Pharmacokinetics of prolonged-release tacrolimus versus immediate-release tacrolimus in de novo liver transplantation: A randomized phase III substudy

Background With the same dose of tacrolimus, lower systemic exposure on the first day of dosing has been reported for prolonged-release tacrolimus compared with immediate-release tacrolimus, prompting investigation of differing initial doses. Methods This sub-study of a double-blind, randomized, phase III trial in de novo liver transplant recipients compared the pharmacokinetics of once-daily prolonged-release tacrolimus (initial dose: 0.2mg/kg/day) versus twice-daily immediate-release tacrolimus (initial dose: 0.1mg/kg/day) during the first 2 weeks post-transplant. Results Pharmacokinetic data were analysed from patients receiving prolonged-release tacrolimus (n=13) and immediate-release tacrolimus (n=12). Mean systemic exposure (AUC0–24) was higher with prolonged-release versus immediate-release tacrolimus. Dose-normalized AUC0–24 (normalized to 0.1mg/kg/day) showed generally lower exposure with prolonged-release tacrolimus versus immediate-release tacrolimus. There was good correlation between AUC0–24 and concentration at 24 hours after the morning dose (r=0.96 and r=0.86, respectively), and the slope of the line of best fit was similar for both formulations. Conclusions Doubling the initial starting dose of prolonged-release tacrolimus compared with immediate-release tacrolimus overcompensated for lower exposure on Day 1. A 50% higher starting dose of prolonged-release tacrolimus than immediate-release tacrolimus may be required for similar systemic exposure. However, doses of both formulations can be optimized using the same trough-level monitoring system. (ClinicalTrials . gov number: NCT00189826) Discipline liver transplantation/hepatology, immunosuppression/immune modulation. This article is protected by copyright. All rights reserved

Liver transplantation for acute liver failure – a 30-year single center experience

<p><b>Objective:</b> To determine overall long-term patient and graft survival rates among the recipients liver transplanted due to acute liver failure (ALF). Secondary aims included assessment of whether diagnosis, donor-recipient blood group compatibility and time-era of transplantation affected the outcome, and whether prescription-free availability of acetaminophen increased the need for liver transplantation (LTx).</p> <p><b>Materials and Methods:</b> A Retrospective cohort study of 78 patients who underwent LTx for ALF at Karolinska University Hospital 1984–2014. Patients were divided into two cohorts according to two 15-year periods: early cohort transplanted 1984–1999 (<i>n</i> = 40) and late cohort transplanted 2000–2014 (<i>n</i> = 38). Survival rates were established using Kaplan-Meier analyses.</p> <p><b>Results:</b> ALF patient survival rates for 1-year, 5-years, 10-years and 20-years were 71%, 63%, 52% and 40%, respectively. Survival for the late cohort at 1, 5 and 10 years was 82%, 76% and 71%, respectively. A high early mortality rate was noted during the first three months after transplantation when compared to LTx patients with chronic disease. Long-term survival rates were comparable between patients with ALF and chronic liver disease. Prescription-free access to acetaminophen did not increase the need for LTx. There was a strong trend towards improved survival in blood group identical donor-recipient pairs and blood group O recipients may have benefitted from this.</p> <p><b>Conclusions:</b> The high early mortality rate most likely reflects the critical pre-transplant condition in these patients and the urgent need to sometimes accept a marginal donor liver. Long-term survival improved significantly over time and variation in patient access to acetaminophen did not influence the rate of LTx in our region.</p

Atrial Fibrillation and Central Nervous Complications in Liver Transplanted Hereditary Transthyretin Amyloidosis Patients

Background. Central nervous system (CNS) complications are increasingly noted in liver transplanted (LTx) hereditary transthyretin amyloid (ATTRm) amyloidosis patients; this suggests that the increased survival allows for intracranial ATTRm formation from brain synthesized mutant TTR. However, atrial fibrillation (AF), a recognised risk factor for ischemic CNS complications, is also observed after LTx. The aim of the study was to investigate the occurrence of CNS complications and AF in LTx ATTRm amyloidosis patients. Methods. The medical records of all LTx ATTRm amyloidosis patients in the county of Vasterbotten, Sweden, were investigated for information on CNS complications, AF, anticoagulation (AC) therapy, hypertension, cardiac ischemic disease, hypertrophy, and neurological status. Results. Sixty-three patients that had survived for 3 years or longer after LTx were included in the analysis. Twenty-five patients had developed 1 or more CNS complications at a median of 21 years after onset of disease. AF was noted in 21 patients (median time to diagnosis 24 years). Cerebrovascular events (CVE) developed in 17 (median time to event 21 years). CVEs occurred significantly more often in patients with AF (P &lt; 0.002). AC therapy significantly reduced CVEs, including bleeding in patients with AF (P = 0.04). Multivariate analysis identified AF as the only remaining regressor with a significant impact on CVE (hazard ratio, 3.8; 95% confidence interval 1.1-9.5; P = 0.029). Conclusions. AF is an important risk factor for CVE in LTx ATTRm amyloidosis patients, and AC therapy should be considered. However, the increased bleeding risk with AC therapy in patients with intracranial amyloidosis should be acknowledged

Luciferase activity in a HepG2 cell line transfected with either of the constructs (pmirGLO-TTR-3′UTR–C/T for rs62093482).

<p>Luciferase activity was measured after 40 h, and normalized to a transfected empty vector. Data are presented as the mean of 20 measures ±CI. No difference between the two constructs was seen.</p

Luciferase activity in a COS-7 cell line co-transfected with the constructs (pmirGLO-TTR-3′UTR–C/T for rs62093482) together with different concentrations of miRNA.

<p>Luciferase activity was measured after 26 h, and normalized to a transfected empty pmirGLO vector. All experiments were made in triplicate, and data are shown as mean ±CI. a: miRNA-622 b: miRNA-643 c: miRNA-337-3p d: miRNA-325. No significant difference between the two constructs was seen regardless of concentration.</p

Allele specific expression from eight liver biopsies.

<p><b>A</b>. mRNA expression from the V30M and wild type allele were measured using a SNapShot assay. All eight samples were measured three times in independent assays. For each sample, the peak height from the cDNA sample was normalized by the peak height from the DNA samples. The results are presented as the allelic ratio between wild type and V30M expression for each sample, with the total expression from both the wild type allele and V30M allele set to 100%. Data are shown as mean ±CI. No difference between the two alleles was noted. b. Representative example of DNA and cDNA samples after SNaPshot assay measurements.</p