A Single Animal Species-Based Prediction of Human Clearance and First-in-Human Dose of Monoclonal Antibodies: Beyond Monkey

These days, there is a lot of emphasis on the prediction of human clearance (CL) from a single species for monoclonal antibodies (mabs). Many studies indicate that monkey is the most suitable species for the prediction of human clearance for mabs. However, it is not well established if rodents (mouse or rat) can also be used to predict human CL for mabs. The objectives of this study were to predict and compare human CL as well as first-in-human dose of mabs from mouse or rat, ormonkey. Four methods were used for the prediction of human CL of mabs. These methods were: use of four allometric exponents (0.75, 0.80, 0.85, and 0.90), a minimal physiologically based pharmacokinetics method (mPBPK), lymph flow rate, and liver blood flow rate. Based on the predicted CL, first-in-human dose of mabs was projected using either exponent 1.0 (linear scaling) or exponent 0.85, and human-equivalent dose (HED) from each of these species. The results of the study indicated that rat or mouse could provide a reasonably accurate prediction of human CL as well as first-in-human dose of mabs. When exponent 0.85 was used for CL prediction, there were 78%, 95%, and 92% observations within a 2-fold prediction error for mouse, rat, and monkey, respectively. Predicted human dose fell within the observed human dose range (administered to humans) for 10 out of 13 mabs for mouse, 11 out of 12 mabs for rat, and 12 out of 15 mabs for monkey. Overall, the clearance and first-in-human dose of mabs were predicted reasonably well by all three species (a single species). On average, monkey may be the best species for the prediction of human clearance and human dose but mouse or rat especially; rat can be a very useful species for conducting the aforementioned studies.

Cardiopulmonary values and organ blood flows before and during heat stress: data in nine subjects at rest in the upright position

Physiological changes associated with thermoregulation can influence the kinetics of chemicals in the human body, such as alveolar ventilation (VA) and redistribution of blood flow to organs. In this study, the influence of heat stress on various physiological parameters was evaluated in nine male volunteers during sessions of exposure to wet blub globe temperatures (WBGT) of 21, 25 and 30°C for four hours. Skin and core temperatures and more than twenty cardiopulmonary parameters were measured. Liver, kidneys, brain, skin and muscles blood flows were also determined based on published measurements. Results show that most subjects (8 out of 9) have been affected by the inhalation of hot and dry air at the WBGT of 30°C. High respiratory rates, superficial tidal volumes and low VA values were notably observed. The skin blood flow has increased by 2.16-fold, whereas the renal blood flow and liver blood flow have decreased by about by 11 and 18% respectively. A complete set of key cardiopulmonary parameters in healthy male adults before and during heat stress was generated for use in PBPK modeling. A toxicokinetic studies are ongoing to evaluate the impact of heat stress on the absorption, biotransformation and excretion rates of volatile xenobiotics.

NON-INVASIVE LIVER BLOOD FLOW ASSESSMENT DEVICE

Клетки печени наиболее подвержены отрицательным последствиям, т.к. печень принимает активное участие в обменных процессах и в выведении из организма вредных и токсичных веществ. С появлением методов исследования, позволяющих изучать локальный кровоток в различных отделах печени, значительно увеличились возможности распознавания патологии. Реогепатография позволяет оценить функциональное состояние сосудов печени, их тонус, эластичность и кровенаполнение, объемную скорость кровотока и выявить застойные явления в венах. Целью данной статьи являлась разработка технического проекта по созданию прибора для неинвазивной оценки кровотока печени. Разработанный прибор оценивает кровоток печени по изменению ее удельного сопротивления. Метод оценки - электроимпедансная реогепатография. Данный метод позволяет регистрировать динамические изменения в импедансе ткани, вызванные изменениями кровотока печени в период сердечного цикла при пропускании через ткань электрического тока высокой частоты и малой амплитуды. Предложена оптимальная конструкция реографа, состоящего из системы электродов, источника тока, биоусилителя, системы сбора данных и блока питания. Электродная система состоит из 6 электродов (2 токовых и 4 измерительных). Портативный прибор позволяет измерять импеданс в диапазоне 0-250 Ом Liver cells are most exposed to negative consequences, because the liver takes an active part in metabolic processes and in the removal of harmful and toxic substances from the body. With the introduction of research methods that allow the study of local blood flow in different parts of the liver, the ability to recognize pathology has increased significantly. Rheohepatography can assess the functional state of liver vessels, their tone, elasticity and blood flow, the volume rate of blood flow and to identify stagnation in the veins. The purpose of this article was to develop a technical project to create a device for non-invasive assessment of blood flow in the liver. The developed device evaluates blood flow of the liver by changing its resistivity. The method of evaluation is electroimpedance rheopathography. This method allows to register dynamic changes in tissue impedance caused by changes in blood flow of the liver during the cardiac cycle when passing through the tissue of high frequency and small amplitude electrical current. The optimal design of the rheograph, consisting of a system of electrodes, current source, bioamplifier, data acquisition system and power supply unit is proposed. The electrode system consists of 6 electrodes (2 current and 4 measurement electrodes). The portable device allows measuring impedance in the range of 0-250 Ohm

Placental corticotrophin releasing hormone is a modulator of fetal liver blood perfusion

Context Variation in fetal liver blood flow influences fetal growth and postnatal body composition. Placental corticotrophin-releasing hormone has been implicated as a key mediator of placental-fetal perfusion. Objective To determine whether circulating levels of placental corticotrophin-releasing hormone across gestation are associated with variations in fetal liver blood flow. Design Prospective cohort study Methods Fetal ultrasonography was performed at 30 weeks’ gestation to characterize fetal liver blood flow (quantified by subtracting ductus venosus flow from umbilical vein flow). Placental corticotrophin-releasing hormone was measured in maternal circulation at approximately 12, 20 and 30 weeks’ gestation. Multiple regression analysis was used to determine the proportion of variation in fetal liver blood flow explained by placental corticotrophin-releasing hormone. Co-variates included maternal age, parity, pre-pregnancy BMI, gestational weight gain, and fetal sex. Results A total of 79 uncomplicated singleton pregnancies were analyzed. Fetal liver blood flow was 68.4 ± 36.0 ml/min (mean ± SD). Placental corticotrophin-releasing hormone concentrations at 12, 20 and 30 weeks were 12.5 ± 8.1, 35.7 ± 24.5 and 247.9 ± 167.8 pg/ml, respectively. Placental corticotrophin-releasing hormone at 30 weeks, but not at 12 and 20 weeks, was significantly and positively associated with fetal liver blood flow at 30 weeks (r = 0.319, p = 0.004), and explained 10.4% of the variance in fetal liver blood flow. Conclusions Placental corticotrophin-releasing hormone in late gestation is a possible modulator of fetal liver blood flow, and may constitute a biochemical marker in clinical investigations of fetal growth and body composition.

The liver, a functionalized vascular structure

The liver is not only the largest organ in the body but also the one playing one of the most important role in the human metabolism as it is in charge of transforming toxic substances in the body. Understanding the way its blood vasculature works is key. In this work we show that the challenge of predicting the hepatic multi-scale vascular network can be met thanks to the constructal law of design evolution. The work unveils the structure of the liver blood flow architecture as a combination of superimposed tree-shaped networks and porous system. We demonstrate that the dendritic nature of the hepatic artery, portal vein and hepatic vein can be predicted, together with their geometrical features (diameter ratio, duct length ratio) as the entire blood flow architectures follow the principle of equipartition of imperfections. At the smallest scale, the shape of the liver elemental systems—the lobules—is discovered, while their permeability is also predicted. The theory is compared with good agreement to anatomical data from the literature.

Serum Scoring and Quantitative Magnetic Resonance Imaging in Intestinal Failure-Associated Liver Disease: A Feasibility Study

(1) Background: Intestinal failure-associated liver disease (IFALD) in adults is characterized by steatosis with variable progression to fibrosis/cirrhosis. Reference standard liver biopsy is not feasible for all patients, but non-invasive serological and quantitative MRI markers for diagnosis/monitoring have not been previously validated. Here, we examine the potential of serum scores and feasibility of quantitative MRI used in non-IFALD liver diseases for the diagnosis of IFALD steatosis; (2) Methods: Clinical and biochemical parameters were used to calculate serum scores in patients on home parenteral nutrition (HPN) with/without IFALD steatosis. A sub-group underwent multiparameter quantitative MRI measurements of liver fat fraction, iron content, tissue T1, liver blood flow and small bowel motility; (3) Results: Compared to non-IFALD (n = 12), patients with IFALD steatosis (n = 8) demonstrated serum score elevations in Enhanced Liver Fibrosis (p = 0.032), Aspartate transaminase-to-Platelet Ratio Index (p < 0.001), Fibrosis-4 Index (p = 0.010), Forns Index (p = 0.001), Gamma-glutamyl transferase-to-Platelet Ratio Index (p = 0.002) and Fibrosis Index (p = 0.001). Quantitative MRI scanning was feasible in all 10 sub-group patients. Median liver fat fraction was higher in IFALD steatosis patients (10.9% vs 2.1%, p = 0.032); other parameter differences were non-significant; (4) Conclusion: Serum scores used for non-IFALD liver diseases may be useful in IFALD steatosis. Multiparameter MRI is feasible in patients on HPN.

Prevention of Nonalcoholic Hepatic Steatosis by Shenling Baizhu Powder: Involvement of Adiponectin-Induced Inhibition of Hepatic SREBP-1c

Background. Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, and its incidence is increasing annually, but there is currently no specific drug for treating NAFLD. Shenling Baizhu powder (SL) is a safe herbal compound commonly used in clinical practice. Our previous research has shown that SL has the effect of preventing NAFLD, but its specific mechanism has not been determined. In this study, the potential mechanism of SL on NAFLD was explored by in vivo experiments. Methods. Wistar rats fed a choline-deficient amino acid-defined diet (CDAA) were treated with SL for 8 weeks. Then, serum samples were collected to obtain biochemical indicators; adipose tissue and liver samples were collected for pathological detection; a moorFLPI-2 blood flow imager was used to measure liver microcirculation blood flow, and a rat cytokine array was used to screen potential target proteins. The expression of liver adiponectin/SREBP-1c pathway-related proteins was determined by Western blotting. Results. SL effectively reduced the liver wet weight, as well as the levels of total cholesterol (TC) and triglyceride (TG) in the liver, and ameliorated liver injury in CDAA-fed rats. Pathological examinations showed that SL markedly reduced liver lipid droplets and improved liver lipid accumulation. In addition, the detection of liver blood flow showed that SL increased liver microcirculation in CDAA-fed rats. Through the cytokine array, a differentially expressed cytokine, namely, adiponectin, was screened in the liver. Western blotting assays showed that SL increased the expression of adiponectin and phosphoacetyl-CoA Carboxylase (p-ACC) in the liver and decreased the expression of steroid regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS). Conclusion. These results suggest that SL can increase the levels of adiponectin in the liver and serum and can inhibit the expression of SREBP-1c, thereby regulating systemic lipid metabolism and reducing liver lipid accumulation.

Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [99mTc]mebrofenin Imaging in Rats

The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [99mTc]mebrofenin may be employed as a probe for hepatic MRP2 activity because its biliary excretion is predominantly mediated by this transporter. As the liver uptake of [99mTc]mebrofenin depends on organic anion-transporting polypeptide (OATP) activity, a safe protocol for targeted inhibition of hepatic MRP2 is needed to study the intrinsic role of each transporter system. Diltiazem (DTZ) and cyclosporin A (CsA) were first confirmed to be potent MRP2 inhibitors in vitro. Dynamic acquisitions were performed in rats (n = 5–6 per group) to assess the kinetics of [99mTc]mebrofenin in the liver, intestine and heart-blood pool after increasing doses of inhibitors. Their impact on hepatic blood flow was assessed using Doppler ultrasound (n = 4). DTZ (s.c., 10 mg/kg) and low-dose CsA (i.v., 0.01 mg/kg) selectively decreased the transfer of [99mTc]mebrofenin from the liver to the bile (k3). Higher doses of DTZ and CsA did not further decrease k3 but dose-dependently decreased the uptake (k1) and backflux (k2) rate constants between blood and liver. High dose of DTZ (i.v., 3 mg/kg) but not CsA (i.v., 5 mg/kg) significantly decreased the blood flow in the portal vein and hepatic artery. Targeted pharmacological inhibition of hepatic MRP2 activity can be achieved in vivo without impacting OATP activity and liver blood flow. Clinical studies are warranted to validate [99mTc]mebrofenin in combination with low-dose CsA as a novel substrate/inhibitor pair to untangle the role of OATP and MRP2 activity in liver diseases.