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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.
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2.
Elagolix Pharmacokinetic Profiles in Women With Renal or Hepatic Impairment.
Ng, J, Duan, WR, Marbury, T, Schmidt, JM, Klein, CE
Clinical pharmacology in drug development. 2019;(8):1053-1061
Abstract
The aim of these studies was to assess the safety and pharmacokinetics of elagolix, an oral nonpeptide gonadotropin-releasing hormone antagonist following oral administration in women with renal or hepatic impairment. Two phase 1 studies were conducted in adult women with normal renal function versus renal impairment (reduced study), and normal hepatic function versus hepatic impairment (full study design). All women received a single dose of elagolix 200 mg (renal) or 150 mg (hepatic). Intensive pharmacokinetic blood samples were collected. Elagolix exposures were comparable in women with normal renal function and those with moderate/severe renal impairment or end-stage renal disease. Elagolix exposures also appeared to be similar in women with normal hepatic function and women with mild hepatic impairment. Elagolix area under the curve in women with moderate hepatic impairment and with severe hepatic impairment was approximately 3-fold and 7-fold higher than in women with normal hepatic function. The adverse event incidence was low, with the main events being mild nausea and headache. No dosage adjustment was needed in women with renal impairment or women with mild hepatic impairment. Although an elagolix dose of 150 mg once daily may be used in women with moderate hepatic impairment for up to 6 months, this elagolix dose should not be used in women with severe hepatic impairment.
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Measurement of the enriched stable isotope 58Fe in iron related disorders- comparison of INAA and MC-ICP-MS.
Yagob, T, van de Wiel, A, Bode, P, Demir, A, van der Wagt, B, Krystek, P, Wolterbeek, B
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2019;:77-83
Abstract
As a safer alternative for the use of radioactive tracers, the enriched stable 58Fe isotope has been introduced in studies of iron metabolism. In this study this isotope is measured with instrumental neutron activation analysis (INAA) in blood samples of patients with iron related disorders and controls after oral ingestion of a 58Fe containing pharmaceutical. Results were compared with those derived from MC-ICP-MS, applied on the same samples, and analytical and practical aspects of the two techniques were compared. Both techniques showed an increased absorption and incorporation in red blood cells of the 58Fe isotope in iron deficient patients in contrast to the controls. In all individuals results of INAA measurements were in good agreement with those of MC-ICP-MS (|zeta| < 2). Uncertainties in INAA are substantially higher than those achievable by MC-ICP-MS but the INAA technique offers a high specificity and selectivity for iron close to 100%. In contrast to INAA, sample preparation before measurement is very critical in MC-ICP-MS and interferences with 58Ni and 54Cr may hamper the measurement of 58Fe and 54Fe respectively. Since it takes at least five days after irradiation to reduce the activity of interfering radionuclides (mainly 24Na), INAA is a more time consuming procedure; the need of a nuclear reactor facility makes it also less accessible than MC-ICP-MS. Costs are comparable. Both INAA and MC-ICP-MS are able to adequately measure changes in iron isotope composition in blood when an enriched stable iron isotope is applied in clinical research. Although MC-ICP-MS is more sensitive, is faster and has easier access, in INAA preparative steps before measurement are simpler and there are hardly demands on the kind and size of the samples. This may be relevant working with biomaterials in a clinical setting.
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Pharmacokinetics, Safety, and Tolerability of Oral Semaglutide in Subjects With Hepatic Impairment.
Baekdal, TA, Thomsen, M, Kupčová, V, Hansen, CW, Anderson, TW
Journal of clinical pharmacology. 2018;(10):1314-1323
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Abstract
Semaglutide is a human glucagon-like peptide-1 analog that has been co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, for oral administration. This trial (NCT02016911) investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of oral semaglutide. Subjects were classified into groups: normal hepatic function (n = 24), and mild (n = 12), moderate (n = 12), or severe (n = 8) hepatic impairment according to Child-Pugh criteria, and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days). Semaglutide plasma concentrations were measured during dosing and for up to 21 days post-last dose. Area under the semaglutide plasma concentration-time curve from 0-24 hours after the 10th dose (primary end point) and maximum semaglutide concentration after the 10th dose appeared similar across hepatic function groups. Similarly, there was no apparent effect of hepatic impairment on time to maximum semaglutide concentration (median range 1.0-1.5 hours) or half-life (geometric mean range 142-156 hours). No safety concerns were identified in subjects with hepatic impairment receiving semaglutide. Reported adverse events were in line with those observed for other glucagon-like peptide-1 receptor agonists. There was no apparent effect of hepatic impairment on the pharmacokinetics, safety, and tolerability of oral semaglutide. The results of this trial suggest that dose adjustment of oral semaglutide is not warranted in subjects with hepatic impairment.
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Elemental Zinc Is Inversely Associated with C-Reactive Protein and Oxidative Stress in Chronic Liver Disease.
Uddin, MG, Hossain, MS, Rahman, MA, Uddin, AHMM, Bhuiyan, MS
Biological trace element research. 2017;(2):189-193
Abstract
Chronic liver disease (CLD) is associated with the destruction of liver parenchyma cell. It is the main cause of morbidity and mortality in most of the developed countries. Oxidative stress and altered levels of different trace elements in serum have been documented for different diseases including inflammation and many liver diseases. This study aims to evaluate the serum level of malondialdehyde (MDA), nitric oxide (NO), antioxidant vitamin C, C-reactive protein (CRP), and zinc (Zn) in CLD patients and to establish a correlation among the study parameters with the severity of inflammatory conditions of CLD. In this study, CLD patients and healthy volunteers were recruited. Total cholesterol and triglyceride were determined by colorimeter using enzymatic method. Serum non-enzymatic antioxidant vitamin C, reactive oxygen species nitric oxide (NO), and malondialdehyde (MDA) were determined by UV-spectrophotometric method. Trace element (Zn) levels were determined by graphite furnace atomic absorption spectroscopy. Independent sample t test and Pearson's correlation test were performed for statistical analysis using the statistical software package SPSS, Version 20. Studies showed that the MDA (p < 0.001), NO (p < 0.001), and CRP levels were significantly higher in CLD patients than in control subjects. The antioxidant vitamin C (p < 0.001) and trace element zinc (p < 0.001) were comparatively lower in the CLD patients than in control subjects. Elemental Zn showed an inverse relationship with MDA, NO, and CRP but positively correlated with antioxidant capacity, whereas MDA showed a positive correlation with CRP level. Thus, we conclude that attenuated level of Zn and antioxidant in serum play an important role in the inflammatory status of CLD patients by elevating the concentration of MDA, NO, and CRP.
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Efficacy and safety of linagliptin in type 2 diabetes patients with self-reported hepatic disorders: A retrospective pooled analysis of 17 randomized, double-blind, placebo-controlled clinical trials.
Inagaki, N, Sheu, WH, Owens, DR, Crowe, S, Bhandari, A, Gong, Y, Patel, S
Journal of diabetes and its complications. 2016;(8):1622-1630
Abstract
AIMS: Liver disease is highly prevalent among people with type 2 diabetes mellitus (T2DM). We evaluated the dipeptidyl peptidase-4 inhibitor linagliptin in subjects with T2DM and hepatic disorders. METHODS Data were pooled from 17 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2DM subjects that included individuals with self-reported history of hepatic disorders at baseline. The primary endpoint was change in HbA1c from baseline to week 24. RESULTS Of the 7009 participants (56% white, 39% Asian), 574 had hepatic disorders, most commonly hepatic steatosis (60%). At week 24, adjusted mean±standard error (SE) change in HbA1c from baseline in those with hepatic disorders was -0.75%±0.05 with linagliptin and -0.20%±0.08 with placebo [treatment difference: -0.54% (95% confidence interval-0.72 to -0.36); P<.0001]. There was no significant difference in HbA1c reduction between subjects with or without baseline hepatic disorders (P=.4042). Among subjects with hepatic disorders, 13.5% and 14.8% of the linagliptin and placebo groups, respectively, reported drug-related adverse events while 10.4% and 15.9%, respectively, reported hypoglycemia. Overall, adverse event rates were similar in individuals with or without hepatic disorders. CONCLUSIONS This large pooled analysis suggests that linagliptin is effective and well tolerated in people with T2DM and liver disease.
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Gastrointestinal side effects in liver transplant recipients taking enteric-coated mycophenolate sodium vs. mycophenolate mofetil.
Lopez-Solis, R, DeVera, M, Steel, J, Fedorek, S, Sturdevant, M, Hughes, C, Humar, A
Clinical transplantation. 2014;(7):783-8
Abstract
In the setting of liver transplantation, mycophenolate mofetil (MMF) may be used as an adjuvant therapy for immunosuppression to prevent graft rejection; however, its use may be limited due to severe gastrointestinal (GI) side effects. In contrast, enteric-coated mycophenolate sodium (EC-MPS) may be associated with less severe side effects and hence better tolerability. We compared the side effects of EC-MPS to MMF in liver transplant patients in a de novo study (Study I-randomized, prospective, double-blinded) and a conversion study (Study II). In both studies, the severity of GI symptoms was assessed at various time points using the Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation). In Study I, the symptoms of 30 recipients receiving EC-MPS (n = 15) were compared to 15 recipients receiving MMF. A multivariate analysis of variance (MANOVA) of the total GSRS scores and symptom syndrome subscores revealed no significant difference (p > 0.05) between the two medications over time. A conversion study (Study II) with 29 participants, however, showed that over time, all GI symptoms improved significantly (p < 0.001) when the patients were treated with EC-MPS instead of MMF.
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Evaluation of MRI fat fraction in the liver and spine pre and post SPIO infusion.
Liau, J, Shiehmorteza, M, Girard, OM, Sirlin, CB, Bydder, M
Magnetic resonance imaging. 2013;(6):1012-6
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Abstract
This study evaluates the robustness of a magnetic resonance (MR) fat quantification method to changes in R2* caused by an intravenous infusion of superparamagnetic iron oxide (SPIO) contrast agent. The R2* and proton density fat fraction (PDFF) were measured in liver and spine in 14 subjects using an investigational sequence (IDEAL IQ) provided by the MR scanner vendor. Measurements were made before and after SPIO infusion. Results showed SPIO significantly increased R2* in both liver (p=8.8×10(-8)) and spine (p=1.3×10(-2)) but PDFFs were not significantly different in either the liver (p=5.5×10(-1)) or the spine (p=5.6×10(-1)). These results confirm that the IDEAL IQ method of fat quantification is robust to changes in R2*.
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Estimation of liver function using T1 mapping on Gd-EOB-DTPA-enhanced magnetic resonance imaging.
Katsube, T, Okada, M, Kumano, S, Hori, M, Imaoka, I, Ishii, K, Kudo, M, Kitagaki, H, Murakami, T
Investigative radiology. 2011;(4):277-83
Abstract
OBJECTIVES To investigate the ability of T1 mapping of liver on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging for the estimation of liver function. MATERIALS AND METHODS Local institutional review board approved this study. Ninety-one patients (64 men, 27 women; mean age, 67.4 years) were classified into 4 groups as follows: normal liver function (NLF), n = 16; chronic hepatitis (CH), n = 38; liver cirrhosis with Child-Pugh A (LCA), n = 20; and liver cirrhosis with Child-Pugh B (LCB), n = 17. Look-Locker sequences (single slice multiphase imaging using gradient-echo sequence with inversion recovery pulse) were obtained before and at 3, 8, 13, and 18 minutes after Gd-EOB-DTPA administration. T1 mapping of liver parenchyma was calculated from the Look-Locker sequence. T1 relaxation time of liver and reduction rate of T1 relaxation time between pre- and postcontrast enhancement were measured. The Bonferroni t test was used for comparisons between the 4 groups. RESULTS Precontrast T1 relaxation times were significantly longer for LCA and LCB than for NLF, and that of LCB was longer than that of chronic hepatitis (P < 0.05). Postcontrast T1 relaxation times were significantly longer for LCB than for other groups at all time points. Those of LCA were longer than those of NLF at all time points. Reduction rates were significantly lower for LCB than for the other groups at ≥8 minutes. CONCLUSIONS Evaluation of hepatic uptake of Gd-EOB-DTPA using T1 mapping of liver parenchyma can help estimate liver function.
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A pharmacokinetics evaluation of a new, low-volume, oral sulfate colon cleansing preparation in patients with renal or hepatic impairment and healthy volunteers.
Pelham, RW, Alcorn, H, Cleveland, Mv
Journal of clinical pharmacology. 2010;(3):350-4
Abstract
The pharmacokinetics (PK) of an oral sulfate solution (OSS) for bowel cleansing preparation was studied. OSS (30 g of sulfate) was split between 2 doses, 12 hours apart. Safety measures included electrocardiography, vital signs, adverse events, hematology, blood chemistry, and urinalysis. Six adult patients with moderate renal disease (MRD), 6 with mild-moderate hepatic disease (M/MHD), and 6 normal healthy volunteers (NHVs) completed the study. Adverse events were mild to moderate in severity and were mainly limited to headache and expected gastrointestinal symptoms. Serum sulfate levels were highly variable at all times, even after adjusting for baseline. Sulfate was higher in MRD in comparison to the other groups. The C(max) and AUC were higher in the patients, but no statistically significant differences emerged. Sulfate levels returned to predose values within 54 hours after dosing. No electrolyte disturbances occurred. Urinary sulfate excretion was approximately 20% of the dose. OSS was well tolerated. The types and severity of adverse events were similar to those seen in large phase III trials. While patients with MRD had elevated sulfate, the levels were less than those in renal failure and did not alter biochemical parameters that are associated with hypersulfatemia.