes by exposing patients to either the risks of graft rejection or adverse events (AEs) associated with immunosuppressive therapy. This study is designed to compare the clinical follow-up of our kidney transplant recipients receiving once-daily, prolonged-release (PR-T; Advagraf) and twice-daily, immediate-release (IR-T; Prograf) tacrolimus in the early posttransplant period. Method This randomized study included 78 de novo, adult kidney transplant recipients to PR-T 0.15 mg/kg/day (Group I=39) and IR-T 0.15 mg/kg/day (Group II=39) for seven days in the posttransplant period. Demographic features and clinical parameters regarding levels of whole blood tacrolimus and serum creatinine were compared between the two groups. Presence of acute rejection and AEs were investigated. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations in all patients. SPSS 15 for Windows was used for statistical analysis. Results None of the patients suffered from acute rejection and there were no AEs in the early posttransplant period. However, Group II patients were found to have higher whole blood tacrolimus levels on the posttransplant 1st, 4th and 7th days (p=0.02, p=0.009 and p=0.013 respectively). Also serum creatinine levels were significantly increased in Group II patients on the posttransplant 7th day (p=0.02). Conclusion Prolonged release tacrolimus seems promising in preventing acute transplant rejection with adequate blood levels, as well as making it possible to avoid the interindividual variation in absorption and early calcineurin inhibitor toxicity.

Unexpected overdose blood concentration of tacrolimus: Keep in mind the role of inflammation.

Tacrolimus is the cornerstone of the therapeutic immunosuppressive strategy in liver transplantation. The inter-individual and intra-individual variability of its trough blood concentrations is a surrogated biomarker of allograft rejection. Here we described two cases of patients with liver transplant who exhibited increases of tacrolimus blood trough concentration adjusted on the dose while experiencing acute inflammatory episodes. These case reports highlight the inhibitory effect of acute inflammation on tacrolimus metabolism and show that it accounts for the longitudinal intra-individual variability of tacrolimus blood concentrations, beyond drug-drug interaction and observance.

Study on the evaluation of Rivaroxaban′s blood concentration by anti-FX activity assay

Objective The anti-FⅩa assay can be used to monitor the blood concentration of Rivaroxaban. The aim is to evaluate the critical value and diagnostic performance of this test on bleeding risk assessment. Methods From September 2017 to June 2019, 368 patients were enrolled for retrospective cohort study, including 201 males and 167 females, aged (62.8±15.7) years old. They were divided into groups by age:≤60 years old group 105 cases,61-70 years old group 135 cases,≥71 years old group 128 cases. Anti-FⅩa was detected on ACL TOP 700 coagulation analyzer using chromogenic substrate method to quantitatively determine the plasma concentration of rivaroxaban. Anti-FⅩa data were expressed as M (P25-P75);Kruskal-Wallis H test was used for comparison among groups; Mann-Whitney U test was for data comparison between two groups; positive rate comparison was performed by χ2 test; the diagnostic performance of anti-FⅩa to assess bleeding risk was evaluated by ROC curve;Kaplan-Meier curve was used for the survival analysis;the risk ratio (HR) was obtained by Cox proportional hazard regression model. Results Both the peak and trough plasma concentrations were higher in patients aged 61-70 years old than ≤60 years old (U values were 5 618 and 5 725,respectively, P values were 0.006 and 0.011, respectively); higher in patients ≥71 years old than 61-70 years old (U values were 6 438 and 6 317, respectively, P values were 0.05).Both peak and trough blood concentrations were higher in patients with bleeding than without bleeding(U values were 1 429 and 2 185, respectively, P<0.001 and 0.001, respectively).ROC showed that the cut-off values of peak blood concentration in evaluation of the overall and the ≥61 year-old population′s bleeding risk were 200.8 ng/ml and 209.9 ng/ml,respectively, corresponding respectively with the sensitivity of 90.9% and 95.0%; the trough cut-off values were 35.1 ng/ml and 39.1 ng/ml, respectively, corresponding respectively with the sensitivity of 72.7% and 70.0%. However, all the above cut-off values gave a low diagnostic specificity. Survival analysis showed with 35.1 ng/ml as the trough cut-off value, the cumulative risk of bleeding significantly increased in patients above the cut-off value (Log-rank χ2=4.513,P=0.034). The Cox proportional regression model demonstrated that the hazard ratios for peak and trough blood concentration predictions of bleeding risk were 1.023 (95%CI: 0.834-1.256) and 0.948 (95%CI: 0.773-1.164). respectively. Conclusions Both the peak and trough values of blood concentration in bleeding patients are higher than non-bleeding patients. The peak blood concentration is highly sensitive to the risk of bleeding, and the elevated trough blood concentration levels indicate that the probability of bleeding risk increases in the short term. However, the specificity of both peak and trough values is relatively low in bleeding risk assessment. When used alone, the prediction of bleeding events does not have direct guiding significance. Dynamic monitoring and joint evaluation are recommended. Key words: Factor Ⅹa; Rivaroxaban; Plasma concentration; Blood coagulation tests; Hemorrhage; Forecasting

SUN-342 UNUSUAL HIGH DOSE OF TACROLIMUS IN RENAL TRANSPLANT PATIENTS: A CASE SERIES

Tacrolimus, is an immunosuppressant, characterized by highly variable pharmacokinetics (PK) and a small therapeutic window, which make therapeutic drug monitoring (TDM) mandatory for maintaining adequate exposure. TDM allows dose adjustment in order to avoid graft rejection and tac-induced adverse effects, which are the most challenging after transplantation. Tacrolimus is metabolized specifically by the CYP3A isoenzyme: CYP3A4 and CYP3A5. Many single nucleotide polymorphisms (SNPs) such as CYP3A4*1B -392A>G, CYP34*22 15389C>T, and CYP3A5*3 6986A>G related to the expression levels of CYP enzymes may explain a part of the variability in tacrolimus PK. It is admitted that patients harboring the predominant CYP3A5*3, associated with enzymatic function loss, require roughly 50% lower tacrolimus doses than those with CYP3A5*1. CYP3A4*1B. Recently, it has been shown that CYP3A4*22 carriers had a lower clearance of tacrolimus (-16%). We describe herein two cases of renal transplant patients who have great difficulty in reaching the desired trough blood levels despite the use of high dose tacrolimus. It is a retrospective study reporting the case of 2 patients with difficulty in reaching the desired trough blood levels of tacrolimus. Our first patient is a 34-year-old man who received a living donor kidney transplant (his mother) on March 15, 2017. He was prescribed Tacrolimus at an initial dose of 14 mg/day divided every 12 hours (0.12-0.15 mg/kg/day) in association with a corticosteroid and mycophenolate mofetil. The trough blood concentration C0 was 5ng/ml. The dose was progressively increased reaching a daily dose of 22 mg divided every 12 hours with the trough blood concentration C0 = 6.4 ng/ml.CYP3A4 and CYP3A5 genotyping were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP). The patient was heterozygous for the CYP3A5*3 allele (*1/*3) and homozygous for the CYP3A4*1B (*1B/*1B) and CYP3A4*22 alleles (*1/*1). So the patient was considered a high metabolizer, the reason behind the need for elevated doses of tacrolimus to achieve a therapeutic trough concentration. Our second patient is a 42-year-old man who received a living donor kidney transplant (his sister) on September 28, 2016. He was initially prescribed Tacrolimus at 12mg/day in two divided doses (0.12-0.15 mg/kg/day) in association with a corticosteroid and mycophenolate mofetil. The trough blood concentration (C0) was 3 ng/ml. The dose was then progressively increased reaching a daily dose of 20 mg/day. C0 was 4.1 ng/ml. The patient was homozygous for the three alleles (CYP3A5*1/*3, CYP3A4*1B/*1B, and CYP3A4*1/*1). Our patient is a CYP3A5 expressor and a CYP3A4*1B and CYP3A4*22 carrier, thereby making him a high metabolizer and requiring high doses of tacrolimus in order to achieve a therapeutic trough concentration. The present case series appears to confirm the main responsibility of the CYA3A4 and CYP3A5 genetic polymorphisms in determining the dose requirements of tacrolimus in renal transplant patients. Although pharmacogenetic analysis cannot substitute TDM, the availability of genotyping renders possible to better define the initial tacrolimus dosage.

Goal-Oriented Monitoring of Cyclosporine Is Effective for Graft-versus-Host Disease Prevention after Hematopoietic Stem Cell Transplantation in Sickle Cell Disease and Thalassemia Major.

Graft-versus-host disease (GVHD) is an important challenge and a major cause of morbidity and mortality in children after hematopoietic stem cell transplant (HSCT). Herein we report our institution's experience of goal-oriented Bayesian monitoring for cyclosporine (CsA) used alone as GVHD prophylaxis during the post-transplant period in pediatric patients with thalassemia major (TM) or sickle cell anemia (SCA) undergoing HLA-matched HSCT. We also studied evolution of chimerism. Twenty-six consecutive patients (SCA, 14; TM, 12) underwent matched sibling donor (MSD) HSCT from 2004 to 2014. All patients received a myeloablative conditioning regimen. GVHD prophylaxis consisted of 20 mg/kg antithymocyte globulin in the conditioning regimens and then CsA alone in the post-transplant period. Target CsA trough blood concentration (TBC) was 150 ± 20 ng/mL. At last follow-up, all patients were alive and free of disease, even in cases of mixed chimerism. Engraftment occurred in all patients. No patient developed grades II to IV acute GVHD, 4 patients developed acute grade I skin GVHD, and only 1 presented with chronic pulmonary GVHD. A better control of GVHD and immunosuppression by a strict monitoring of CsA TBC as described herein is promising and could play a crucial role. Further investigations are required, but this study opens new perspectives to improve survival and safety of HSCT from alternative donors in TM and SCA to levels compatible with that obtained with MSDs.

Therapeutic drug monitoring of regorafenib and its metabolite M5 can predict treatment efficacy and the occurrence of skin toxicities.

Regorafenib is a multiple tyrosine kinase inhibitor, and the use of this drug is approved for the treatment of cancers that are resistant to chemotherapy, which include advanced colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. However, the drug causes adverse events, including skin toxicities that require dose modification in approximately 75% of cases. At present, the blood concentration of regorafenib is not assessed in clinical settings; thus, we recently developed a method that can assess the blood concentration of the drug using high-performance liquid chromatography. We measured the trough blood concentrations (Ctrough) of regorafenib and its metabolites (M2 and M5) in 14 and 4 patients with advanced colorectal cancer and gastrointestinal stromal tumor, respectively, using high-performance liquid chromatography. Then, the correlation between the Ctrough and therapeutic outcomes of regorafenib was analyzed. In patients who were receiving regorafenib 40-160mg/day, the Ctrough values of regorafenib, M2, and M5 were 318-9467, 34-3594, and 38-3796ng/mL, respectively. The difference in the values was significant. Although the specific factors influencing this difference were not elucidated, the Ctrough of regorafenib was extremely lower in some patients, even though the drug was administered at a standard dose, which may explain the lower response rate. Moreover, the Ctrough value of M5 was significantly correlated to the incidence of skin toxicities, which is the most frequent cause of dose modification. The use of regorafenib may not be suitable in patients with a low Ctrough value. To prevent skin toxicities, the Ctrough value of M5 should be monitored.

The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients

Available data of early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TAC-OD) in de novo kidney transplant (KT) recipients are limited. We conducted a prospective study of early conversion to TAC-OD in de novo KT recipients. Eligible patients were enrolled to receive TAC-BID (Prograf®) and then converted to TAC-OD (Advagraf®) by 1:1 ratio, approximately 14 days after KT (range 9–22). Blood samples were investigated for pharmacokinetic parameters before and 7–14 days after the conversion. Fifteen patients were included and provided AUC0-24 of 202.9 ± 44.4 ng h/mL for TAC-BID (pre-conversion) and 193.0 ± 63.4 ng h/mL for TAC-OD (post-conversion) (p = 0.41). Mean trough blood concentration (Cmin) of TAC-BID and TAC-OD was 6.4 ± 1.4 ng/mL and 4.9 ± 1.6 ng/mL (p = 0.01). Correlation coefficient (r) between Cmin and AUC0-24 of TAC-BID and TAC-OD were 0.620 and 0.875. Additional analysis found that patients with a drop of Cmin > 30% had a significant lower AUC0-24 after conversion. Renal function remains stable. We conclude that early conversion to TAC-OD is safe and well tolerated with an indifferent systemic exposure. However, patients with a drop of Cmin > 30% after conversion to TAC-OD will require additional dose adjustment.

Melding Pharmacogenomic Effect of MDR1 and CYP3A5 Gene Polymorphism on Tacrolimus Dosing in Renal Transplant Recipients in Northern India

IntroductionTacrolimus (TAC) is the mainstay immunosuppressant for renal transplantation. A narrow therapeutic index, multiple drug interactions, and interindividual variability in pharmacokinetics make it obligatory to monitor therapeutic drug levels. The Multidrug resistance gene 1 (MDR1) and CYP3A5 gene polymorphism may blend to achieve the optimal level. The optimal dose as per body weight is difficult to single out in the early posttransplantation period. In this study, we aimed to analyze the melding effect of both gene polymorphisms and to elicit the dose depending on the combination of genetic single nucleotide polymorphisms (SNPs) in northern Indian transplant recipients, for whom data are limited.MethodsThe daily TAC dose, weight-adjusted doses (mg/kg per day), TAC trough blood concentration (average of at least 3 levels), dose normalized with a corresponding dose using TAC concentration/weight-adjusted dose ratio (ng/ml per mg/kg per day) of 248 patients were recorded. All recipients were genotyped for the SNPs of CYP3A5 at intron 3 A6986G (the *3 or *1 allele), MDR1 at exons 12 (C1236T), 21 (G2677A/T), and 26 (C3435T). We analyzed the blending effect of mutant SNPs of the MDR gene and CYP3A5 for optimized TAC levels.ResultsAmong CYP3A5 genotypic variants, the dose-adjusted TAC level was significantly lower, and the TAC dose required to achieve the target level was significantly higher, in CYP3A5*1*1 (expressor) than that of CYP3A5*1*3 and CYP3A5*3*3. Of the MDR1 gene SNPs, only the G2677T/A homozygous mutant was significantly associated with TAC level, and it was strongly correlated with P-gp expression.The daily TAC dose requirement was highest with a combination of CYP3A5*1*1 and homozygous mutant TT+AA genotype of G2677T/A, and was lowest with CYP3A5*3*3 and wild-type GG of the G2677T/A genotype.ConclusionBoth CYP gene and MDR1 gene polymorphism affect TAC dose requirements, and there is a need to look for both in an individual to achieve the target trough concentration.

A Multicenter, Prospective, Observational Study of Conversion from Twice-Daily Immediate-Release to Once-Daily Prolonged-Release Tacrolimus in Liver Transplant Recipients in France: The COBALT Study.

BackgroundIn adult liver transplant patients, the use of prolonged-release tacrolimus may have treatment adherence benefits over the immediate-release formulation. The aim of this study was to characterise real-world practice data on conversion of liver transplant recipients from immediate- to prolonged-release tacrolimus in France.Material/MethodsA prospective, observational study (NCT02143479) was conducted in 18 transplant centers in France between June 2014 and March 2016. Liver transplant recipients (n=398) included patients who changed from immediate-release to prolonged-release tacrolimus within the first three months (early conversion group) (n=205) or between three and 12 months after transplantation (late conversion group) (n=184). Clinical data were collected at an initial baseline outpatient visit and six-month and 12-month follow-up visits. Endpoints included the dose conversion ratio from immediate-release to prolonged-release tacrolimus, number of and reasons for additional visits due to conversion, safety, and tolerability.ResultsBaseline clinical and demographic characteristics were similar between the two cohorts. The mean ±SD ratio of conversion of tacrolimus dose was 1.04±0.28; 1.01±0.28 (early) and 1.08±0.28 (late) (p=0.0247). The mean ±SD time from conversion to the first tacrolimus trough blood concentration was 30.8±42.8 days; 24.8±45.4 days (early) and 37.5±38.7 days (late). Only one patient required an additional visit due to conversion. Reasons for conversion included the physician’s preference (56.3%), center practice (38.6%), and the dosing frequency (36.0%). Conversion was associated with a low rate of graft rejection, and no new safety issues were reported.ConclusionsConversion of liver transplant recipients from immediate-release to prolonged-release tacrolimus within three to 12 months of transplantation was easy to manage and associated with favorable clinical outcomes and safety profiles.

Tacrolimus exposure after liver transplantation for alcohol-related liver disease: Impact on complications

BackgroundAlcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects. ObjectiveThe aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD. MethodsAll patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed. ResultsThe study population consisted in 251 patients, mean age 53.4 ± 7.3 years, and followed during 11.6 ± 4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers. ConclusionOur results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.

Fast Tac Metabolizers at Risk ⁻ It is Time for a C/D Ratio Calculation.

Tacrolimus (Tac) is a part of the standard immunosuppressive regimen after renal transplantation (RTx). However, its metabolism rate is highly variable. A fast Tac metabolism rate, defined by the Tac blood trough concentration (C) divided by the daily dose (D), is associated with inferior renal function after RTx. Therefore, we hypothesize that the Tac metabolism rate impacts patient and graft survival after RTx. We analyzed all patients who received a RTx between January 2007 and December 2012 and were initially treated with an immunosuppressive regimen containing Tac (Prograf®), mycophenolate mofetil, prednisolone and induction therapy. Patients with a Tac C/D ratio <1.05 ng/mL × 1/mg at three months after RTx were characterized as fast metabolizers and those with a C/D ratio ≥1.05 ng/mL × 1/mg as slow metabolizers. Five-year patient and overall graft survival were noticeably reduced in fast metabolizers. Further, fast metabolizers showed a faster decline of eGFR (estimated glomerular filtration rate) within five years after RTx and a higher rejection rate compared to slow metabolizers. Calculation of the Tac C/D ratio three months after RTx may assist physicians in their daily clinical routine to identify Tac-treated patients at risk for the development of inferior graft function, acute rejections, or even higher mortality.

Tacrolimus Pharmacokinetics in Living-Donor and Deceased-Donor Liver Transplant in Saudi Patients

Introduction: Tacrolimus is a macrolide immunosuppressant. It has a narrow therapeutic index and serious side effects which necessitate monitoring of tacrolimus blood concentration. The trough concentration of the drug may also differ based on the type of liver transplant. This study was conducted to investigate differences in pharmacokinetics between transplant types and to determine tacrolimus population pharmacokinetic in liver transplant recipients in Saudi Arabia.&#x0D; Method: Patients on tacrolimus, as the main immunosuppressant, who underwent liver transplant throughout2012-2014 were retrospectively studied. Demographic characteristic, tacrolimus blood trough concentrations, liver, renal, biochemistry, and hematology lab results were all collected. The pharmacokinetic parameters were estimated assuming one compartment model.&#x0D; Results: Tacrolimus pharmacokinetic parameters were found to be as following; elimination rate constant () 0.094 ± 0.0123, apparent volume of distribution () 112.48±63.033 L/hr, elimination half-life () 7.46± 1.01 hr and apparent total body clearance () 10.27± 5.69 L/hr (mean ± SD).&#x0D; Statistically significant difference was found between living-donor and deceased-donor liver transplant with respect to apparent clearance and apparent volume of distribution. Living-donor liver transplant recipients have apparent volume of distribution of 97.39±47.00 L (mean ± SD) and an apparent clearance of 8.89±4.24L/hr (mean± SD). On the other hand, deceased-donor liver transplant has an apparent clearance of 12.97±7.09L/hr (mean ± SD) and an apparent volume of distribution of 142.17± 78.65 L (mean ± SD).&#x0D; Conclusions: Tacrolimus pharmacokinetics parameters were accurately determined in liver transplant recipients in Saudi Arabia. The results of the present study can be clinically used in the therapeutic drug monitoring of tacrolimus in the individualization of drug dosage and taking the appropriate clinical decisions to prevent allograft rejection.

Single-centre retrospective observational study comparing trough blood concentration and safety of teicoplanin formulations

Teicoplanin formulations are marketed as antibiotic mixtures with several compounds that share the same core structure. Recent studies conducted in vitro have reported differences in the composition ratio of different teicoplanin products. In this retrospective study, we examined the trough blood concentration of the originator brand and a generic teicoplanin product. Target patients were retrospectively assigned to the originator (Targocid) or generic group. The groups were matched 1:1 using propensity scores. The initial trough blood concentration analysis identified 44 matches. In both groups, the median dosing day for the first measurements was 4, respectively. The initial trough blood concentration of the originator group was significantly higher (mean ± SD, 16.3 ± 4.5 mg/L) than that of the generic group (12.8 ± 4.7 mg/L; 95% CI, −5.4 to −1.6). A significant difference was observed in the frequency of serum creatinine elevation in the study of the frequency of adverse events using Common Terminology Criteria for Adverse Events (originator group, 41.9% vs generic group, 20.9%). In cases where discontinuation was necessary due to side effects, there were three patients in the originator group and one patient in the generic group. This study found that trough blood concentration differed between formulations. Therefore, correction might be necessary while monitoring drug concentration in the blood. Trough blood concentrations are used as surrogate markers for efficacy and safety, so further studies on differences in efficacy and safety between formulations are required.

Long-term relationship between everolimus blood concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma: a prospective study

BackgroundEverolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Recently, personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. In this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC.MethodsPatients with mRCC were enrolled following treatment with everolimus at Tohoku University Hospital between April 2012 and December 2016. The relationship between everolimus trough blood concentration on day 8 of everolimus therapy and just before discontinuation or dose reduction, and their adverse events were evaluated. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the profiles of adverse events, and efficacy [time to treatment failure (TTF) and progression-free survival (PFS)] were evaluated.ResultsThe median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1–28.0) ng/mL and 14.8 (6.4–58.4) ng/mL, respectively, with no significant difference between these values (P = 0.3594). Patients (n = 6) with discontinuation or dose reduction following adverse events in everolimus therapy had significantly higher blood concentrations than patients (n = 4) with dose maintenance on both day 8 (median, 18.0 vs 8.2 ng/mL; P = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; P = 0.0142). Median TTF and PFS of the total patients (n = 10) were 96 days (95% confidence interval [CI], 26–288) and 235 days (95% CI, 28–291), respectively. Subgroup analysis showed that TTF of the patients with > 15.3 ng/mL (n = 5) was not significantly different from that of the patients with ≤15.3 ng/mL (n = 5; P = 0.5622). Similarly, PFS of the patients with > 15.3 ng/mL was not significantly different from that of the patients with ≤15.3 ng/mL (P = 0.3436).ConclusionsThis study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and adverse events in Japanese patients with mRCC. Thus, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events for Japanese patients with mRCC.

Cyclosporine Administration and Graft Versus Host Disease: Continuous Intravenous Infusion vs. Intravenous Bolus Dosing

Introduction Continuous infusion (CIVI) cyclosporine (CSA) is an alternative for allograft recipients intolerant of twice daily infusions (TDI). Trough concentrations are an accepted surrogate for monitoring therapy, however total exposure may be dependent on peak concentrations not obtained when given via CIVI. Therefore, maintaining the same trough goals for both routes of administration may lead to decreased CSA exposure and subsequent increased rates of graft versus host disease (GVHD). The purpose of this study was to evaluate the incidence of acute GVHD and overall survival among patients receiving CIVI vs. TDI CSA. Methods We performed a retrospective study of adult patients undergoing first allogeneic HCT at the University of Minnesota Medical Center between 2011 and 2017 that received > 48 hours of CSA. All patients initially received CSA via TDI per institutional standard and targeted whole blood trough concentrations of 200-400 ng/mL via HPLC. Any change to CIVI was made at the discretion of the treating physician. All patients were changed to oral CSA when able. Patients were grouped according to administration method; those that received cyclosporine via CIVI for > 48 hours at any time during initial transplant admission were classified as CIVI and those that received CSA exclusively as TDI were classified as TDI. Results 308 patients met inclusion criteria (CIVI 42, TDI 266). Donor type, GVHD prophylaxis, underlying diagnosis, and conditioning intensity were similar between groups. The majority of subjects received HLA-matched sibling or cord blood allografts. There were an equal proportion of myeloablative and reduced intensity conditioning regimens, and nearly all GVHD prophylaxis therapy consisted of cyclosporine combined with either mycophenolate or methotrexate. Forty two patients received CSA via CIVI for > 48 hours for a median of 9 days (range, 3-32 days). The average time of change from TDI to CIVI was 3 days after transplant. The TDI group received only TDI for a median 17 days (range 4-62 days) prior to conversion to oral CSA. CSA concentrations at day -1 and weeks 1, 2, and 3 were similar between the groups (Figure 1). We found no difference between the rates of grade II-IV acute (45% vs 53%, p = 0.59) or chronic (17% vs 30%, p = 0.20) GVHD or overall survival (57% vs 67%, p = 0.10) between groups. Subgroup analysis of patients that received myeloablative conditioning did not reveal significant differences in GVHD or overall survival. Conclusion In contrast to previous studies, we did not observe an association of CIVI CSA administration with acute GVHD. Among patients intolerant of bolus CSA infusions, a brief transition to CIVI CSA appears to be a safe and acceptable route of administration without increased risk of GVHD or adverse effects on overall survival.

Effect of tacrolimus dispositional genetics on acute rejection in the first 2 weeks and estimated glomerular filtration rate in the first 3 months following kidney transplantation.

CYP3A4/5 and P-glycoprotein (P-gp, ABCB1) affect tacrolimus (TAC) exposure in T cells and kidney cells. Genetic variability of these genes has been widely studied for effects on acute rejection and kidney function after transplantation, but findings remain contradictory. In addition, cytochrome P450 reductase (POR) is important for CYP3A4/5 activity, and the pregnane X receptor (NR1I2) regulates CYP3A4/5 and P-gp expression. However, the relationship between POR and NR1I2 genetics and acute rejection and kidney function has not been extensively investigated. The aim of this study was to investigate the effect of ABCB1 (61A>G, 1199G>A, 1236C>T, 2677G>T, 3435C>T), CYP3A4*22, CYP3A5*3, NR1I2 (8055C>T, 63396C>T) and POR*28 genotypes/haplotypes on acute rejection and kidney function in the first 3 months after transplant. The study included 165 kidney transplant recipients, who received TAC, mycophenolate and prednisolone, and 129 donors. TAC dose was adjusted to target trough blood concentrations of 8-15 ng/ml by therapeutic drug monitoring. Recipient and donor genotype/haplotype differences in acute rejection incidence within the first 2 weeks after transplant were assessed by logistic regression, adjusting for induction therapy, human leucocyte antigen mismatches, kidney transplant number, peak panel-reactive antibodies and donor type. Recipient and donor genotype/haplotype differences in estimated glomerular filtration rate in the first 3 months after transplant were assessed by linear mixed effects analysis, adjusting for acute rejection, delayed graft function and donor type. No genetic factors significantly affected acute rejection or estimated glomerular filtration rate after correction for multiple comparisons (P>0.004). Recipient and donor dispositional genetics had no significant effect on short-term clinical outcomes in kidney transplant patients receiving TAC therapeutic drug monitoring.

TLR9 rs352139 Genetic Variant Promotes Tacrolimus Elimination in Chinese Liver Transplant Patients During the Early Posttransplantation Period.

There are limited markers that could facilitate individualized tacrolimus treatment in the early posttransplantation period. Genetic factors have been found to play critical roles in determining tacrolimus pharmacokinetics. We aimed to examine the association of donor and recipient Toll-like receptor (TLR) polymorphisms with tacrolimus elimination and the potential mechanism for TLR gene polymorphism-mediated tacrolimus metabolism. Two independent cohorts including 297 patients receiving liver transplantation (LT) were enrolled in this study (cohort A was composed of 200 patients; cohort B included 97 patients and served as a validation set). Toll-like receptors polymorphisms were genotyped using TaqMan single nucleotide polymorphisms (SNPs) assays. The protein expressions were detected by Western blotting. The metabolism assay was used to quantify tacrolimus elimination. The activity of nuclear factor-kB (NF-kB) was evaluated by luciferase reporter assay. Tacrolimus dose-adjusted trough blood concentrations (C/D) ratios were significantly lower for donor TLR9 rs352139 AG/GG carriers than AA carriers at weeks 1, 2, and 3 after LT. In multivariate analysis, donor and recipient CYP3A5 rs776746 and donor TLR9 rs352139 were independent predictors of tacrolimus C/D ratios in the early period after transplantation in both cohorts. When investigating the combined effects of donor CYP3A5 rs776746 and donor TLR9 rs352139 genotypes, the C/D ratios were remarkably significant at all time points during the first month after LT within the four groups. Furthermore, CYP3A5 mRNA expression in liver tissue was significantly higher for AG/GG patients than AA carriers after LT. In addition, we demonstrated that the TLR9 rs352139 genetic variant promotes tacrolimus metabolism of liver cells via upregulation of CYP3A5, which is dependent on the repression of NF-κB/pregnane X receptor (PXR) signaling. Donor TLR9 rs352139 genetic variant facilitated tacrolimus elimination during the early stage after LT in Chinese patients, which might be related to the upregulation of CYP3A5 enzyme via the NF-kB/PXR signaling pathway.

Tacrolimus: Influence of the Posttransplant Concentration/Dose Ratio on Kidney Graft Function in a Two-Year Follow-Up

Introduction: Tacrolimus (TAC) metabolism rate has the potential to impact graft function after kidney transplantation (KTx). We aimed to analyze the relationship between the early post-KTx TAC C/D ratio (blood trough concentration normalized by total daily dose) and kidney graft function in a 2-year follow-up. Methods: We retrospectively analyzed data from 101 post-KTx patients at 3, 6, 12, and 24 months after KTx to identify the C/D ratio cutoff value optimal for dividing patients into fast and slow TAC metabolizers. We investigated the relationship between their TAC metabolism rate and graft function. Results: Patients were divided based on the TAC C/D ratio at 6 months after KTx of 1.47 ng/mL * 1 mg. Fast metabolizers (C/D ratio <1.47 ng/mL * 1 mg) presented with significantly worse graft function throughout the whole study period (p < 0.05 at each timepoint) and were significantly less likely to develop good graft function (estimated glomerular filtration rate ≥45 mL/min/1.73 m2) than slow metabolizers. Our model based on donor and recipient age, recipient sex and slow/fast metabolism status allowed for identification of patients with compromised graft function in 2-year follow-up with 66.7% sensitivity and 94.6% specificity. Conclusion: Estimating TAC C/D ratio at 6 months post-KTx might help identify patients at risk of developing deteriorated graft function in a 2-year follow-up.

Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in De Novo Kidney Transplant Recipients: A Randomized, Parallel-Group, Open-Label, Multicenter Study.

IntroductionDifferent prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus®) has not been compared with PR-Tac (Advagraf®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations.MethodsThis randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations.ResultsPK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (tmax), lower maximum concentration (Cmax) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar.ConclusionIn de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac.Trial registrationRegistered at ClinicalTrials.gov; study number NCT02500212.FundingChiesi Farmaceutici S.p.A.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0855-1) contains supplementary material, which is available to authorized users.