Tacrolimus Blood Levels Research Articles

Severe proteinuria during the administration of bevacizumab plus mFOLFOX6 in a colorectal cancer patient after kidney transplantation: a case report

BackgroundBevacizumab (BEV) leads to proteinuria and renal damage. It is not clear whether the administration of immunosuppressive drugs after renal transplantation affects the safety of BEV administration. We report a case of severe proteinuria caused by BEV plus 5-fluorouracil, levofolinate, and oxaliplatin (mFOLFOX6) in a patient who had previously undergone kidney transplantation and the administration of tacrolimus.Case presentationThe patient was a 67-year-old man with a history of diabetes and hypertension. He developed chronic renal failure 14 years earlier and underwent right kidney transplantation from a living donor followed by the administration of tacrolimus and mycophenolate mofetil for immunosuppression. After kidney transplantation, the patient was diagnosed with colorectal cancer with multiple lung and liver metastases and received BEV plus mFOLFOX6. After 5 cycles, proteinuria was observed, with a urinary protein concentration of > 300 mg/dL (urine protein creatinine ratio: 3.5), and after 16 cycles, the urinary protein concentration was > 1000 mg/dL (urine protein creatinine ratio: 7.1). Subsequently, BEV was discontinued, and only mFOLFOX6 administration was continued. Tacrolimus continued to be administered during chemotherapy. There was no association between serum tacrolimus concentration and proteinuria.ConclusionsIn this case, BEV administration caused severe proteinuria without affecting blood levels of tacrolimus. Patients with risk factors for renal impairment should be carefully evaluated for the risks and benefits of BEV administration.

CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients.

Tacrolimus has been used to induce remission in patients with steroid-refractory ulcerative colitis. It poses a problem of large individual differences in dosage necessary to attain target blood concentration and, often, this leads to drug inefficacy. We examined the difference in mRNA expression levels of ATP binding cassette transporter B1 (ABCB1) between inflamed and non-inflamed tissues, and the influence of CYP3A5 genotype on tacrolimus therapy. The mRNA expression of CYP3A4 in colonic mucosa and that of cytochrome p450 3A5 (CYP3A5) and ABCB1 in inflamed and non-inflamed areas were examined in 14 subjects. The mRNA expression levels of CYP3A5 were higher than that of CYP3A4. The mRNA expression of ABCB1 was lower in the inflamed than in the non-inflamed mucosa, despite that of CYP3A5 mRNA level being not significantly changed. Hence, the deterioration of the disease is related to the reduction of the barrier in the inflamed mucosa. The relationship between CYP3A5 genotype and blood concentration, dose, and concentration/dose (C/D) ratio of tacrolimus in 15 subjects was studied. The tacrolimus dose to maintain equivalent blood concentrations was lower in CYP3A5*3/*3 than in CYP3A5*1 carriers, and the C/D ratio was significantly higher in the latter. Thus, CYP3A5 polymorphism information played a role in determining the initial dose of tacrolimus. Furthermore, since the effect of tacrolimus appears earlier in CYP3A5*3/*3 than in CYP3A5*1/*1 and *1/*3, it seems necessary to change the evaluation time of therapeutic effect by CYP3A5 genotype. Additionally, the relationship between CYP3A5 genotype and C/D ratio of tacrolimus in colonic mucosa was investigated in 10 subjects. Tacrolimus concentration in the mucosa was two-fold higher in CYP3A5*3/*3 than in CYP3A5*1 carriers, although no significant difference in tacrolimus-blood levels was observed. Therefore, the local concentration of tacrolimus affected by CYP3A5 polymorphism might be related to its therapeutic effect.

Failure of Achieving Tacrolimus Target Blood Concentration Might Be Avoided by a Wide Genotyping of Transplanted Patients: Evidence from a Retrospective Study.

Precise tacrolimus treatment in transplanted patients is achieved in the clinical setting by performing therapeutic drug monitoring (TDM) and consequently adjusting therapy. The aim of this study was to retrospectively analyze the variability in tacrolimus blood levels throughout 2 years of observation in 75 transplanted patients and to investigate if tacrolimus blood levels correlate with presence of genetic polymorphisms, thus modifying tacrolimus pharmacokinetics. CYP3A5*1 (G6986A), CYP3A4*1B (A392G), CYP3A4*22, ABCB1 (C3435T; C1236T; G2677A/T), SLCO1B1 (T521C), polymorphisms were analyzed. Based on the effect of their genotypes, patients were stratified into 5 groups: (1) reduced tacrolimus metabolism (RM), (2) increased metabolism (IM), (3) transporters polymorphisms (TM), (4) metabolism and transporter polymorphisms (AM) and (5) no mutations (Wild Type, WT). The percentage of the samples out of therapeutic range was significantly higher in the IM group than in the WT group (p = 0.001), as well as compared to the TM group (p = 0.004). Only IM pattern (p = 0.015) resulted as an independent predictor of number of tacrolimus blood levels out of therapeutic range. RM pattern (p = 0.006) was inversely related to the administered dose. Therefore, genotyping could become a standard practice before tacrolimus prescription thus decreasing side effects, increasing efficacy and reducing the economic burden for the national health system.

P1691URINARY CXCL10 AT SIX AND TWELVE MONTH PREDICTS SUBCLINICAL ANTIBODY MEDIATED REJECTION AT 1 YEAR

Abstract Background and Aims Despite the improvement in renal transplant results, the rate of graft loss from the first year has improved poorly, antibody-mediated rejection (AbMR) being the first cause of renal graft loss. Renal transplantation is usually monitored by measuring creatinine, proteinuria, immunosuppressive blood levels and, recently, donor specific antibodies and polyomavirus load. However, currently the only way to detect the alloimmune graft damage is to perform a surveillance o by indication renal biopsy. Non-invasive monitoring of the alloimmune response could contribute to improving renal transplant results. Previous studies have shown that urinary CXCL10 relates to both clinical and subclinical allograft rejection and graft loss. Our aim was to analyze the relationship between urinary CXCL10 and the biopsy findings of 1-year surveillance biopsies. Method From Dec/2013 to Nov/2017 90 surveillance biopsies were performed in our center at 1 year after kidney transplantation. Urine were prospectively collected at 6 and 12 month and urine samples were frozen at -70º. CXCL10 was measured by using human CXCL10/IP-10 DuoSet ELISA kits (R&D Systems) according to the protocols recommended by the company. Biopsies were classified according to Banff criteria. Results Median values of CXCL10 were 51.2 pg/ml (IQR 38.5 – 98.9 pg/ml) at 6 month and 62.8 pg/ml (IQR 42.7 – 99.4 pg/ml) at 12 month after transplantation. Both values were statistically related (r = 0.400, p = 0.012), and there were no significant statistical differences between both (Wilcoxon`s test p = 0.063). CXCL10 did not relate to serum creatinine, glomerular filtration rate, albuminuria, tacrolimus blood levels or prednisone dose at 1 year. Some 16.7% allograft biopsies showed subclinical cellular rejection, 26.7% showed antibody mediated rejection and 20.0% transplant glomerulopathy. Patients with antibody mediated rejection (AbMR) had higher levels of 1-year urinary CXCL10 [55.4 pg/ml (IQR 39.3) vs. 97.4 pg/ml (IQR 103.9), p = 0.021], lower GFR [68.0 ml/min/1.73m2 (IQR 33.5) vs. 43.5 ml/min/1.73m2 (IQR 22.8), p < 0.001] and similar albuminuria (p = 0.079). According to ROC curve, 1-year urinary CXCL10 could discriminate patients with subclinical AbMR (AUC-ROC 0.660, 95%CI 0.511-0.809, p = 0.021). After adjusting by GFR and albuminuria, 1-year urinary CXCL10 in a logarithmic scale was able to predict subclinical AbMR (OR 2.254, 95%CI 1.012-5.021, p = 0.047) by logistic regression analysis. Similarly, patients with subclinical AbMR at 1 year had higher levels of 6-month urinary CXCL10 [45.9 pg/ml (IQR 41.4) vs. 102.3 pg/ml (IQR 1935), p = 0.026]. Moreover, 6-month urinary CXCL10 could discriminate those patients who were going to show subclinical AbMR at 1-year (see figure; AUC-ROC 0.731, 95%CI 0.545-0.916, p = 0.027). After logistic regression, each tertil of 6-month urinary CXCL10 increased the risk of suffering subclinical AbMR more than thrice (OR 3.346, 95%CI 1.184-9.456, p = 0.023). Conclusion Both 6- and 12-month urinary CXCL10 relate to the diagnosis of subclinical AbMR by 1-year surveillance biopsies independently of other variables such as renal function and albuminuria. Of interest, by a non-invasive monitoring of urinary CXCL10 as early as at 6 months we can predict some subclinical histologic findings at 1 year, such as AbMR, that can have a strong impact on the transplant outcome.

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.

Beyond 10years, with or without an intestinal graft: Present and future?

Long-term outcomes in children undergoing intestinal transplantation remain unclear. Seventy-one children underwent intestinal transplantation in our center from 1989 to 2007. We report on 10-year posttransplant outcomes with (group 1, n=26) and without (group 2, n=9) a functional graft. Ten-year patient and graft survival rates were 53% and 36%, respectively. Most patients were studying or working, one third having psychiatric disorders. All patients in group 1 were weaned off parenteral nutrition with mostly normal physical growth and subnormal energy absorption. Graft histology from 15 late biopsies showed minimal abnormality. However, micronutrient deficiencies and fat malabsorption were frequent; biliary complications occurred in 4 patients among the 17 who underwent liver transplantation; median renal clearance was 87mL/min/1.73m2 . Four patients in group 1 experienced late acute rejection. Among the 9 patients in group 2, 4 died after 10years and 2 developed significant liver fibrosis. Liver transplantation and the use of a 3-drug regimen including sirolimus or mycophenolate mofetil were associated with improved graft survival. Therefore, intestinal transplantation may enable a satisfactory digestive function in the long term. The prognosis of graft removal without retransplantation is better than expected. Regular monitoring of micronutrients, early psychological assessment, and use of sirolimus are recommended.

Allograft Injury and Outcomes in African American Lung Transplant Recipients

African American patients (AA) have poorer outcomes than White patients (W) after heart and kidney transplant. Little is known about differential outcomes in lung transplantation (LTx). This study compares allograft injury and chronic allograft dysfunction (CLAD) in AA and W LTx. The 469 LTx enrolled in two multicenter prospective cohort studies were categorized by self-reported race. Time from transplant to CLAD-free survival adjudicated by a committee using ISHLT standard definitions. Serial post-transplant plasma samples (n=2152) were assayed for %ddcfDNA by shotgun sequencing. Baseline characteristics, post-transplant %ddcfDNA trends, tacrolimus trough levels and CLAD-free survival were compared between AA and W. LTx recipients were 79% W and 14 % AA. Donor-recipient race mismatch was more commonly observed for AA than for W (75.0% vs. 27.3%, p<0.01). Other baseline characteristics were similar in AA and W. During follow-up (median 19.8 months, IQR = 10.7 - 36.9), tacrolimus trough levels were similar in AA and W (9.2±0.1 vs. 9.0±0.1, p = 0.19). However, AA showed 1.5X higher rejection rates (HR = 1.6, CI = 1.0 - 2.6), and higher %ddcfDNA levels particularly beyond 6 months when maintenance immunosuppression doses were lowest (Figure A). Higher %ddcfDNA trends correlated inversely with CLAD-free survival; AA developed CLAD and/or died 18.8 (mean) months before W (Figure B). Similarly, acute rejection was inversely with CLAD-free survival. AA LTx show higher allograft injury and poorer CLAD-free survival than W LTx despite equivalent tacrolimus blood levels. Studies to understand the mechanisms of allograft injury and poor outcomes in AA are warranted across all solid organ transplants.

Influence of POR*28 Polymorphisms on CYP3A5*3-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation

It is well known that the CYP3A5*3 polymorphism is an important marker that correlates with the tacrolimus dose requirement after organ transplantation. Recently, it has been revealed that the POR*28 polymorphism affects the pharmacokinetics of tacrolimus in renal transplant patients. In this study, we examined whether POR*28 as well as CYP3A5*3 polymorphism in Japanese recipients and donors would be another biomarker for the variation of tacrolimus blood levels in the recipients during the first month after living-donor liver transplantation. We enrolled 65 patients treated with tacrolimus, who underwent liver transplantation between July 2016 and January 2019. Genomic DNA was extracted from whole-blood samples, and genotyping was performed to examine the presence of CYP3A5*3 and POR*28 polymorphisms in the recipients and donors. The CYP3A5*3/*3 genotype (defective CYP3A5) of the recipient (standard partial regression coefficient [median C/D ratio of CYP3A5 expressor vs. CYP3A5 non-expressor, p value]: Pod 1–7, β= −0.389 [1.76 vs. 2.73, p < 0.001]; Pod 8–14, β = −0.345 [2.03 vs. 2.83, p < 0.001]; Pod 15–21, β= −0.417 [1.75 vs. 2.94, p < 0.001]; Pod 22–28, β = −0.627 [1.55 vs. 2.90, p < 0.001]) rather than donor (Pod 1–7, β = n/a [1.88 vs. 2.76]; Pod 8–14, β = n/a [1.99 vs. 2.93]; Pod 15–21, β = −0.175 [1.91 vs. 2.94, p = 0.004]; Pod 22–28, β = n/a [1.61 vs. 2.67]) significantly contributed to the increase in the concentration/dose (C/D) ratio of tacrolimus for at least one month after surgery. We found that the tacrolimus C/D ratio significantly decreased from the third week after transplantation when the recipient carried both CYP3A5*1 (functional CYP3A5) and POR*28 (n = 19 [29.2%], median C/D ratio [inter quartile range] = 1.58 [1.39–2.17]), compared with that in the recipients carrying CYP3A5*1 and POR*1/*1 (n = 8 [12.3%], median C/D ratio [inter quartile range] = 2.23 [2.05–3.06]) (p < 0.001). In conclusion, to our knowledge, this is the first report suggesting that the POR*28 polymorphism is another biomarker for the tacrolimus oral dosage after liver transplantation in patients carrying CYP3A5*1 rather than CYP3A5*3/*3.

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.

Tacrolimus treatment in childhood refractory nephrotic syndrome: A retrospective study on efficacy, therapeutic drug monitoring, and contributing factors to variable blood tacrolimus levels

Tacrolimus, an immunosuppressive drug, was recommended by the 2012 KDIGO guidelines to treat nephrotic syndrome (NS) in children and adults. However, it has high interpatient pharmacokinetic variability and exposure levels should be monitored, although there are no specified target concentrations. This retrospective study aimed to review efficacy and safety after concomitant treatment with tacrolimus and prednisone, and to identify factors that contribute to the variable blood-trough-concentration-to-dose (C0/Dose) ratio in children with refractory NS (RNS). A 6-month therapy induced complete or partial remission in 95% of patients. One-year follow-up indicated a high remission rate and low nephrotoxicity. Under maintenance dosages, approximately 95% of the C0 values were 2–7 ng/mL. Body weight (BW), age, CYP3A5 polymorphisms were the factors affecting the C0/Dose ratio. The C0/Dose ratio in patients with a BW of <20 kg was 1.5-fold than that in patients with BW of ≥40 kg. Moreover, the C0/Dose ratio in patients aged 1–≤6 and 6–≤12 years was significantly lower than that in patients aged 12–≤18 years, by 25% and 48%, respectively. There were no significant association between CYP3A5 genotyping and C0/Dose ratio in younger children (1–≤6 years), rather than older children (6–≤18 years). In conclusion, routine CYP3A5 genotyping should be considered in children aged over 6 years and exposure levels (C0) of 2–7 ng/mL may be feasible when tacrolimus is combined with low-dose prednisone to treat childhood RNS.

Evaluation of Tacrolimus Levels and Risk of Graft-Versus-Host Disease, Relapse and Non-Relapse Mortality after Haploidentical Transplantation with Post-Transplant Cyclophosphamide

Following haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy), the range of target tacrolimus blood levels is wide (5-15 ng/ml). This fact, combined with pharmacogenomic variation and effects of drug interactions, leads to significant variability in tacrolimus serum concentrations. In the setting of matched related or unrelated donor transplantation using conventional graft-versus-host disease (GVHD) prophylaxis, several published studies have correlated higher post-transplant tacrolimus levels with a lower risk of GVHD. Therefore, we hypothesized that early post-transplant tacrolimus levels following haplo-HCT might impact the incidence of GVHD and other post-transplant endpoints and that more precise tacrolimus level targeting may improve post-transplant outcomes. To this end, we analyzed the relationship between mean weekly tacrolimus levels and acute and chronic GVHD, relapse, non-relapse mortality (NRM) and survival in 158 consecutive patients with hematologic malignancies receiving haplo-HCT using PTCy, tacrolimus and mycophenolate for GVHD prophylaxis between 2013-2018. Transplanted patients had a median age of 51 years (range, 19-75) and comorbidity index was ≥3 in 97 (61%). Peripheral blood was the graft source in 142 (90%), and regimen intensity was myeloablative in 90 (57%). Mean weekly tacrolimus levels were calculated each week for the first 4 weeks starting on day +7 and ending day +35 post-transplant, as well as aggregate mean tacrolimus level for 2- and 4-week intervals. Table 1 depicts a summary of the univariate analysis of weekly mean tacrolimus levels and various clinical endpoints (hazard ratios are depicted for each 1 ng/ml increment in mean tacrolimus levels). In this analysis, there were no significant associations between higher mean weekly tacrolimus levels and acute GVHD, chronic GVHD, relapse, NRM, or survival. Using tertiles, mean tacrolimus levels during weeks 1-4 were divided into <10.9 ng/ml, 10.9-13 ng/ml, and ≥13 ng/ml subgroups. In univariate analysis, there were no significant differences between mean weekly tacrolimus level subgroups and cumulative incidence of acute GVHD, chronic GVHD, relapse or NRM (Figure 1). In conclusion, following haplo-HCT with PTCy, there were no significant associations found between serum tacrolimus concentrations and the incidence of GVHD or other post-transplant outcomes. Given the lack of an obvious detrimental effect of lower tacrolimus levels, combined with the known toxicities associated with tacrolimus use (i.e. renal, neurologic, cardiovascular, diabetes mellitus), we speculate that lower target tacrolimus serum concentrations may be preferable following PTCy-based haplo-HCT.

Safety and efficacy of direct-acting antivirals for chronic hepatitis C in patients with chronic kidney disease

BackgroundThis is a real-world evidence study that aims to analyze the efficacy, tolerability and safety profile of paritaprevir/ombitasvir/ritonavir and dasabuvir, in patients with renal impairment.MethodsWe conducted an observational prospective study, on 232 patients with chronic kidney disease, undergoing treatment with paritaprevir/ombitasvir/ritonavir and dasabuvir, for chronic hepatitis C infection - genotype 1b. Renal and liver function were assessed at the beginning of therapy, monthly during treatment and three months after therapy completion.ResultsAll patients achieved sustained virologic response. Common side effects were nausea, fatigue and headache. Close monitoring of tacrolimus blood levels and dose reduction was required in kidney transplant recipients.ConclusionsHCV therapy in the setting of renal dysfunction has always been a challenging topic. Direct-acting antivirals have shown promising effects, demonstrating good tolerance and efficacy in patients with HCV infection and renal impairment. Sustained virologic response within our study population was 100%.

P466 Is it possible avoid colectomy with rescue dual therapy with vedolizumab plus tacrolimus in ulcerative colitis that losing response to anti-tumour necrosis factor?

Abstract Background There is an increasing number of ulcerative colitis (UC) patients that losing response to anti-tumour necrosis factor (TNF) drugs. There is low evidence about combining Tacrolimus (TAC) with vedolizumab (VED) for UC patients, who have failed treatment with anti-TNF therapy. The aim of the present study was to assess the efficacy and safety of TAC with VED in UC patient refractory to anti-TNF therapies. Methods Inclusion criteria: patients with moderately to severely active UC and who failed or showed intolerance to at least one TNF antagonists that received dual therapy with VED and oral TAC (Envarsus®). TAC blood levels were monitored at weeks 2,4,8 and then every 2 months. Rates of clinical response and remission were evaluated in November 2019 using the Mayo score. Clinical response was considered when PCR and calprotectin were decreased ³50% and biological remission was considered when PCR and calprotectin achieved normal values. Results Seven UC patients (1 proctitis, 3 left colon disease, 2 Pancolitis and 1 pouchitis) had sufficient dTNF for analysis. Demographic dTNF: age 51 ± years and 10.4 ± years since UC was diagnosed. All patients received thiopurine therapy and 86% received corticosteroids. 43% of patients were corticodependent and 43% were corticosteroid-refractory. 29% of patients failed to one TNF antagonists and 71% of patients failed to two TNF antagonists. Previous to started dual therapy; 29% of patients with moderate endoscopic activity and 71% of patients with severe endoscopic activity. Thiopurine treatment was suspended and 3 corticosteroid-refractory patients received IV cyclosporine therapy. The median dual therapy follow-up was 12.8 months (range 6–30 months). At the end of the study period; all patients presented clinical response, 86% of patients were corticosteroids free and biological remission was achieved in 71% of patients and any patient required colectomy. Fifty-seven per cent of patients needed VED dose intensification. Side effects were mild; abdominal pain (1), tremor (4), hypertension (1), moderate decrease creatinine clearance (1), insomnia (1) and arthralgías (1). Any patient discontinued dual therapy by adverse drug effect. At the end of the study, 4 patients continued with the dual therapy and 3 patients TAC was discontinued due to maintained clinical remission Conclusion In UC patients that losing response to anti-tumour necrosis factor (TNF) drugs and corticosteroid-refractory, the dual therapy with VED plus TAC could be an alternative, effective and safe therapy.

A prospective study of correlation of blood levels of tacrolimus to graft function and adverse effect of tacrolimus in postrenal transplant patients

Introduction: There are limited data on the symptoms of immune-suppressive therapy after transplant on Indian patients and how tacrolimus blood level correlates with graft function and its adverse effects. This study was planned to study these factors. Materials and Methods: The study was conducted as a prospective longitudinal study. Adult patients who underwent the live renal transplant and matched the inclusion criteria from March 2018 to April 2019 were enrolled for the study. Trends of all the parameters were analyzed and their correlation was done with corresponding tacrolimus blood levels. Blood for tacrolimus level was collected at d1, 5, 15, 30, 90, and 180, and values of serum creatinine, diabetes status, hypertensive status, lipid profile, infection occurrence, and liver function tests were recorded at the same time. The subjective symptom occurrence was also recorded by Modified Transplant Symptom Occurrence and Symptom Distress Scale questionnaire at 3 months. Results: The mean age of the study population was 33.7 ± 10.1 years. The incidence of infection was highest at 48% in the 1–3 month period. The incidence of posttransplant diabetes mellitus (PTDM) was 13.7%. Patients requiring antihypertensive decreased from 93.1% immediate posttransplant to 51.5% after 6 months of transplant. There was an increase in posttransplant triglyceride levels, total cholesterol, and low-density lipoprotein level with only high-density lipoprotein showing a protective trend. Liver functions did not show any derangements during the study period. There was no significant correlation between any of the adverse effects and tacrolimus blood levels. Excessive appetite was the most commonly experienced symptoms whereas tremor was the most distressing one. There was a statistically significant increase in symptoms experienced in patients whose tacrolimus blood level was above the normal level for that period. Conclusion: Our study showed no significant correlation between blood levels of tacrolimus and graft function and also with hypertension, dyslipidemia, PTDM, and incidence of posttransplant infections. The incidence of adverse effects was significantly higher in patients who had tacrolimus blood levels higher than recommended.

Assessment of knowledge and practice of Sudanese renal transplant recipients about tacrolimus usage: A cross-sectional study

BACKGROUND: Tacrolimus is an immunosuppressive drug used for the prevention of rejection in kidney transplant recipients (KTRs). There are many factors that can affect tacrolimus blood levels, include nonadherence, blood sampling time, food effect, and co-medication. This study aimed to assess Sudanese KTRs knowledge and practice about tacrolimus use. MATERIALS AND METHODS: This was a descriptive cross-sectional hospital-based study. The study population was Sudanese KTRs under tacrolimus-based therapy attending the renal transplant outpatient clinic in Khartoum renal dialysis and transplantation center from April to July 2018. A total of 190 KTRs were interviewed. The collected data were manually scored, coded, and then analyzed using SPSS. RESULTS: Regarding overall knowledge, approximately 46% of enrolled KTRs have a low level of knowledge about tacrolimus therapy, and there is a significant association between KTRs knowledge and their level of education. There is a variation between the knowledge about tacrolimus monitoring and KTRs' practice. The primary source of information for the KTRs was doctors, and more than half of them never forget to take the tacrolimus. Only 32.1% of KTRs have nonadherence problems. The association between KTRs knowledge and their level of education and the transplantation period was statistically significant. Regarding tacrolimus side effects, 50% of KTRs said they have been informed or read about the drug side effects. CONCLUSION: Knowledge of the Sudanese KTRs enrolled in this study was inadequate, and the behavior of them when suffering from a new complaint was relatively good. Great efforts are needed to improve their knowledge, to maintain graft function, and to prevent graft loss.

Topical treatment of oral lichen planus

Oral lichen planus (OLP) is a skin disease affecting the mouth, which can cause a burning or stinging discomfort in the mouth when eating or drinking. Ulcers may occur and these are especially painful. The cause of oral lichen planus is not known in most instances, but it is likely to be related to the body's immune system. In this study, the authors from China aimed to compare the efficacy and safety of drugs called topical calcineurin inhibitors (TCI) with medicines applied to the skin called topical corticosteroids (TCS), in the treatment of OLP. The authors looked at globally published randomized controlled trials (RCTs) reporting TCI (tacrolimus, pimecrolimus, and cyclosporine) compared with TCS for OLP from eight medical databases. Twenty‐one RCTs with a total of 965 patients published between 1995 and 2017 were included (tacrolimus‐TCS: 12 studies, 578 patients; pimecrolimus‐TCS: 3 studies, 98 patients; cyclosporine‐TCS: 6 studies, 289 patients). The authors found that TCI including tacrolimus, pimecrolimus and cyclosporine were similar to TCS in efficacy for the short‐term treatment of OLP (3‐8 weeks). In addition, tacrolimus 0.1% was similar to TCS in relapse rate. The blood levels of tacrolimus and cyclosporine were usually extremely low, while the few cases of patients with high levels may have been caused by swallowing the drug accidentally. Although a few adverse events (unwanted side effects) were observed in the tacrolimus and cyclosporine groups, no serious events were found. Therefore, TCI may be an alternative approach when OLP does not improve with use of TCS. Due to the limited trials of pimecrolimus and cyclosporine, as well as a few adverse events and high cost of cyclosporine, tacrolimus 0.1% should be the first drug of choice in TCI for the short‐term treatment of OLP that is not improving with TCS. More well‐designed RCTs are needed to evaluate the long‐term efficacy and safety of TCI compared with TCS.

Validation and evaluation of four sample preparation methods for the quantification of intracellular tacrolimus in peripheral blood mononuclear cells by UHPLC-MS/MS

Rejection and toxicity occur despite monitoring of tacrolimus blood levels during clinical routine. The intracellular concentration in lymphocytes could be a better reflection of the tacrolimus exposure. Four extraction methods for tacrolimus in peripheral blood mononuclear cells were validated and evaluated with UHPLC-MS/MS.Methods based on protein precipitation (method 1), solid phase extraction (method 2), phospholipids and proteins removal (method 3) and liquid–liquid extraction (method 4) were evaluated on linearity, lower limit of quantification (LLOQ), imprecision and bias. Validation was completed for the methods within these requirements, adding matrix effect and recovery.Linearity was 0.126 (LLOQ)-15 µg/L, 0.504 (LLOQ)-15 µg/L and 0.298 (LLOQ)-15 µg/L with method 1, 2 and 3, respectively. With method 4 non-linearity and a LLOQ higher than 0.504 µg/L were observed. Inter-day imprecision and bias were ≤4.6%, ≤10.9%; ≤6.8%, ≤-11.2%; ≤9.4%, ≤10.3% and ≤44.6%, ≤23.1%, respectively, with methods 1, 2, 3 and 4. Validation was completed for method 1 and 3 adding matrix effect (7.6%; 15.0%) and recovery (8.9%; 10.8%), respectively.The most suitable UHPLC-MS/MS method for quantification of intracellular tacrolimus was protein precipitation due to the best performance characteristics and the least time-consuming rate and complexity.

Pharmacokinetics of Tacrolimus in Egyptian Liver Transplant Recipients: Role of the Classic Co-variables

Objectives: This work was performed to study the pharmacokinetics of tacrolimus in adult liver transplant recipients after optimization of all the known classic factors contributing to inter-patient variability in whole blood tacrolimus levels. Also, to detect if any variability in whole blood tacrolimus levels still exists or this variability is only a function of the classic co-variables so that their optimization will diminish or eliminate it. Methods: Twenty-Six male patients with end-stage liver disease undergoing living donor liver transplantation were selected from the Gastroenterology Department of the International Medical Center, Cairo, Egypt, were enrolled in the study. A patient is initially considered to be a candidate for this study when tacrolimus was indicated as a part of a triple immune suppressive regimen with mycophenolate mofetil and prednisolone. Patients were selected to have non-significant variations in their demographics and pretreatment clinical data. Blood samples were drawn from each patient before the morning dose at specified intervals and the whole blood was assayed for tacrolimus, using Chemiluminescent Microparticle Immunoassay method (CMIA). Six months after liver transplantation, patients were classified into 3 groups based on their tacrolimus trough levels; normalized by its daily dose (C/D ratio), into fast, intermediate and slow metabolizers. Results: The results revealed unpredictable variability in whole blood tacrolimus levels among patients at each sampling time and a marked inter-patient variability in mean whole blood tacrolimus levels among individuals throughout the six months post transplantation period, (P value: <0.0001). Considerable inter-patient variability was also evident in tacrolimus pharmacokinetics. During 1st month post-transplant, tacrolimus C/D ratio varied from 0.53 to 12.2 (ng/ml*1/mg) and tacrolimus oral clearance (CL/F) varied from 3.4 to 79.4 L/hr. At 3rd month post-transplant, tacrolimus C/D ratio varied from 0.78 to 8.50 (ng/ml*1/mg) and tacrolimus CL/F varied from 4.9 to 53.2 L/hr. At 6th month post-transplant, tacrolimus C/D ratio varied from 0.73 to 7.10 (ng/ml*1/mg) and tacrolimus CL/F varied from 5.9 to 56.8 L/hr. The overall mean C/D ratio and oral clearance also showed a great variability among patients with a mean of 2.80±1.89 (CV: 67.5%) and 21.3±12.9 (CV:60.7%), respectively. Conclusion: The variability in whole blood tacrolimus concentrations and tacrolimus pharmacokinetics existed in spite of careful patient selection and optimization of all the classic co-variables known to affect tacrolimus concentrations, suggesting the presence of other unstudied factors; the recently evolving genetic factors might contribute to this variability. It is recommended to still considering therapeutic drug monitoring as an integral part of tacrolimus therapy to control variations in response until the discovery of a model that considers all the expected covariates to predict the response.

The Evolving Clinical Presentation of Acute Rejection in Facial Transplantation.

Acute rejection is one of the most frequent complications in facial transplantation, with potentially severe consequences for the recipient if overlooked. Clinical signs, such as erythema or edema, are helpful to diagnose acute rejection in the early follow-up stage; however, it is not well known whether these clinical signs remain reliable markers of acute rejection beyond the second posttransplant year. To determine the diagnostic value of clinical signs of acute rejection after facial transplantation over time. A retrospective, single-center cohort study was conducted of patients who underwent facial transplantation at Brigham and Women's Hospital between April 2009 and October 2014, with up to an 8-year follow-up. Medical records were reviewed until September 30, 2017. The medical records from 104 encounters with 7 patients who underwent partial or full facial transplantation were analyzed for symptoms of rejection, immunosuppressive therapy, and histopathologic findings. The occurrence of 5 clinical signs of acute rejection were evaluated: erythema, edema, exanthema, suture line erythema, and mucosal lesions. Odds ratios (ORs) were calculated to determine the statistically significant association of these signs with the histopathologic diagnosis of rejection. In addition, tacrolimus blood levels, as a surrogate marker of immunosuppressive therapy, were evaluated. Of the 7 patients included in the study, 5 were men. The mean follow-up was 66 months (range, 35-101). Of 104 clinical encounters, 46 encounters (44.2%) represented rejection episodes and 58 encounters (55.8%) represented no-rejection episodes. Beyond 2 years posttransplantation, only erythema (OR, 6.53; 95% CI, 1.84-20.11; P = .004) and exanthema (OR, ∞; 95% CI, 2.2-∞; P = .004) were demonstrated to be reliable clinical signs of acute rejection in facial transplantation. There was also a statistically significant association of subtherapeutic tacrolimus levels with late rejection episodes (OR, 3.79; 95% CI, 1.25-12.88; P = .03). In addition, the occurrence of subclinical rejection was more frequent during later follow-up times (7 [24.1%] late rejections vs 1 [5.9%] early rejection). Five of 8 subclinical rejections (62.5%) were associated with subtherapeutic tacrolimus levels. Clinical signs of acute rejection in facial transplantation appear to be of limited diagnostic value, particularly after the second postoperative year. Until alternative biomarkers for rejection are identified, protocol skin biopsies will remain necessary for guiding assessments of allograft rejection. 3.

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients.

Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1month and 2years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady-state blood concentrations collected 12hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log-transformed tacrolimus dose-normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (β=0.019, 95% confidence interval [CI], 0.010-0.028) and ALT values (β=0.00030, 95% CI, 0.00002-0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (β=-0.349, 95% CI, -0.631 to -0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1month and 2years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out-of-range therapeutic window that may lead to adverse drug reactions or acute rejection.