Blood Trough Levels Research Articles

Influence of ensitrelvir or nirmatrelvir/ritonavir on tacrolimus clearance in kidney transplant recipients: a single-center case series

BackgroundAmong the oral antivirals used for treating patients with mild-to-moderate novel coronavirus disease 2019 (COVID-19), nirmatrelvir/ritonavir (NMV/RTV) and ensitrelvir (ESV) are inhibitors of cytochrome P450 (CYP) 3A, and therefore, can cause drug–drug interactions with concomitant medications. Tacrolimus (TAC), a substrate of CYP3A4/5, is administered for a long period to prevent rejection after kidney transplantation. TAC should be discontinued while using NMV/RTV because blood TAC levels significantly increase when these drugs are concomitantly administered. However, the influence of ESV on blood TAC levels has not yet been reported, and the management of TAC doses during the use of ESV remains unclear.Case presentationWe experienced three kidney transplant recipients with COVID-19, whose blood trough levels of TAC increased by the concomitant use of NMV/RTV or ESV. In two patients administering NMV/RTV, blood trough levels of TAC increased more than tenfold after combination therapy, whereas in one patient administering ESV, TAC level increased approximately threefold.ConclusionsThese cases suggest that TAC administration should be discontinued during NMV/RTV treatment to maintain blood TAC levels within the therapeutic range, and a reduced TAC dose is sufficient during ESV treatment.

Pharmacodynamic monitoring by residual gene expression of the nuclear factor of activated T cell-regulated genes in lung transplant recipients and its correlation with tacrolimus blood levels.

Trough blood levels (C0) of tacrolimus are used to adjust drug dosage, but they do not consistently correlate with clinical outcomes. Measurement of residual gene expression of nuclear factor of activated T cell (NFAT)-regulated genes (NFAT-RGE) has been proposed as a pharmacodynamic biomarker to assess the degree of immunosuppression in certain solid organ transplantations, but little is known regarding lung transplant recipients (LTR). Our primary objective is to correlate tacrolimus blood levels with NFAT-RGE. NFAT-RGE and tacrolimus C0 and peak (C1.5) levels were determined in 42 patients at three, six and 12 months post-transplantation. Tacrolimus C0 did not exhibit a correlation with NFAT-RGE, whereas C1.5 did. Besides, over 20% of measurements indicated high levels of immunosuppression based on the below 30% NFAT-RGE threshold observed in many studies. Among those measurements within the therapeutic range, 19% had an NFAT-RGE<30%. Consequently, a subset of patients within the tacrolimus therapeutic range may be more susceptible to infection or cancer, potentially benefiting from NFAT-RGE and tacrolimus peak level monitoring to tailor their dosage. Further quantitative risk assessment studies are needed to elucidate the relationship between NFAT-RGE and the risk of infection, cancer, or rejection.

Contribution of genetic polymorphism in ABCB1 to individual variations of imatinib plasma levels in patients with gastrointestinal stromal tumor.

Imatinib mesylate (IM) is a first-line treatment option for the majority of patients diagnosed with gastrointestinal stromal tumors (GISTs). Although the clinical benefit is high, interindividual response is variable. This study thus aimed to assess how genetic polymorphisms can affect the blood levels of IM and treatment outcomes in patients with GIST. A total of 31 single-nucleotide polymorphisms (SNPs) in selected cytochrome P450 (P450), ATP-binding cassette transporter (ABC), solute carrier family (SLC), interleukin-4 receptor (IL4R), and vascular endothelial growth factor (VEGF) genes were genotyped using an SNP mass array platform. A total of 192 consecutive patients with GIST who received 400 mg of IM daily were enrolled into the study, with 1,485 blood samples being analyzed. According to genotypes, IM trough concentrations were tested and compared. Progression-free survival (PFS) and overall survival (OS) were also assessed. With a mean follow-up of 75.99 months, trough concentrations of imatinib were examined at average time points of 7.73 for each patient. Polymorphism in ABCB1 rs1045642 was found to be associated with steady-state IM trough plasma levels (P=0.008). Patients with the C genotype (CT + CC) of rs1045642 exhibited higher IM trough concentrations (1,271.09±306.69 ng/mL) compared to those with the TT genotype (1,106.60±206.05 ng/mL). No statistically significant differences in IM plasma concentration were observed for the other SNPs tested. None of the tested SNPs displayed a significant association with patients' survival in this study. This is the largest cohort study evaluating the associations of SNP and imatinib blood trough levels. The ABCB1 rs1045642 genetic polymorphism may exert an effect on the pharmacokinetics of imatinib. The presence of the C allele in ABCB1 rs1045642 is predictive of a higher plasma concentration of IM.

Ceftazidime/avibactam serum concentration in patients on ECMO.

The use of extracorporeal membrane oxygenation (ECMO) may alter blood levels of several drugs, including antibiotics, leading to under dosing of these drugs and thus to potential treatment failure. No data exist on pharmacokinetics of new antimicrobial, in particular ceftazidime/avibactam. We therefore perform this study to evaluate ceftazidime/avibactam blood levels in ECMO patients and find factors associated with underdosing. Retrospective observational study of patients on ECMO having received ceftazidime/avibactam and in whom trough blood levels of ceftazidime and avibactam were available. Main outcome measurement was the number of patients with ceftazidime and avibactam blood levels above predefined cut-off values, derived from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa, namely 8 mg/L for ceftazidime and 4 mg/L for avibactam, and explored factors associated with underdosing. Twenty-three ceftazidime/avibactam trough levels were available in 14 ECMO patients, all of them having received veno-venous ECMO for SARS-CoV-2-associated pneumonia. Although ceftazidime levels were above 8 mg/L in all except one patient, nine (39%) of the avibactam dosages were below 4 mg/L. Increased renal clearance (creatinine clearance > 130 mL/min) was the main factor associated with under dosing, since 7 out of the 10 dosages below the predefined cut-offs were measured in patients with this condition. In ECMO patients receiving ceftazidime/avibactam, ceftazidime and avibactam serum levels are above EUCAST breakpoints in most cases, justifying the use of normal dosing in ECMO patients. Increased renal clearance may lead to ceftazidime and avibactam under dosing.

Studying the Blood Trough Level of Tacrolimus on Patients after Kidney Transplant at the Uronephreulogical Department, Bach Mai Hospital, Vietnam

Tacrolimus, a calcineurin inhibitor, is a first-choice drug for the anti-rejection treatment regimen after kidney transplantation. The daily adjusted Tacrolimus dose by therapeutic drug monitoring is essential for patients to achieve optimal effects and minimize complications. We conducted a retrospective analysis of 70 kidney transplant patients at Bach Mai Hospital from January 2019 to the end of June 2020 to monitor changes in the blood trough level of Tacrolimus over time and analyze some risk factors affecting the blood trough level of Tacrolimus after a kidney transplant. Total whole-blood samples were collected at 6 time points: pre-transplant, on transplant day, and the 1st, 2nd, 4th, and 8th day after surgery. During the study, we recorded 4 cases with accelerated acute rejection with the blood trough level of Tacrolimus on the first day after transplantation of 5.325 ± 1.531 ng/mL and lower than the medium level in the remaining group of patients 10.371 ± 4.550 ng/mL at the same time (p = 0.031). There was no significant difference between the two groups of patients in age, gender, BMI, chronic disease status (hypertension, hepatitis C, type 2 diabetes), pre-transplant blood urea, and serum creatinine concentrations. These characteristics were included in the linear regression models which affected the blood trough level of Tacrolimus. This showed that none of the above risk factors had a significant effect on the blood trough level of Tacrolimus on the first day after transplantation (p &gt; 0.05).&#x0D; &#x0D;

Acute Diarrhea in Early Post-Transplant Period in Living Donor Kidney Transplant Recipients

Background: Acute diarrhea is common in Myanmar. People are so used to diarrhea at least once a year that they do not think diarrhea as an important problem. Acute diarrhea in early post-operative period in renal transplant recipient may result in pre-renal failure and delay graft function. This study aimed to identify the prevalence of diarrhea, its severity and response to treatment in early post-operative period (3 weeks after transplant) in living donor kidney transplant (LDKT) recipients. Patients and Methods: LDKT recipients having acute diarrhea in early post-transplant period at two transplant centers (Mingaladon and Nay Pyi Taw) in Myanmar were analyzed over 10 years period; from 2013 to 2023 September. Acute diarrhea is defined as three or more semisolid or liquid stools per day for a minimum of 1 day duration. It was a hospital based observational study. After obtaining diet history and physical examination, laboratory tests were done. Clinical parameters (diet, fever, features of oral candidiasis, features of dehydration, examination of abdomen), stool examination (stool inspection, stool examination for ova and cyst, stool for Clostridium difficle toxin, stool culture), blood tests (total WBC count, serum creatinine, liver function tests) and blood trough level for Tacrolimus and mycophenolate mofetil were done. Management was given according to algorithm and their response to treatment was recorded. Dose modification of immunosuppressants were done depending on full blood count and blood level of them. Results: A total of 230 LDKT recipients were observed; among them, thirteen percent (30/230) of recipients developed acute diarrhea in early post-operative period. The age ranged from 14 to 73 years. A majority of them had mild form; mild dehydration without significant changes in hemodynamic status. The peak onset of diarrhea was 4 to 5 days after transplant; majority resolved over one week. They did not have oral candidiasis. Abdominal examination was normal except mild tenderness over grafted kidney in all of them. Total WBC count and platelet count were normal except in two cases. Stool examination did not show trophozoite or cyst. Stool for Clostridium difficile toxin was not identified. With dietary modification and oral rehydration solution, their motion was back to normal in sixteen percent (5/30). Folic acid therapy with or without probiotics made resolution of diarrhea in 33.3% (10/30). Anti-infective therapy was given in 10% (3/30) of cases; norfloxacin to 2 cases. Intravenous colistin to one case as he had enterocolitis and septicemia due to Klebsiella pneumonia. His stool culture as well as blood culture showed Carbepenem resistant Klebsiella pneumonia; he was known case of myelodysplastic syndrome. Blood level of mycophenolate mofetil was normal; however, the dose was reduced in 2 cases owing to leucopenia or thrombocytopenia. Blood tacrolimus trough level was normal in two-third (20/30); and, it was high in one-third of them (20/30). They passed formed stool 24 - 48 hours after dose reduction of tacrolimus. Conclusion: In this study, 13% of the LDKT recipients had acute diarrhea in early post-operative period. Majority of them had mild form. Half of them recovered with oral rehydration solution, diet modification, folic acid and probiotics. Only one tenth of them had infective in origin and responded to anti-infective therapy. Raised blood tacrolimus trough level was found in one third of LDKT recipients with acute diarrhea; diarrhea improved dramatically after reduction of tacrolimus dose.

Tacrolimus monitoring in hair samples of kidney transplant recipients.

Calcineurin inhibitors, including tacrolimus, remain a cornerstone of immunosuppressive therapy after kidney transplantation. However, the therapeutic window is narrow, and nephrotoxic side effects occur with overdose, while the risk of alloimmunization and graft rejection increases with underdose. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows quantification of tacrolimus in biological samples from patients. This study investigates the feasibility of quantifying tacrolimus in scalp hair from kidney transplant (KT) recipients and correlates hair tacrolimus concentrations with tacrolimus dosage and blood trough levels. The aim was to provide proof-of-principle for hair tacrolimus drug monitoring in KT recipients. Single-center prospective study between September 9, 2021 and December 4, 2021, including KT recipients under tacrolimus. Minors, patients with active skin or hair diseases, and patients with scalp hair shorter than 4 cm were excluded from participation. Scalp hair was collected from the posterior vertex of patients, cut into segments, and analyzed for tacrolimus by LC-MS/MS. Patients filled out a questionnaire on hair treatments and washing habits. In parallel, tacrolimus trough levels were measured in whole blood and correlated with hair tacrolimus concentrations. In total, 39 consenting KT recipients were included, and hair samples were collected at 53 visits. Tacrolimus was detected in 98% of hair samples from patients exposed to the drug. Tacrolimus hair levels and whole blood trough levels were correlated with a beta coefficient of 0.42 (95% CI: -0.22-1.1, p = n.s.). Age and dark hair affected hair tacrolimus measurements, while different tacrolimus formulations (immediate release vs. extended release), hair washes, and permanent coloring did not. Longitudinal measurements in a subgroup of patients indicate that long-term measurement of hair tacrolimus levels is feasible. Measuring tacrolimus in hair is a potentially reliable method to monitor drug exposure in KT patients. Rapid wash-in effects and consistent concentrations over time indicate that tacrolimus is incorporated into the hair matrix, allowing temporal resolution in the analysis of recent exposure and exposure history. This method provides a simple and low-risk alternative to regular blood sampling, sparing patients from frequent hospital visits through the self-collection of hair samples.

Tacrolimus-why pharmacokinetics matter in the clinic.

The calcineurin inhibitor (CNI) Tacrolimus (Tac) is the most prescribed immunosuppressant drug after solid organ transplantation. After renal transplantation (RTx) approximately 95% of recipients are discharged with a Tac-based immunosuppressive regime. Despite the high immunosuppressive efficacy, its adverse effects, narrow therapeutic window and high intra- and interpatient variability (IPV) in pharmacokinetics require therapeutic drug monitoring (TDM), which makes treatment with Tac a major challenge for physicians. The C/D ratio (full blood trough level normalized by daily dose) is able to classify patients receiving Tac into two major metabolism groups, which were significantly associated with the clinical outcomes of patients after renal or liver transplantation. Therefore, the C/D ratio is a simple but effective tool to identify patients at risk of an unfavorable outcome. This review highlights the challenges of Tac-based immunosuppressive therapy faced by transplant physicians in their daily routine, the underlying causes and pharmacokinetics (including genetics, interactions, and differences between available Tac formulations), and the latest data on potential solutions to optimize treatment of high-risk patients.

Therapeutic Drug Monitoring of Tacrolimus in Tunisian Renal Transplant Patients during the Tuberculosis Infection: A Retrospective, Observational, Single-centre Analysis.

A retrospective, observational, single-center analysis was performed at the Department of Clinical Pharmacology (National Centre of Pharmacovigilance, Tunisia). We analyzed the database of patients who received TAC from 2009 until 2018. We included samples provided from renal transplant patients infected by Mycobacterium tuberculosis after transplantation. Trough blood levels (C0) were determined using an immunoassay analyzer. The Therapeutic Range (TR) of TAC was considered between 5 and 10 ng/mL. Pharmacokinetic parameters were compared between the period of co-administration of TAC/ATT (period A) and the period during which patients received only TAC (period B). Seven renal transplant patients treated by TAC were included. 41 samples were analyzed (16; period A, 25; period B). Only 6 % of C0 values were found within TR during period A, while this rate was 44% during period B. During period A, 88% of TAC C0 was under the lower limit of TR, indicating a high risk of transplant rejection. The mean C0 and C0/D were significantly lower during period A (3.11±1.53 ng/mL vs 7.11 ± 3.37 ng/mL; p = 0.001 and 33.06 ± 24.89 vs 83.14 ± 44.46; p = 0.0006, respectively), without difference in doses between periods. Considering the results of this study, clinicians are suggested to monitor TAC closely in this particular circumstance.

Torque Teno Virus Load Predicts Opportunistic Infections after Kidney Transplantation but Is Not Associated with Maintenance Immunosuppression Exposure.

Measuring the non-pathogenic Torque Teno Virus (TTV) load allows assessing the net immunosuppressive state after kidney transplantation (KTx). Currently, it is not known how exposure to maintenance immunosuppression affects TTV load. We hypothesized that TTV load is associated with the exposure to mycophenolic acid (MPA) and tacrolimus. We performed a prospective study including 54 consecutive KTx. Blood TTV load was measured by an in-house PCR at months 1 and 3. Together with doses and trough blood levels of tacrolimus and MPA, we calculated the coefficient of variability (CV), time in therapeutic range (TTR) and concentration/dose ratio (C/D) of tacrolimus, and the MPA-area under the curve (AUC-MPA) at the third month. TTV load at the first and third month discriminated those patients at risk of developing opportunistic infections between months 1 and 3 (AUC-ROC 0.723, 95%CI 0.559-0.905, p = 0.023) and between months 3 and 6 (AUC-ROC 0.778, 95%CI 0.599-0.957, p = 0.028), respectively, but not those at risk of acute rejection. TTV load did not relate to mean tacrolimus blood level, CV, TTR, C/D and AUC-MPA. To conclude, although TTV is a useful marker of net immunosuppressive status after KTx, it is not related to exposure to maintenance immunosuppression.

A203 EARLY PROACTIVE DRUG MONITORING STRATEGY OF INFLIXIMAB AS MONOTHERAPY FOR INFLAMMATORY BOWEL DISEASE IN PAEDIATRIC PATIENTS IS ASSOCIATED WITH GOOD SUSTAINED CLINICAL REMISSION

Abstract Background Monotherapy with Infliximab (IFX) can be as efficient as combotherapy with immunomodulators in the treatment and maintenance of remission for children with inflammatory bowel disease (IBD) if an early proactive therapeutic drug monitoring strategy is adequately performed. This strategy may allow optimization of blood levels of IFX in order to obtain a sustained clinical response. Purpose This study demonstrated that with appropriate early trough levels of IFX before dose #3 and dose #4 , monotherapy was very efficient in inducing remssion at week 52 . Method A retrospective study was conducted at CHU Sainte-Justine, Montréal,Canada .Children with IBD 2 to 18 years old diagnosed between 01/2018 and 06/2020 and treated with IFX less than 30 days after diagnosis were included .IFX blood levels were collected before the 3rd and/or 4th dose of IFX and regularly thereafter. Adjustments were done in IFX dose per infusion according to blood levels and clinical response. The primary outcome was clinical remission at one year after diagnosis.The secondary outcomes included: (1) At 52 weeks, the median (IQR) dose of IFX (mg/kg) and the intervals between IFX infusions ; (2) the median (IQR) number of IFX dose changes and the median (IQR) number of blood trough levels of IFX done. Result(s) 101 patients were included : 56.4% males; 81CD; 18 UC; 2 IBDU. Mean age at diagnosis was 13.2 years (IQR = 11.20 to 15. 20). Median time to IFX initiation after diagnosis was 5 days (IQR :3-14).Median IFX dose #1: was 8.4 mg/kg (IQR = 5. 8 to 10). 90% of patient had an IFX optimisation (increasing dose and/or shortening intervals) after dose 3 or dose 4. At week 52, 36,5% of patients were receiving IFX infusion every 4 weeks and 30,6% every 6 weeks. The median IFX dose per infusion was 8,9mg/kg (IQR = 7.4- 9,8 ). The IFX doses at week 52 varied greatly according to age at diagnosis The median number of IFX blood level dosage was 4 per patient over a year (IQR=3-5).At week 52, 83 patients (84.6%) achieved clinical remission with a median IFX level of 10.96 (7.05-15.59). 74 /83 (89%) were on monotherapy and 9/83(10.8%) on combotherapy Image Conclusion(s) Early treatment for IBD with IFX as monotherapy and an early proactive optimization strategy is associated with a good sustained steroid free clinical remissionAt week 52, 83 patients (84.6%) achieved clinical remission with a median IFX level of 10.96 (7.05-15.59). 74 /83 (89%) were on monotherapy and 9/83(10.8%) on combotherapy.The majority of the patients required IFX optimization during their first year of treatment. We therefore recommend to proactively monitor blood levels of IFX before the third and fourth dose of IFX and thereafter, in order to lower the risk of treatment failure and anti-infliximab antibodies occurrence. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest C. Girard: None Declared, S. Ackhar: None Declared, S. Sassine: None Declared, L. Chapuy: None Declared, P. Jantchou: None Declared, C. Deslandres Speakers bureau of: moderator and speaker Abbvie and Janssen

Successful Multimodal Therapy with Intracerebral Liposomal Amphotericin B and Systemic High-Dose Isavuconazole in Proven Disseminated Aspergillosis

We report the case of a 32-year-old man receiving chemotherapeutics for an acute B-lymphoblastic leukemia who developed proven cerebral and pulmonary aspergillosis with Aspergillus flavus. Because of progressive fungal disease with neurological deterioration despite adequate systemic antifungal therapy and surgical debridement, intracerebral administration of liposomal amphotericin B was initiated at 5 mg twice weekly. This led to improvement of the cerebral infection. Surgical debridement of a pleural Aspergillus empyema was necessary, and pleural trough level of isavuconazole was found to be subtherapeutic despite adequate blood trough levels, which led us to increase the dose of isavuconazole. We conclude that intralesional amphotericin B might be beneficial at 5 mg twice weekly in cerebral aspergillosis if systemic antifungals and surgical debridement fail. In Aspergillus empyema, measurement of pleural isavuconazole trough levels should be considered.

Visual evoked potentials as a method for the prospective assessment of tacrolimus neurotoxicity in patients after kidney transplantation

IntroductionNeurotoxicity, including optic nerve injury, is one of the most common adverse effects of tacrolimus, the principal calcineurin inhibitor used after kidney transplantation (KTx). The electrophysiologic measurements of both pattern visual evoked potentials (PVEP) and flash visual evoked potentials (FVEP) are valuable when drug-induced optic neuropathy is suspected.ObjectivesTo determine whether VEP measurement is a sensitive and repeatable method for monitoring tacrolimus neurotoxicity.Material and methodsThis prospective study focused on 35 patients (20 M, 15F, 69 eyes, mean age 43 ± 11 years) who were at a median of 3.0 (IQR, 2.2–3.7) months after KTx at the time of the initial VEP evaluation and were treated with tacrolimus since KTx. The follow-up VEP examination was done after a median of 24 (22–27) months (both VEP measurements followed the ISCEV standards). The P100 wave latency and amplitude for the 1° and 15’ PVEP simulations, and the P2 wave latency and amplitude for the FVEP were analyzed.ResultsFor the 1° checks, the P100 wave latency and amplitude values were significantly worse in the follow-up examination compared to the early post-transplant time-point. Independent associations between FVEP parameters and the tacrolimus blood trough level were observed in the follow-up examination but not at the early post-transplant period. The P2 wave latency correlated with the tacrolimus trough level only in patients treated with the twice-daily, but not the once-daily, tacrolimus formulation. The brain derived neurotrophic factor (BDNF) level correlated with the P100 (15’) latency (R = 0.499; p = 0.005) and the P2 latency (R = 0.409; p = 0.025) only in patients treated with the once-daily, but not the twice-daily, tacrolimus formulation.ConclusionThe observations in this study may support the rationale for the use of VEP measurements as non-invasive monitoring of subclinical tacrolimus neurotoxicity.

P8.127: Risk Factors for Chronic Allograft Rejection After Kidney Transplantation: A Systematic Review and Meta-Analysis

Introduction: Kidney transplantation has better outcome compared to dialysis patients. With high demand and low supply, it is important to maximize graft longevity. One of risk factors for graft failure is allograft rejection. Chronic allograft rejection occurs months or years after transplantation. Multiple studies have been analyzing risk factors for this entity. Our study aimed to evaluate risk factors for chronic allograft rejection after kidney transplantation. Method: We systematically searched Pubmed, Directory of Open Access Journal (DOAJ), Cochrane Central Register of Controlled Trials (CENTRAL) and Science Direct on March 8th, 2022. Result: Total ten studies of 25,774 kidney transplant patients were included in this study. Mean age difference between chronic allograft rejection and non-chronic allograft rejection was -3.41 years (p < 0.00001). Human leucocyte antigen (HLA) was a risk factor. Lower body surface area (BSA) ratio was associated with higher risk. Higher triglyceride and IL-6 was a risk factor. In association with kidney function, worse kidney function (proteinuria, higher creatinine post-transplant and higher urea) was a risk factor. Acute rejection was a risk factor (RR 2.37 [1.91, 2.96]; p < 0.00001; I2=7%; p = 0.30). Low cyclosporin A (CsA) whole blood trough levels post transplantation (< 110 ng/mL) was a risk factor. Conclusion: Younger recipient age, HLA, lower BSA ratio were risk factors for chronic allograft rejection. Post transplantation, worse kidney function, higher triglyceride, higher IL-6, acute rejection and low CsA whole blood trough levels were risk factors. The authors would like to thank all authors from the analyzed studies. The authors would also thank all staff of the Division of Nephrology and Hypertension in Department of Internal Medicine in Udayana University Sanglah Hospital, Denpasar, Bali-Indonesia.

MO1007: Intestinal Permeability in Patients After Kidney Transplantation Treated with Two Different Formulations of Extended-Release Tacrolimus

Abstract BACKGROUND AND AIMS A prompt achieving of adequate tacrolimus blood exposure is crucial in early period after kidney transplantation. A gut epithelial barrier integrity may play a role in tacrolimus absorption. The aim of this study was to investigate the intestinal fatty acid binding protein (I-FABP) concentrations as a marker of intestinal permeability in recent kidney transplant recipients (KTRs) treated with two different tacrolimus extended-release formulations. METHOD 48 pairs of consecutive KTRs were analyzed. Within each pair, an early conversion was performed from twice-daily (Prograf) to a once-daily tacrolimus formulation: Advagraf or Envarsus. On the day of discharge from the hospital, I-FABP plasma levels were measured and the tacrolimus concentration-to-dose (C/D) ratio was calculated. Tacrolimus exposure was assessed with an area under the curve (AUC) based on blood trough level and 3-h post-dose measurement. RESULTS There were no differences in recipient age, dialysis vintage, BMI and residual diuresis between the Advagraf and Envarsus groups. The median I-FABP plasma levels [Advagraf: 1450 (750–2100) versus Envarsus 1200 (600–1790) pg/mL; P = .18] and mean tacrolimus AUC [154 (143–164) versus 145 (132–158) ng.h/mL, respectively; P = .30] were similar. As expected, C/D ratio was significantly greater in the Envarsus group [2.06 (1.32–3.09) versus 1.16 (0.72–1.52) in the Advagraf group; P &amp;lt; .001]. Interestingly, log I-FABP correlated inversely with tacrolimus AUC only in the Envarsus group (r = –0.431; P &amp;lt; .01) but not in the Advagraf group (r = 0.05; P = .72). CONCLUSION Our findings suggest that destabilization of the enterocyte membrane integrity may influence the intestinal tacrolimus absorption, which may cause lower tacrolimus exposure in KTRs treated with Envarsus. However, explanation of this phenomenon needs further investigation.

Plasma Drug Concentration of Propranolol and Genetic Study in Chinese Han Patients With Infantile Haemangioma.

Background and PurposeThis study was conducted to explore the plasma drug concentration of propranolol in Chinese Han patients with infantile haemangioma (IH) and the influencing factors, as well as the relationship among plasma drug concentrations of propranolol, β1-AR mutation and CYP2D6 188C>T, efficacy, and safety.Experimental ApproachFrom January 2018 to April 2019, 140 patients with IH who were admitted to the hospital for oral propranolol and agreed to have their plasma concentration of propranolol tested, including 112 patients with β1-AR and CYP2D6 gene tested.Key Results and Conclusions and ImplicationsThe mean peak blood levels of propranolol, 4-hydroxypropranolol (4-OH-P), and N-deisopropylpropranolol (NDP) were 60.35 ± 37.90, 1.90 ± 2.37, and 0.24 ± 0.18 ng/ml, respectively. The mean trough blood levels of propranolol, 4-OH-P, and NDP were 24.98 ± 17.68, 0.45 ± 0.52, and 0.05±0.05 ng/ml, respectively. The higher the dose of propranolol, the higher the plasma concentration of propranolol (p = 0.031). The plasma concentration of propranolol was not related to the treatment efficacy.

Rapamycin in Cerebral Cavernous Malformations: What Doses to Test in Mice and Humans.

Cerebral cavernous malformations (CCMs) are hemorrhagic neurovascular lesions that affect more than 1 million people in the United States. Rapamycin inhibits CCM development and bleeding in murine models. The appropriate dosage to modify disease phenotype remains unknown. Current approved indications by the U.S. Food and Drug Administration and clinicaltrials.gov were queried for rapamycin human dosing for various indications. A systematic literature search was conducted on PubMed to investigate mouse dosimetry of rapamycin. In humans, low daily doses of <2 mg/day or trough level targets <15 ng/mL were typically used for benign indications akin to CCM disease, with relatively low complication rates. Higher oral doses in humans, used for organ rejection, result in higher complication rates. Oral dosing in mice, between 2 and 4 mg/kg/day, achieved blood trough levels in the 5-15 ng/mL range, a concentration likely to be targeted in human studies to treat CCM. Preclinical studies are needed utilizing dosing strategies which achieve blood levels corresponding to likely human dosimetry.

Role of Immunosuppression on Efficacy of Anti-SARS-CoV-2 Vaccines in Heart Transplanted (HT) Patients

PurposeVaccines against COVID-19 have a lower efficacy in HT patients (pts); factors influencing their immunogenicity are unknown. The aim of this study is to investigate the role of immunosuppression on mRNA vaccines efficacy.MethodsWe included all HT pts followed in our Center completing the vaccine cycle (03-06/21), for whom levels of IgG anti-RBD after the second dose were known, excluding those with a previous COVID infection. Demography, immunosuppression (drugs and trough blood level), lymphocyte count, previous rejection episodes were collected before the first dose. The endpoint was vaccine-induced immunization after the second dose according to our laboratory's threshold of IgG anti-RBD.ResultsAmong 201 vaccinated, IgG anti-RBD values were available for 63 pts at 2± 1 months after the second dose (22±3 days after the first; 89% BNT162b2; 60±11 yrs, 5±1 yrs from HT, 75% males, 3 with rejection > 1R in the previous 6 months). All pts were on CNI-inhibitors (35% tacrolimus, TAC, 65% cyclosporine, CyA), 57% on MMF, 23% mTOR, 69% steroids (CS). 41.7% had no response to vaccine. At univariate analysis the predictors of lack of response to vaccine were: MMF (43% vs 71%), TAC vs CSA (27% vs 73%), steroids (46% vs 76%), steroid dose > 5mg, lymphocytes <18% of leukocytes (both identified by ROC), more than 5 years from HT; mTOR was more likely associated with protection (80% vs 49%), p<0.05 all. Importantly, age was not predictive of immunogenicity. At stepwise multivariate analysis all these factors maintained statistical significance (p<0.05 all). IgG anti-RBD values were influenced by low lymphocytes, steroids and TAC trough levels (p< 0.05 all).Response to vaccine was the lowest for MMF+TAC+CS (23.1%), intermediate for MMF+CyA+CS (53.3%) and steroid-free regimens (68.7%), highest (87.5%) for mTOR+CNI+CS (20%,23%,24%,23% of pts, p=0.01). No rejection episodes were registered 3 months after the second dose of vaccine.ConclusionWhile confirming a low response to COVID-19 vaccines a in HT pts, our study underscores the negative effect of immunosuppression, particularly of MMF, high doses of steroids and TAC. Given that MMF is a cornerstone of most protocols, from these results it arises the hypothesis (to be tested in larger studies) if switching stable patients from TAC to Cya or to lower steroid doses may favor the attempts to increase the response to vaccines.

The Relationship between Initial Tacrolimus Metabolism Rate and Recipients Body Composition in Kidney Transplantation.

There are several premises that the body composition of kidney transplant recipients may play a role in tacrolimus metabolism early after transplantation. The present study aimed at analyzing the relationship between the body composition parameters assessed by bioimpedance analysis (BIA) and initial tacrolimus metabolism. Immediately prior to transplantation, BIA using InBody 770 device was performed in 122 subjects. Tacrolimus concentration-to-dose (C/D) ratio was calculated based on the first blood trough level measurement. There was no difference in phase angle, visceral fat area, lean body mass index (LBMI) and the proportion of lean mass as a percentage of total body mass between the subgroups of slow and fast metabolizers. However, subjects with LBMI ≥ median value of 18.7 kg/m2, despite similar initial tacrolimus dose per kg of body weight, were characterized by a significantly lower tacrolimus C/D ratio (median 1.39 vs. 1.67, respectively; p < 0.05) in comparison with the subgroup of lower LBMI. Multivariate regression analysis confirmed that age (rpartial = 0.322; p < 0.001) and LBMI (rpartial = −0.254; p < 0.01) independently influenced the tacrolimus C/D ratio. A LBMI assessed by BIA may influence the tacrolimus metabolism in the early post-transplant period and can be a useful in the optimization of initial tacrolimus dosing.

Association Between Blood and Lymphocyte Levels of Cyclosporin A and Infectious Complications in Renal Transplant Patients.

ObjectivesThis study aims to investigate a potential association between whole blood and lymphocyte Cyclosporin A (CyA) levels and the occurrence and frequency of infectious complications in kidney transplant patients.MethodsThe study involves 130 kidney transplant recipients who received CyA in addition to Mycophenolate Mofetil and steroids. CyA whole blood trough and maximum level (CyA BL0 and CyA BLm) as well as the corresponding levels in the lymphocytes (CyA L0 and CyA Lm) were measured for 6 months post-transplantation.ResultsCytomegalovirus (CMV) as well as urinary tract infections (UTIs) were the most commonly diagnosed with an incidence of 24.6% and 26.2%, respectively. Only CyA L0 showed a significant association with CMV infection occurrence (adjusted OR = 1.051, 95% CI .997–1.025, P-value 0.046). A positive linear correlation was found between CyA BL0, CyA BLm and CyA Lm and the number of CMV episodes per patient.ConclusionWe showed an association between the CMV infections occurrence and the trough lymphocyte level of CyA (CyA L0). Both lymphocyte CyA levels also correlated with the frequency of CMV infections. Further studies are needed to establish the optimal range of both CyA blood and lymphocyte levels and decrease the risk of opportunistic infections in high risk patients.