Liver Function In Group Research Articles

Single-Dose Tolerability and Pharmacokinetics of Onradivir in Chinese Patients with Hepatic Impairment and Healthy Matched Controls.

This study compared the safety and pharmacokinetics of a single oral dose of onradivir, an inhibitor of polymerase basic protein 2 in influenza A virus, in patients with hepatic impairment and healthy participants with normal hepatic function. Eight participants with mild hepatic impairment (Child-Pugh A), eight participants with moderate hepatic impairment (Child-Pugh B), and eight healthy matched controls were enrolled in this open-label, parallel-group clinical trial. After the administration of 600 mg of onradivir, pharmacokinetic parameters were calculated for each cohort and compared. Onradivir was generally well tolerated by all participants. No serious adverse events (AEs) and no deaths were reported during the study. Six patients with moderate hepatic impairment and three patients with mild hepatic impairment reported AEs, all of which were mild and quickly resolved. Compared with the normal liver function group, the maximum concentration, area under the curve from time zero to the last measurable concentration, and area under the curve from time zero to infinity were 103%, 68.5%, and 69.2% higher, respectively, in the mild hepatic impairment group. In the moderate hepatic impairment group, these increases were 101%, 197%, and 204%, respectively. Overall, there were clinically relevant differences in onradivir exposure between patients with mild or moderate hepatic impairment and normal controls. These data imply that onradivir dose adjustment is warranted in patients with mild or moderate hepatic impairment. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT05856513).

Liver injury in paraquat poisoning: A retrospective cohort study.

Liver injury is one of the common complications of paraquat (PQ) poisoning, but whether the degree of liver injury is related to patient prognosis is still controversial. This study aimed to investigate whether liver injury was a risk factor for death in PQ-poisoned patients. We conducted a retrospective cohort study of PQ-poisoned patients from the past 10 years (2011-2020) from a large tertiary academic medical centre in China. PQ-poisoned patients were divided into a normal liver function group (n = 580) and a liver injury group (n = 60). Propensity score matching (PSM) analysis was then performed. A total of 640 patients with PQ poisoning were included in this study. To reduce the impact of bias, dose of PQ, urinary PQ concentration and time from poisoning to hospital admission were matched between the two groups. A 3:1 PSM analysis was performed, ultimately including 240 patients. Compared with the normal liver function group, patients in the liver injury group were older, had a higher R value ([ALT/ULN]/[ALP/ULN]) (p < .001) and had a higher mortality rate. Cox regression analysis showed that there was no significant association between alanine aminotransferase, alkaline phosphatase, total bilirubin levels and hazard of death, but age, PQ dose, creatine kinase isoenzyme, creatine kinase, white blood cell count, neutrophil percentage and lymphocyte percentage were associated with mortality in patients with PQ poisoning. The occurrence of liver injury within 48 h after PQ poisoning was a risk factor for mortality, and such liver injury was likely of a hepatocellular nature. Age, PQ dose, creatine kinase isoenzyme and white blood cell count were positively correlated with mortality, while creatine kinase, percentage of neutrophils and lymphocytes were inversely correlated.

Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Proline Henagliflozin in Chinese Subjects with Varying Degrees of Liver Dysfunction.

Proline henagliflozin, a novel selective inhibitor of sodium glucose cotransporter 2, is a treatment for type 2 diabetes mellitus. We designed a parallel-group, open-label, and multicenter study to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of henagliflozin in Chinese subjects with varying degrees of liver dysfunction. Thirty-two subjects were enrolled and divided into four groups based on liver function (normal liver function, mild, moderate, or severe liver dysfunction). The area under the plasma concentration from time zero to infinity of henagliflozin in subjects with mild liver dysfunction, moderate liver dysfunction, and severe liver dysfunction compared with normal liver function was increased by 137%, 197%, and 204%, respectively. The maximum plasma concentration was also increased by 123%, 129%, and 139%, respectively. PK parameters of three metabolites varied to different degrees in the liver dysfunction groups than in the normal liver function group. The mean accumulative excretion amounts and fraction of dose excreted in urine expressed as a percentage were all increased with the decrease of liver function. The PD parameters were significantly higher in liver dysfunction groups than those in the normal liver function group. However, the urine creatinine (UCr) was not significantly different among the groups. No notable adverse events or adverse drug reactions were observed. Due to the higher exposures in subjects with liver dysfunction, the benefit: risk ratio should be individually assessed because the long-term safety profile and efficacy have not been specifically studied in this population.

Associations between one-carbon metabolism and valproic acid-induced liver dysfunction in epileptic patients.

Valproic acid (VPA) has been widely used as an antiepileptic drug for decades. Although VPA is effective and well-tolerated, long-term VPA treatment is usually associated with hepatotoxicity. However, the underlying mechanisms of VPA-caused hepatotoxicity remain unclear. In this study, a total of 157 pediatric patients with epilepsy were recruited and divided into normal liver function (NLF, 112 subjects) group and abnormal liver function (ABLF, 45 subjects) group. We observed that MTHFR A1298C and MTHFR C677T variants may be linked to VPA-induced liver dysfunction (p = 0.001; p = 0.023, respectively). We also found that the MTHFR A1298C polymorphism was associated with a higher serum Hcy level (p = 0.001) and a lower FA level (p = 0.001). Moreover, the serum Hcy levels was strongly correlated with the GSH and TBARS concentrations (r = -0.6065, P < 0.001; r = 0.6564, P < 0.001, respectively). Furthermore, logistic analysis indicated that MTHFR A1298C/C677T polymorphisms and increased Hcy concentrations may be risk factors for VPA-induced liver dysfunction. These results suggested that individual susceptibility to VPA-induced liver dysfunction may result from MTHFR A1298C/C677T polymorphisms and increased Hcy levels. This study may be helpful for the prevention and guidance of VPA-induced liver dysfunction.

A Phase I Clinical Study of the Pharmacokinetics and Safety of Prusogliptin Tablets in Subjects with Mild to Moderate Hepatic Insufficiency and Normal Liver Function.

Prusogliptin is a potent and selective DPP-4 inhibitor. In different animal models, Prusogliptin showed potential efficacy in the treatment of type 2 diabetes. However, the knowledge of its pharmacokinetics and safety in patients with liver dysfunction is limited. The present study evaluated the pharmacokinetics and safety of Prusogliptin in subjects with mild or moderate hepatic impairment compared with healthy subjects. According to the liver function of the subjects, we divided them into a mild liver dysfunction group, a moderate liver dysfunction group and a normal liver function group. All subjects in three groups received a single oral dose of Prusogliptin 100-mg tablets. Pharmacokinetics and safety index collection was carried out before and after taking the drug. Plasma pharmacokinetics of Prusogliptin were evaluated, and geometric least- -squares mean (GLSM) and associated 90% confidence intervals for insufficient groups versus the control group were calculated for plasma exposures. After a single oral administration of 100 mg of Prusogliptin tablets, the exposure level of Prusogliptin in subjects with mild liver dysfunction was slightly higher than that in healthy subjects. The exposure level of Prusogliptin was significantly increased in subjects with moderate liver dysfunction. There were no adverse events in this study. The exposure level of Prusogliptin in subjects with liver dysfunction was higher than that in healthy subjects. No participant was observed of adverse events. Prusogliptin tablets were safe and well tolerated in Chinese subjects with mild to moderate liver dysfunction and normal liver function.

Liver dysfunction on admission worsens clinical manifestations and outcomes of coronavirus disease 2019.

Liver dysfunction was common in coronavirus disease 2019 (COVID-19), but its association with clinical features and poor prognosis has not been fully delineated. Our study aimed to determine the role of liver dysfunction in COVID-19 and understand the predictors for worse outcomes in patients with liver injury. We conducted this multicenter, retrospective study in five designated hospitals for COVID-19 management. Laboratory-confirmed COVID-19 patients were enrolled and classified into the normal live function group and liver dysfunction group according to liver enzymes, bilirubin, and albumin on admission, respectively. Data of baseline, clinical manifestations, and outcomes were collected and compared in the paired groups. Of the 649 included COVID-19 patients, 200 (30.8%), 69 (10.6%), and 267 (41.1%) patients had elevated liver enzymes, increased bilirubin, and low-level albumin, respectively. Fever, cough, and dyspnea were the most common symptoms and showed an increased proportion in the liver dysfunction group. Compared with patients in the normal liver function group, patients with liver dysfunction manifested decreased lymphocytes, higher level of leukocytes, neutrophils, inflammatory indicators, and cytokines, as well as more severe impairment in kidney function and myocardium. They were more likely to show bilateral involvement and more pulmonary lobes involved according to chest images. With increased proportion of patients who developed severe/critical conditions and needed mechanical ventilation and systemic glucocorticoid therapy, patients with liver dysfunction on admission showed significantly higher in-hospital mortality. Moreover, cardiac troponin I ≥1.5ng/mL was identified as an independent mortality predictor in the elevated liver enzymes group. Patients with liver dysfunction on admission had worse clinical manifestation, and resulted in higher rate of severe/critical type, receiving mechanical ventilation and in-hospital mortality.

Serum levels of IL-6/IL-10/GLDH may be early recognition markers of anti-tuberculosis drugs (ATB) -induced liver injury

To explore the potential value of serum glutamate dehydrogenase (GLDH) combined with inflammatory cytokines as diagnostic biomarkers for anti-tuberculosis drug -induced liver injury (ATB-DILI). We collected the residual serum from the patients who met the criteria after liver function tests. We have examined these parameters including GLDH which were determined by enzyme-linked immunosorbent assay and cytokines which were determined by cytokine combination detection kit. Multivariate logistics stepwise forward regression was applied to establish regression models. A total of 138 tuberculosis patients were included in the diagnostic markers study of ATB-DILI, including normal liver function group (n = 108) and ATB-DILI group(n = 30). Serum GLDH, IL-6 and IL-10 levels were significantly increased in the ATB-DILI group. Receiver operating characteristic curve (ROC) curve showed that the area under curve (AUC) of serum GLDH, IL-6 and IL-10 for the diagnosis of ATB-DILI were 0.870, 0.714 and 0.811, respectively. In logistic regression modeling, the AUC of GLDH combined with IL-10 as an ATB-DILI marker is 0.912. Serum IL-6、IL-10 and GLDH levels began to rise preceded the increase in ALT by 7 days, with significant differences in IL-6 compared with 7 days. Serum GLDH, IL-6 and IL-10 levels were correlated with the severity of liver injury. In conclusion, we found that GLDH, IL-6 and IL-10 alone as diagnostic markers of ATB-DILI had good diagnostic efficacy. Logistic regression model established by GLDH and IL-10 had better diagnostic efficacy and IL-6 may be an early predictor of liver injury in the setting of ATB poisoning.

Treatment and outcome of hepatorenal syndrome in Japan: a retrospective cohort study using a national inpatient database

BackgroundHepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease. This study aimed to clarify the status of HRS in Japan by analyzing the Japanese Diagnosis Procedure Combination database.MethodsPatients hospitalized for cirrhosis and HRS from July 2010 to March 2019 were sampled. They were divided into two groups according to their prognosis upon discharge: the transplant-free survival group and the death or liver transplantation group. The two groups’ baseline patient characteristics and treatments were compared.ResultsThe mean age of the 1,412 participants was 67.3 years (standard deviation: 12.3 years), and 65.4% were male. The Child–Pugh grades was B and C in 18.8% and 81.2%, respectively. Hepatocellular carcinoma was present in 27.1% of the patients, and the proportion of spontaneous bacterial peritonitis was 2.3%. Albumin, noradrenaline, and dopamine were administered to 57.9%, 8.0%, and 14.9% of the patients, respectively; 7.0% of the patients underwent renal replacement therapy; and 5.0% were admitted to the intensive care unit. Intravenous antibiotics were administered to 30.8% of the patients. A total of 925 patients (65.5%) died or underwent liver transplantation. In addition to a higher proportion of patients with poor baseline liver function, the death or liver transplantation group included more males, patients with hepatocellular carcinoma, and those with spontaneous bacterial peritonitis.ConclusionsHRS in Japan has a high mortality rate. Albumin was administered to over 50% of participants. Although noradrenaline is recommended in Japanese clinical guidelines, dopamine was more frequently used as a vasoconstrictor in clinical practice.

Evaluation of liver function using Gd-EOB-DTPA-enhanced MRI with T1 mapping

PurposeTo evaluate the value of MRI T1 mapping with Gd-EOB-DTPA for assessing liver function.MethodsSeventy-two patients who underwent Gd-EOB-DTPA-enhanced MRI for focal liver lesions at Beijing Friendship Hospital from August 2020 to March 2022 were prospectively enrolled, and variable-flip-angle T1 mapping was performed before and 20 min after enhancement. The Child–Pugh (C-P) score and albumin-bilirubin (ALBI) grade of liver function were assessed using the clinical data of the patients. Correlation analysis was used to evaluate the correlation between T1 mapping parameters and liver function grading and laboratory tests. Nonparametric tests were used to compare the differences among different liver function groups. The liver function classification efficiency of each image index was evaluated with receiver operating characteristic (ROC) curves.ResultsT1post was positively correlated with the C-P grade and the ALBI grade (r = 0.717 and r = 0.652). ΔT1 was negatively correlated with the C-P grade and the ALBI grade (r = -0.790 and r = -0.658). T1post and ΔT1 significantly differed among different liver function grades (p < 0.05). For the C-P grade, T1post and ΔT1 were significantly different between each pair of groups (p < 0.05), and ΔT1 had a better diagnostic efficiency than T1post. For the ALBI grade, ΔT1 and T1post were significantly different between the NLF and ALBI1 groups (p < 0.05), and ΔT1 had a better diagnostic efficacy than T1post. T1post significantly differed between the ALBI1 and ALBI2 + 3 groups (p < 0.05), while ΔT1 had a weak ability to differentiate between these two groups.ConclusionT1post and ΔT1 were strongly correlated with the two liver function grades and can be noninvasive imaging indexes for evaluating liver function.

Relative enhancement index can be used to quantify liver function in cirrhotic patients that undergo gadoxetic acid-enhanced MRI.

To evaluate MRI with gadoxetic acid to quantify liver function in cirrhotic patients using the relative enhancement index (REI) compared with Child-Pugh score (CPS), MELD score, and indocyanine green plasma disappearance rate (ICG-PDR) and to establish cutoffs for REI to stratify cirrhotic patients into good and poor liver function groups. We prospectively evaluated 60 cirrhotic patients and calculated CPS, MELD score, ICG-PDR, and REI for each patient. Spearman's correlation coefficient was used to assess correlation between REI, CPS, MELD, and ICG-PDR. Good and poor liver function groups were created by k-means clustering algorithm using CPS, MELD, and ICG-PDR. ROC curve analysis was performed and optimal cutoff was identified for group differentiation. Good correlations were found between REI and other liver function biomarkers: REI and CPS (rho = - 0.816; p < 0.001); REI and MELD score (rho = - 0.755; p < 0.001); REI and ICG-PDR (rho = 0.745; p < 0.001)]. REI correlation was stronger for patients with Child-Pugh A (rho = 0.642, p = 0.002) and B (rho = 0.798, p < 0.001) than for those with Child-Pugh C (rho = 0.336, p = 0.148). REI is significantly lower in patients with poor liver function (p < 0.001). ROC curve showed an AUC 0.94 to discriminate patients with poor liver function (REI cutoff < 100; 100% sensitivity; 76% specificity). REI is a valuable non-invasive index for liver function quantification that has good correlations with other liver function biomarkers. REI can be easily calculated and can be used to estimate liver function in clinical practice in the routine evaluation of cirrhotic patients that undergo MR imaging with gadoxetic acid contrast. • REI is a valuable non-invasive index for liver function quantification that has good correlations with other liver function biomarkers. • REI can be easily calculated in the routine evaluation of cirrhotic patients that undergo gadoxetic acid-enhanced MRI. • The REI enables stratification of cirrhotic patients into good and poor liver function groups and can be used as additional information, together with morphological and focal liver lesion evaluation.

Multiparametric MRI combined with liver volume for quantitative evaluation of liver function in patients with cirrhosis.

PURPOSE We aimed to establish a liver function evaluation model by combining multiparametric magnetic resonance imaging (MRI) with liver volume (LV) and further verify the effectiveness of the model to evaluate liver function. METHODS This retrospective study included 101 consecutive cirrhosis patients (69 cases for modeling group and 32 cases for validation group) who underwent gadoxetic acid-enhanced MRI. Five signal intensity parameters were obtained by measuring the signal intensities of the liver, spleen, and erector spinae before and 20 minutes after gadoxetic acid disodium enhancement. The dif fusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f) were obtained from intravoxel incoherent motion diffusion-weighted imaging. The LV parameters (Vliver, Vspleen, and Vliver/Vspleen) were obtained using 3-dimensional image generation software. The most effec tive parameter was selected from each of the 3 methods, and a multivariate regression model for liver function evaluation was established and validated. RESULTS In the modeling group, relative enhancement (RE), D*, and Vliver/Vspleen showed significant dif ferences among the different liver function groups (P < .001). Receiver operating characteristic analysis showed that these parameters had the highest area under the curve (AUC) values for dis tinguishing Child-Pugh A from Child-Pugh B and C groups (0.917, 0.929, and 0.885, respectively). The following liver function model was obtained by multivariate regression analysis: F(x)=3.96 - 1.243 (RE) - 0.034 (D*) - 0.080 (Vliver/Vspleen) (R2=0.811, P < .001). In the patients with cirrhosis, the F(x) of Child-Pugh A, B, and C were 1.16 ± 0.44, 1.95 ± 0.29, and 2.79 ± 0.38, respectively. In the validation group, the AUC for F(x) to distinguish Child-Pugh A from Child-Pugh B and C was 0.973. CONCLUSION Combining multiparametric MRI with LV effectively distinguished patients with different Child Pugh grades. This model could hence be useful as a novel radiological marker to estimate the liver function.

Predictive Value of Inflammatory Cytokines in Early Pregnancy for Liver Dysfunction in Pregnant Women with Hepatitis B.

The purpose of this study is to explore the predictive value of cytokine levels in the first trimester of pregnancy on abnormal liver function of pregnant women with hepatitis B in the third trimester of pregnancy. A total of 111 pregnant women with HBV infection at 12 weeks gestation participated in the study. The levels of IL-6, IL-8, TNF-α in peripheral blood of the patients and liver function indexes were detected. Subsequently, the pregnant women were followed up, and the liver function was detected at 36 weeks of gestation. According to liver function indexes, patients were divided into normal liver function group and abnormal liver function group to determine the correlation between cytokines in early pregnancy and abnormal liver function in late pregnancy. Kaplan-Meier survival curve and multivariate Cox analysis were used to evaluate the predictive value of cytokines for liver dysfunction. At 12 weeks of gestation, cytokine levels in the normal liver function group were significantly lower than that in the abnormal liver function group. Kaplan-Meier survival analysis showed that the increased IL-6 level was associated with abnormal liver function in late pregnancy. Multivariate Cox regression analysis revealed that IL-6 level was an independent predictor of abnormal liver function in patients with normal liver function in the late pregnancy. The high expression level of cytokine IL-6 at 12 weeks of pregnancy has noteworthy predictive significance for the abnormal liver function of hepatitis B pregnant women in third trimester of pregnancy.

Pharmacokinetic Study of Nalbuphine in Surgical Patients Undergoing General Anesthesia with Varying Degrees of Liver Dysfunction.

PurposeThis study aimed to characterize the pharmacokinetics of nalbuphine in patients undergoing general anesthesia with varying degrees of liver dysfunction.Patients and MethodsTwenty-four patients were enrolled and divided into three cohorts based on liver function: normal liver function (n = 13), mild liver dysfunction (n = 5), and moderate/severe liver dysfunction (n = 6). During the induction of anesthesia, they received 15 mg of nalbuphine intravenously. Venous blood samples were collected from each patient. The plasma concentration of nalbuphine was determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of nalbuphine were calculated by non-compartmental analysis (NCA) using Phoenix WinNonlin software.ResultsCompared with the normal liver function group, the plasma elimination half-life (T1/2) of nalbuphine was increased by approximately 33% in the moderate/severe liver dysfunction group (2.66 h vs 3.54 h, P<0.05), and the volume of distribution (Vd) increased by approximately 85% (100.08 L vs 184.95 L, P<0.05). Multivariate analysis revealed that weight and platelet were associated with clearance (CL); total bilirubin as an independent factor was associated with T1/2, and weight associated with area under the curve (AUC(0→∞)) independently.ConclusionThe T1/2, mean residence time, and Vd of nalbuphine in patients with moderate/severe liver dysfunction were prolonged or increased significantly compared with those in the normal liver function group. These data suggest that it may need to be used with caution when nalbuphine is administered to patients with moderate or severe liver dysfunction.

Characteristics of liver function changes in 111 elderly patients with COVID-19 pneumonia

Objective: To retrospectively analyze the characteristics and influencing factors of liver function changes in 111 elderly patients with COVID-19 pneumonia. Methods: 111 elderly patients with COVID-19 admitted to the Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from February 5 to March 3, 2020 were enrolled. According to the severity of disease and liver function condition, they were divided into severe group (n=40), normal group (n=71), abnormal liver function group (n=86) and normal liver function group (n=25). The indexes related to liver function changes [total bilirubin (TBil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT)] and related influencing factors were analyzed. Results: Among 111 cases, 86 (77.5%) had abnormal liver function of varying degrees, and 28 (25.2%) had liver injury. The abnormal rates of TBil, AST, ALP and GGT were significantly higher in the severe group than normal group (P<0.05). There were no significant differences in age, ribavirin, glucocorticoid and the application of lopinavir-ritonavir tablets between the abnormal liver function and the normal group (P>0.05). The proportion of male was significantly higher in the abnormal liver function than normal liver function group (P<0.05). Conclusion: Elderly COVID-19 patients have a higher proportion of abnormal liver function, and patients in the severe group are more likely to have higher level of TB, AST, ALP and GGT. The abnormal liver function may be related to the direct viral infection of the liver and the inflammatory immune response of the body after infection in elderly patients.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

이상 간기능 남성 집단의 유산소운동에서 밀크씨슬의 복용여부가 AST 및 ALT개선에 미치는 효과

This study proposes effective treatment means for liver health and disease prevention of the abnormal liver function group by verifying the liver function improvement effect of taking milk thistle as a health functional supplement and exercise therapy for the group with impaired liver function.<BR>To achieve the purpose of the study, 16 adult males with AST or ALT exceeding 40 IU/L were recruited. It was carried out for 10 weeks, divided into 8 people in the non-intake group who performed only aerobic exercise but did not take milk thistle and 8 people in the group that took both aerobic exercise and milk thistle.<BR>As a result of the study, both AST and ALT decreased in the non-intake group, but there was no significant difference by measurement period (p＞.05), and the ingestion group decreased, showing a significant difference (p＜.05), and there was a significant difference between the two groups. In both AST/ALT, it was found that there was a significant effect difference in Time (p＜.001) and Time<SUP>*</SUP>Group (p＜.01). Therefore, when applying aerobic exercise as an exercise therapy for improving liver function in the abnormal liver function group, it is judged that it is recommended to adjust the treatment according to the severity of the AST and ALT test values, because the intake of Mike Thistle is more effective.

Abstract P035: A phase 1 pharmacokinetic trial of single agent trametinib a MEK inhibitor in advanced cancer patients with hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI 9591)

Abstract Background Trametinib (Mekinist ®) is an oral bioavailable MEK 1/2 inhibitor that is FDA approved in combination with BRAF inhibitor Dabrafenib for BRAFV600 mutant solid tumors. The single agent recommended phase 2 dose (RP2D) is 2 mg daily (QD). No clinical data is available on recommendation of trametinib dosing in various degrees of hepatic dysfunction (HD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib as primary endpoints in patients (pts) with genomically unselected advanced solid tumors with various degrees of HD. Methods Advanced cancer pts with ECOG ≤2, adequate renal and bone marrow functions, were stratified (NCI ODWG Criteria) into 4 HD groups: normal (NO), mild (ML), moderate (MD), severe (SV). NO group was enrolled as control subjects and was not evaluable for dose limiting toxicity (DLT). Trametinib was given QD on a 28-days cycle, with dose escalation based on a “3+3” design within each HD group (starting dose: NO, ML: 2mg; MD: 1.5 mg; SV: 1mg). Due to the long half-life of trametinib, PK samples were collected at days 15-16 in cycle 1. Differences in PK parameters among liver function groups were evaluated using analysis of variance (ANOVA). Results Out of 46 pts enrolled (2 pts ineligible), 44 (NO=17, ML=7, MD (1.5mg)=4, MD (2mg)=5, SV (1mg)=9, SV (1.5mg)=2) were evaluable for safety and 22 for PK analysis. The most common cancer type was GI-non CRC cancer (n=16, 36%). The most common all-grade treatment related adverse events (TRAEs) were acneiform rash (NO=53%, HD=48% of pts), nausea (NO=65%, HD=22%), diarrhea (NO=53%, HD=26%) and fatigue (NO=59%, HD=15%). Grade 3/4 TRAEs occurred in 27% (n=12) of pts (NO=8, 47%; HD=4, 15%). No treatment related deaths occurred. DLT was evaluable in 15 pts (ML=6, MD (1.5mg)=3, MD (2mg)=2, SV (1mg)=3 and SV (1.5mg)=1). One DLT (grade 3 acneiform rash) was observed in an SV pt (1.5mg). Dose interruptions or reductions due to TRAEs occurred in 15 pts (34%) [NO=9, 53%; ML=2, 29%; MD (1.5mg)=1, 33%; MD (2mg)=2, 33%; SV (1mg)=1, 11%; SV (1.5mg)=1; 50%]. Best response was stable disease in all HD groups (33 to 75%) and 54% in NO group. There were no significant differences for PK parameters of Cmax (p=0.18), Cmin (p=0.16), Cavg (p=0.62), or AUC0-24 (p=0.11) (NO vs ML, NO vs MD, NO vs SV, ML vs MD, ML vs SV, MD vs SV), when trametinib was normalized to 2 mg dose. However, only limited PK data were available for the MD (n=3) and SV (n=3) groups compared to NO (n=10) and ML (n=6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p=0.26). Conclusion RP2D for trametinib in ML pts is 2 mg QD. There are insufficient number of evaluable pts to declare RP2D for MD and SV HD groups. No DLTs were noted in the highest dose cohorts that reached 3 evaluable pts: 1.5 mg QD in MD group, and 1 mg QD in SV group. It may be appropriate for pts with MD and SV HD to start trametinib at 1.5 mg QD and 1 mg QD respectively, and monitored closely for toxicity. Citation Format: Pei Jye Voon, Eric X. Chen, Helen X. Chen, Albert C. Lockhart, Solmaz Sahebjam, Karen Kelly, Ulka N. Vaishampayan, Vivek Subbiah, Albiruni R. Razak, Daniel J. Renouf, Sebastien J. Hotte, Arti Singh, Philippe L. Bedard, Aaron R. Hansen, Ivy S. Percy, Lisa Wang, Lee-Anne Stayner, Lillian L. Siu, Anna Spreafico. A phase 1 pharmacokinetic trial of single agent trametinib a MEK inhibitor in advanced cancer patients with hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI 9591) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P035.

The Liver Injury and Coagulation Dysfunction in the Patients with Severe/Critical COVID-19

The clinical data of 53 COVID-19 patients were collected from a single center in Wuhan from February 8, 2020 to March 25, 2020. The patients were divided into severe type group (38 patients) and critical type group (15 patients). The clinical characteristics, indexes of liver function, coagulation function and inflammatory markers were analyzed retrospectively. According to the degree of abnormal liver function in the process of diagnosis and treatment, the patients were divided into three groups: combined liver injury, mild abnormal liver function and normal liver function group. Statistical analysis was performed by using Student t test, Mann-Whitney U test, Kruskal-Wallis test and Chi-square test. Among the 53 patients, 29 were male (54.7%) and 24 were female (45.3%), the median age was 57(27－80) years old. The time from onset to admission was (11.5±7.7) days. The levels of AST, TBIL, DBIL, ALP, GGT, LDH, D-dimer, PCT and hsCRP in critical patients were higher than those in severe patients (P<0.05). The levels of Alb in critical patients was lower than those in severe patients (P<0.05). Among the 53 patients, 34 (64%) patients showed abnormal elevation of ALT, AST or TBIL, while 4 (7.5%) patients showed the criteria of COVID-19 with liver injury. After the patients were grouping according to the degree of liver dysfunction, the levels of ALP, GGT and D-dimer of the patients in the liver injury group were significantly higher than those in the normal liver function group, D-dimer levels of the patients in the liver injury group was significantly higher than those in the mild abnormal liver function group, while the levels of ALP and GGT in the mild abnormal liver function group were significantly higher than those in the normal liver function group, and the differences were statistically significant(P<0.05). In this group, the patients with COVID-19 severe/critical type have a certain proportion of liver injury accompanied by significantly increased D-dimer levels, critical type patients have more severe liver function and coagulation dysfunction, which may promote the progression of COVID-19.

Hemodynamic analysis of hepatic arteries for the early evaluation of hepatic fibrosis in biliary atresia

Background and objectiveHepatic fibrosis is the prominent characteristic of biliary atresia (BA), may even progress continually after Kasai procedure (KP). BA, as a devastating pediatric hepatic disease, mainly leads to newborn cholestasis, even liver cirrhosis, eventually hepatic failure. Earlier diagnosis of hepatic fibrosis, which used to be detected by liver biopsy commonly, is consistent with better outcomes of KP. Due to potential risks and uncertainty of liver biopsy, it is an urge to seek a safer and more precise evaluation method as alternative. The purpose of this study is to investigate the hemodynamics of hepatic artery (HA) in hepatic fibrosis of early BA based on computational fluid dynamics (CFD) for evaluating the value of CFD for hepatic fibrosis diagnosis. Methods40 patients were divided into three groups, including the control group, the abnormal liver function group and the mild to moderate hepatic fibrosis group. CFD was applied to quantify primary hemodynamic parameters of HA and related arteries, including blood flow distribution ratio (FDR), pressure, wall shear stress (WSS) and energy loss (EL). Statistical analyses were also performed to compare the differences amongst these above groups. ResultsWith the progression of hepatic fibrosis, the increasing tendency of hemodynamic parameters values of HA and related arteries were observed. Values of FDR, pressure, WSS and EL of the mild to moderate group was higher than those of the control group and the abnormal liver function group. There were significant differences on FDRAA, FDRHA and EL between the control group and the mild to moderate hepatic fibrosis group (t = 0.037, 0.030 and <0.001, P < 0.05). ConclusionSignificant variations of HA hemodynamics acquired by CFD between the control group and the mild to moderate hepatic fibrosis group demonstrated the relationship between the progression of hepatic fibrosis and the hemodynamic disorder, and suggested that CFD had the potential to assist the diagnosis of hepatic fibrosis in early BA.

Should we be reluctant to perform pancreatectomy in patients with chronic liver disease? A single center 10-year experience

Purpose Many studies have shown extra-hepatic surgery in patients with chronic liver disease (CLD) with or without portal hypertension can result in complications. The aim of this study was to analyze the results of major pancreatectomy in patients with CLD including cirrhosis and to evaluate their efficacy and safety. Methods We retrospectively reviewed 319 patients undergoing open pancreatoduodenectomy (PD) or distal pancreatectomy (DP) in our center. Those who received PD and DP in patients without CLD were classified into groups A and D, and those with CLD into groups B and C, respectively. Group B and C were subdivided into groups 1 and 2 according to the presence of portal hypertension. Results Forty-three patients (13.5%) had CLD. Of the 221 patients who received PD, 25 had CLD. Of the 98 patients who received DP, 18 (Group C) had CLD. In the PD group, patients with portal hypertension (group B1) had longer operative time. However, the transfusion rate and complication rate were not significantly different from other groups. There was no mortality in patients with CLD without portal hypertension (group B2) and the complication and mortality rate was comparable to patients with normal liver function (group A). In the DP group, the transfusion rate, complication rate and mortality rate were significantly higher in patients with portal hypertension (group C1). Conclusions Acceptable outcomes were obtainable following pancreatic surgery in cirrhotic, non-portal hypertensive patients with surgical outcomes equivalent to non-cirrhotic patients.