-
1.
Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor.
Chavan, A, Burke, L, Sawant, R, Navarro-Gonzales, P, Vargo, D, Paulson, SK
Clinical pharmacology in drug development. 2021;(8):950-958
Abstract
Vadadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in development for the treatment of anemia of chronic kidney disease. This phase 1, open-label, parallel-group, single-dose study evaluated the pharmacokinetics of 450-mg vadadustat in adults with moderate hepatic impairment (Child-Pugh class B) vs those with normal hepatic function. Primary end points were area under the plasma concentration-time curve (AUC) from dosing to last concentration and to infinity, as well as maximum concentration (Cmax ); additional pharmacokinetic parameters included time to Cmax (Tmax ) and half-life. Safety and tolerability were also assessed. All enrolled participants (n = 16) completed the study. Demographics were similar in both groups (overall, 100% White; 62.5% female; mean age, 59.2 years). Vadadustat plasma exposure was higher in the moderate hepatic impairment group, whereas maximum concentration was similar between groups. Point estimates of the hepatic impairment : normal geometric mean ratios (90% confidence interval) for AUC from dosing to last concentration, AUC from dosing to infinity, and Cmax were 1.05 (0.82-1.35), 1.06 (0.82-1.36), and 1.02 (0.79-1.32), respectively. Mean elimination half-life was 5.8 and 7.8 hours in the normal and hepatic impairment groups, respectively. Treatment-emergent adverse events were mostly mild in severity, and vadadustat was generally well tolerated. In conclusion, moderate hepatic impairment did not significantly impact vadadustat systemic exposure, and mild hepatic impairment is unlikely to alter vadadustat exposure.
-
2.
Contrast-Enhanced Ultrasound for the Characterization of Malignant versus Benign Focal Liver Lesions in a Prospective Multicenter Experience - The SRUMB Study.
Sporea, I, Săndulescu, DL, Şirli, R, Popescu, A, Danilă, M, Spârchez, Z, Mihai, C, Ioanițescu, S, Moga, T, Timar, B, et al
Journal of gastrointestinal and liver diseases : JGLD. 2019;:191-196
Abstract
AIM: This study evaluated the accuracy of contrast-enhanced ultrasound (CEUS) for the differential diagnosis of benign vs. malignant focal liver lesions (FLL) in a real-life, multicenter experience. METHODS This prospective study, including 14 Romanian centers, was performed over a 6 year period (February 2011- April 2017) and included 2062 FLLs assessed by CEUS. Inclusion criteria were: newly diagnosed FLL on B-mode ultrasound, less than three lesions/patient, all FLLs evaluated by CEUS and by a second-line imaging technique (contrast enhanced CT or contrast enhanced MRI) or histology, considered as reference. The trial was registered in clinicaltrials.gov (Identifier NCT01329458). RESULTS From the 2062 FLLs included in the study, 57.2% (1179) were malignant and 42.8% (883) were benign. CEUS had 83.9% sensitivity (Se), 97.8% specificity (Sp), 98.1% positive predictive value (PPV), 82.2% negative predictive value (NPV) and a diagnostic accuracy (Ac) of 89.9% for the positive diagnosis of malignant lesions. For the benign lesions, CEUS had 97.8% Se, 83.9% Sp, 82.2% PPV, 98.1% NPV 89.9% Ac. The diagnostic performance of CEUS for hepatocellular carcinoma was 76.6% Se, 98.4% Sp, and 91.2% Ac; for hemangioma: 89.2% Se, 99% Sp, and 96.9% Ac and for metastases: 90.9% Se, 98.4% Sp, and 96.9% Ac. CONCLUSIONS CEUS proved a high accuracy in differentiating the malignant vs. benign character of a FLL. It can be confidently used as a first line imaging method in daily practice.
-
3.
Long-term follow-up of five yr shows superior renal function with everolimus plus early calcineurin inhibitor withdrawal in the PROTECT randomized liver transplantation study.
Sterneck, M, Kaiser, GM, Heyne, N, Richter, N, Rauchfuss, F, Pascher, A, Schemmer, P, Fischer, L, Klein, CG, Nadalin, S, et al
Clinical transplantation. 2016;(6):741-8
Abstract
BACKGROUND The 12-month (M) PROTECT study showed that de novo liver transplant recipients (LTxR) who switched from a calcineurin inhibitor (CNI)-based immunosuppression to a CNI-free everolimus (EVR)-based regimen showed numerically better renal function. Here, we present the five-yr follow-up data. METHODS PROTECT was a randomized controlled study in which LTxR received basiliximab and CNI-based immunosuppression ± corticosteroids. Patients were randomized 1:1 to receive EVR or continue CNI. Patients completing the core study could enter the extension study on their randomized treatment. RESULTS A total of 81 patients entered the extension study (41, EVR; 40, CNI). At M59 post-randomization, the adjusted mean eGFR was significantly higher in the EVR group, with a benefit of 12.4 mL/min using Cockcroft-Gault (95% CI: 1.2; 23.6; p = 0.0301). Also, there was a significant benefit for adjusted and unadjusted eGFR using the four-variable Modification of Diet in Renal Disease (MDRD4) or Nankivell formula. During the extension period, treatment failure rates were similar. SAEs occurred in 26 (63.4%) and 28 (70.0%) of the patients in EVR and CNI groups, respectively. CONCLUSION Compared with the CNI-based treatment, EVR-based CNI-free immunosuppression resulted in significantly better renal function and comparable patient and graft outcomes after five-yr follow-up.
-
4.
Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation.
Sterneck, M, Kaiser, GM, Heyne, N, Richter, N, Rauchfuss, F, Pascher, A, Schemmer, P, Fischer, L, Klein, CG, Nadalin, S, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2014;(3):701-10
-
-
Free full text
-
Abstract
The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.
-
5.
Detection and characterization of focal liver lesions: a Japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular carcinoma and chronic liver disease.
Ichikawa, T, Saito, K, Yoshioka, N, Tanimoto, A, Gokan, T, Takehara, Y, Kamura, T, Gabata, T, Murakami, T, Ito, K, et al
Investigative radiology. 2010;(3):133-41
Abstract
OBJECTIVES To prospectively evaluate the safety and efficacy of combined unenhanced and gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging compared with unenhanced MR imaging and triphasic contrast-enhanced spiral computed tomography (CT) for the detection and characterization of focal liver lesions. MATERIALS AND METHODS The study was reviewed and approved by the institutional review board at each of the 15 centers involved in the study, and informed written consent was given by all patients. In total, 178 patients with suspected focal hepatic lesions (based, in most patients, on CT, tumor marker and ultrasound examinations) underwent combined MR imaging with a single, rapid injection of Gd-EOB-DTPA 0.025 mmol/kg, including T1-weighted dynamic and delayed MR images 20 to 40 minutes postinjection. Triphasic contrast-enhanced CT, the comparator examination, was performed within 4 weeks of MR imaging. Standard of references (SOR) were resection histopathology and intraoperative ultrasonography, or combined CT during arterial portography and CT hepatic arteriography; in cases where, although the major lesions were treated, some lesion(s) were not treated, follow-up superparamagnetic iron oxide-enhanced MR imaging was additionally performed. All images were assessed for differences in lesion detection and characterization (specific lesion type) by on-site readers and 3, blinded (off-site) reviewers. All adverse events (AEs) occurring within 72 hours after Gd-EOB-DTPA administration were reported. RESULTS Overall, 9.6% of patients who received Gd-EOB-DTPA reported 21 drug-related AEs. A total of 151 patients were included in the efficacy analysis. Combined MR imaging showed statistically higher sensitivity in lesion detection (67.5%-79.5%) than unenhanced MR imaging (46.5%-59.1%; P < 0.05 for all). Combined MR imaging also showed higher sensitivity in lesion detection than CT (61.1%-73.0%), with the results being statistically significant (P < 0.05) for on-site readers and 2 of 3 blinded readers. Higher sensitivity in lesion detection with combined MR imaging compared with CT was also clearly demonstrated in the following subgroups: lesions with a diameter CONCLUSION In this study, hepatocyte-specific Gd-EOB-DTPA was shown to be safe and to improve the detection and characterization of focal hepatic lesions compared with unenhanced MR imaging. When compared with spiral CT, Gd-EOB-DTPA enhanced MRI seems to be beneficial especially for the detection for smaller lesions or hepatocellular carcinoma underlying cirrhotic liver.
-
6.
Comparison of diagnostic performance of unenhanced vs SonoVue - enhanced ultrasonography in focal liver lesions characterization. The experience of three Italian centers.
Quaia, E, Stacul, F, Gaiani, S, Ricci, P, Passariello, R, Curzio, D, Pozzi Mucelli, R
La Radiologia medica. 2004;(1-2):71-81
Abstract
PURPOSE To evaluate the diagnostic performance of contrast-enhanced US with SonoVue (Bracco, Milan, Italy) compared to baseline US in focal hepatic lesions characterization. MATERIALS AND METHODS A comprehensive number of four operators from 3 hospitals evaluated 57 consecutive patients with 60 focal hepatic lesions (28 hepatocellular carcinomas, 11 metastases, 13 hemangiomas, 1 hepatocellular adenoma and 7 focal nodular hyperplasias) by baseline gray-scale ultrasound (US) and color Doppler US. The same lesions were subsequently scanned by contrast-enhanced US after intravenous bolus administration of 2,4-4,8 ml of SonoVue by employing intermittent high or continuous low transmit power imaging. The diagnosis of lesions nature (benign or malignant) and histotype proposed by the on-site operator was finally compared to the definite diagnosis reached by reference procedures (multiphasic contrast-material enhanced helical-computed tomography or magnetic resonance in 24 lesions and fine needle US guided biopsy in 36 lesions). Diagnostic performance (sensitivity, specificity and overall accuracy expressed by the agreement with the reference procedures) of baseline and contrast enhanced US were compared. RESULTS Differences in sensitivity (baseline vs contrast-enhanced US: 13/39 [33%] vs 32/39 [82%]), specificity (baseline vs contrast-enhanced US: 12/21 [57%] vs 16/21 [76%]) and overall accuracy (baseline vs contrast-enhanced US: 25/60 [41%] vs 47/60 [78%]) were significant (p<0.05; McNemar test). CONCLUSIONS SonoVue-enhanced US determined a significant improvement in diagnostic performance in the characterization of focal liver lesions if compared to baseline US.
-
7.
The influence of Enteral Nutrition in postoperative patients with poor liver function.
Hu, QG, Zheng, QC
World journal of gastroenterology. 2003;(4):843-6
Abstract
AIM: To investigate the safety, rationality and the practicality of enteral nutritional (EN) support in the postoperative patients with damaged liver function and the protective effect of EN on the gut barrier. METHODS 135 patients with liver function of Child B or C grade were randomly allocated to enteral nutrition group (EN, 65 cases), total parenteral nutrition group (TPN, 40 cases) and control group (CON, 30 cases). Nutritional parameters, hepatic and kidney function indexes were measured at the day before operation, 5th and 10th day after the operation respectively. Comparison was made to evaluate the efficacy of different nutritional support. Urinary concentrations of lactulose(L) and mannitol(M) were measured by pulsed electrochemical detection(HPLC-PED) and the L/M ratio calculated to evaluate their effectiveness on protection of gut barrier. RESULTS No significant damages in hepatic and kidney function were observed in both EN and TPN groups between pre- and postoperatively. EN group was the earliest one reaching the positive nitrogen balance after operation and with the lowest loss of body weight and there was no change in L/M ratio after the operation (0.026+/-0.004) at the day 1 before operation, 0.030+/-0.004 at the day 5 postoperative and 0.027+/-0.005 at the day 10 postoperative), but the change in TPN group was significant at the day 5 postoperative (0.027+/-0.003 vs 0.038+/-0.009,P<0.01). CONCLUSION EN is a rational and effective method in patients with hepatic dysfunction after operation and has significant protection effect on the gut barrier.
-
8.
Pharmacokinetics of the ketolide telithromycin after single and repeated doses in patients with hepatic impairment.
Cantalloube, C, Bhargava, V, Sultan, E, Vacheron, F, Batista, I, Montay, G
International journal of antimicrobial agents. 2003;(2):112-21
Abstract
The pharmacokinetic profiles of single and repeated oral doses of telithromycin 800 mg/day were compared in patients with hepatic impairment and healthy subjects in two open-label, non-randomized, parallel-group, multicentre studies. The maximal plasma concentrations (Cmax) and the area under the plasma concentration-time (AUC) curves for telithromycin were similar in hepatically impaired patients and healthy subjects in the single- and repeated-dose studies. The extent of formation of RU 76363, the major circulating metabolite of telithromycin, was decreased following single and repeated doses in patients with hepatic impairment compared with healthy subjects. In the single-dose study, the Cmax of RU 76363 was 2-fold lower (P<0.01) and the initial elimination half-life (t(1/2lambda1)) was 44% higher (P<0.01). The Cmax and AUC from 0 to 24 h post-dose were approximately 50% lower on Day 1 (P< or =0.01) and Day 7 (P< or =0.001) in the repeated-dose study. The terminal elimination half-life (t(1/2lambdaz)) of telithromycin was 1.4-fold higher (P<0.001) in the hepatically impaired patients compared with the healthy subjects in the single-dose study. However, t(1/2lambda1) and t(1/2lambdaz) were similar after repeated doses in both populations, suggesting that the decrease in formation of RU 76363 is compensated by an increase in clearance via other pathways. Telithromycin 800 mg was well tolerated in both populations. In conclusion, a once-daily dose of telithromycin is well tolerated in patients with hepatic impairment. Exposure to telithromycin was comparable in patients with hepatic impairment and healthy subjects and thus, no dosage adjustment is required in this patient group providing renal function is not severely impaired.
-
9.
Multicentre dose-ranging study on the efficacy of USPIO ferumoxtran-10 for liver MR imaging.
Saini, S, Sharma, R, Baron, RL, Turner, DA, Ros, PR, Hahn, PF, Small, WC, Delange, EE, Stillman, AE, Edelman, RR, et al
Clinical radiology. 2000;(9):690-5
Abstract
AIM: A dose ranging multicentre phase-II clinical trial was conducted to evaluate the efficacy of ultrasmall superparamagnetic iron oxide (USPIO) ferumoxtran-10 for magnetic resonance (MR) imaging of focal hepatic lesions. MATERIAL AND METHODS Ninety-nine patients with focal liver lesions received USPIO at a dose of 0.8 (n = 35), 1.1 (n = 32), or 1.7 (n = 32) mg Fe/kg. Liver MR imaging was performed before and after USPIO with T1-weighted and T2-weighted pulse sequences. Images were analysed by two independent readers for additional information (lesion detection, exclusion, characterization and patient management). Signal intensity (SI) based quantitative measurements were also taken. RESULTS Post-contrast medium MR imaging showed additional information in 71/97 patients (73%) for reader one and 83/96 patients (86%) for reader two. The results with all three doses were statistically significant (P < 0.05). Signal intensity analysis revealed that all three doses increased liver SI on T1-weighted images and decreased liver SI on T2-weighted images. On T2-weighted images metastases increased in contrast relative to normal hepatic parenchyma whereas haemangiomas decreased in contrast. On T2-weighted images there was statistically improved efficacy at the intermediate dose, which did not improve at the highest dose. CONCLUSION Ultrasmall superparamagnetic iron oxide was an effective contrast agent for liver MR imaging at all doses and a dose of 1.1 mg Fe/kg was recommended for future clinical trials.