Liver Compartments Research Articles

The Estimation Value of 99mTc-MAA in Comparison with 90Y-PET/MR-based Dosimetry in Selective Internal Radiation Therapy (SIRT) for Liver Malignancies.

This study intended to compare the radiation dose estimates to target and nontarget liver compartments from 99mTc-MAA SPECT/CT and 90Y-PET/MR scans in liver tumors treated by 90Y-glass microspheres. Dose estimation was performed for twenty-three eligible patients (13M, 10F) after 99mTc-MAA simulation using SPECT/CT imaging, and over 90Y-PET/MR images after 90Y-microsphere therapy. Simplicit90Y™ software was used for voxel-based dosimetry over the liver parenchyma. Dose estimates were obtained for whole healthy liver (HL), healthy injected liver (HIL), and tumor volumes. Pearson correlation, Bland-Altman plot, and Wilcoxon signed-ranks test were used for statistical analysis. The mean tumor dose was 270±111 Gy, the whole liver parenchyma dose was 26 ±12 Gy, and the healthy injected liver dose was 55±18 Gy from 99mTc-MAA simulation. 90YPET/ MR dosimetry yielded a mean tumor dose of 271±125 Gy, a HIL mean dose of 54±18 Gy, and a liver parenchyma dose of 25±12 Gy. An excellent agreement was demonstrated between tumor doses (R2=0.90) and liver doses (R2=0.87), while the agreement was less for HIL doses (R2=0.80). Wilcoxon signed-ranks test yielded no significant difference between the dose estimates for all liver compartments. It was deduced that 99mTc-MAA SPECT/CT simulation provides valuable dose prediction in 90Y-glass microsphere therapy. Despite the difference in volume measurements and dose estimates with 90Y-PET/MR, the predictive value of the 99mTc-MAA simulation was not affected.

Multiorgan-on-a-chip for cancer drug pharmacokinetics-pharmacodynamics (PK-PD) modeling and simulations.

Cancer is one of the most common and fatal diseases worldwide and kills millions of people every year. Cancer drug resistance, lack of efficacy, and safety are significant problems in cancer patients. A multiorgan-on-a-chip (MOC) device consisting of breast and liver compartments was designed with AutoCAD software. The MOC molds were printed by a Formlabs Form 2 3D printer. MDA-MB-231, HepG2, and MCF-10A cells were used for the MOC experiments. The cell lines were cultured at 37°C with 5% CO2, and cell viability was assessed via Alamar blue dye to generate pharmacodynamics (PD) data. Drug concentrations from the cell culture media were analyzed via Agilent 1260 Infinity II HPLC with a Waters Symmetry C18 column and used to generate pharmacokinetics (PK) data. The PK and PD data were modeled and simulated by Monolix and Simulix software, respectively. The safety and efficacy of drug dosing regimens were compared, and the best dosing regimens were selected. This research designed and fabricated a unique MOC consisting of liver and breast compartments that overcomes the need for sealing or assembling. It was used for PK-PD modeling and simulations, and its functionality was proven experimentally. The new MOC will be helpful in preclinical trials to evaluate the efficacy and safety of drugs.

Effect of SLC22A1 polymorphism on the pharmacokinetics of proguanil in Korean: A semi-physiologic population pharmacokinetic approach.

Proguanil, an antimalarial drug, undergoes hepatic uptake by the polymorphic organic cation transporter 1 (OCT1) and is subsequently metabolized by the cytochrome P-450 2C19 (CYP2C19) enzyme into its active metabolite, cycloguanil. This study aims to evaluate and mechanistically characterize the effect of genetic polymorphism of SLC22A1, which encodes OCT1, on the pharmacokinetics (PKs) of proguanil and cycloguanil in Korean. This study was based on a post hoc analysis of the PK results of a CYP2C19 mediated drug-drug interaction study (NCT04568772). Among the 16 CYP2C19 normal metabolizers enrolled in the previous study, 13 were prospectively genotyped for six SLC22A1 single nucleotide polymorphisms (SNPs) associated with a decreased function of OCT1. Among these, only the SNP SLC22A1 1022C>T (rs2282143) was observed, with four subjects being heterozygous (CT) and nine subjects homozygous for the wild-type allele (CC). The CT genotype showed a 1.2-fold higher systemic exposure of proguanil and a 0.6-fold lower exposure of cycloguanil compared to those in subjects with the CC genotype, resulting in a 0.5 to 0.6-fold lower metabolic ratio. Based on the PK and genotype data, a parent-metabolite joint population PK model including a well-stirred liver compartment was developed using a nonlinear mixed-effect modeling approach. The OCT1 activity of the CT genotype was estimated to be 0.42-fold lower compared to the CC genotype. In conclusion, the genetic polymorphism of SLC22A1 1022C>T increased the systemic exposure of proguanil, while decreasing the systemic exposure of cycloguanil by reducing the hepatic uptake of proguanil, as mechanistically described by a population PK approach.

The added value of diffusion tensor imaging with systematic bias correction for the assessment of liver morphology and physiology.

Diffusion-weighted images of the human liver are prone to artifacts from bulk motions, poor SNR, non-uniformity of magnetic field gradients, and non-optimal choice of diffusion weightings. These factors markedly affect diffusion tensor imaging (DTI) metrics such as mean diffusivity (MD) and fractional anisotropy (FA). This work presents a simple preprocessing pipeline for enhanced magnetic field gradient non-uniformity calibration and analysis of the systematic bias removal attained in each correction step. Liver DTI scans were conducted in two isotropic phantoms and one healthy volunteer. Diffusion tensor was calculated for the original data and after denoising, B1 correction, rigid body registration, and magnetic field gradient non-uniformity correction applying the B-matrix spatial distribution (BSD) method and then, compared with the standard approach (sDTI). MD and FA were determined in three segments of the right lobe from DTI using four different combinations of b-values from the set 0, 400, and 800 s/mm2. Results showed that the proposed preprocessing and BSD methods have a significant impact on MD and FA values in off- and iso-centered isotropic phantoms. The applied corrections applied to the human liver resulted in a 11% change in MD and a - 64% change in FA. By manipulating the b-values used in the diffusion tensor calculation, DTI metrics that reflect only morphology or additional information about liver tissue physiology can be obtained. Accurate quantification of the human liver by diffusion requires appropriate preprocessing and carefully chosen b-value. Noise, B1 inhomogeneity, mis-registration, and non-uniform magnetic field gradients significantly change distributions of DTI metrics in isotropic phantoms and the human liver. Basic preprocessing and the B-matrix spatial distribution (BSD) method perform differently for off-center and isocenter locations. In the human liver, they removed systematic bias of FA and MD by up to -63% and 11%, respectively. Visible variability of FA and MD among b-value sets indicates the possibility of DTI sensitization to different liver compartments.

A Continuous Intestinal Absorption Model to Predict Drug Enterohepatic Recirculation in Healthy Humans: Nalbuphine as a Model Substrate.

Nalbuphine (NAL) is a κ-agonist/μ-antagonist opioid being developed as an oral extended formulation (ER) for the treatment of chronic cough in idiopathic pulmonary fibrosis and itch in prurigo nodularis. NAL is extensively glucuronidated and likely undergoes enterohepatic recirculation (EHR). The purpose of this work is to develop pharmacokinetic models for NAL absorption and enterohepatic recirculation (EHR). Clinical pharmacokinetic (PK) data sets in healthy subjects from three trials that included IV, oral solution, and ER tablets in fed and fasted state and two published trials were used to parametrize a novel partial differential equation (PDE)-based model, termed "PDE-EHR" model. Experimental inputs included in vitro dissolution and permeability data. The model incorporates a continuous intestinal absorption framework, explicit liver and gall bladder compartments, and compartments for systemic drug disposition. The model was fully PDE-based with well-stirred compartments achieved by rapid diffusion. The PDE-EHR model accurately reproduces NAL concentration-time profiles for all clinical data sets. NAL disposition simulations required inclusion of both parent and glucuronide recirculation. Inclusion of intestinal P-glycoprotein efflux in the simulations suggests that NAL is not expected to be a victim or perpetrator of P-glycoprotein-mediated drug interactions. The PDE-EHR model is a novel tool to predict EHR and food/formulation effects on drug PK. The results strongly suggest that even intravenous dosing studies be conducted in fasted subjects when EHR is suspected. The modeling effort is expected to aid in improved prediction of dosing regimens and drug disposition in patient populations.

Perfluoropolyether-Based Gut-Liver-on-a-Chip for the Evaluation of First-Pass Metabolism and Oral Bioavailability of Drugs.

In the evolving field of drug discovery and development, multiorgans-on-a-chip and microphysiological systems are gaining popularity owing to their ability to emulate in vivo biological environments. Among the various gut-liver-on-a-chip systems for studying oral drug absorption, the chip developed in this study stands out with two distinct features: incorporation of perfluoropolyether (PFPE) to effectively mitigate drug sorption and a unique enterohepatic single-passage system, which simplifies the analysis of first-pass metabolism and oral bioavailability. By introducing a bolus drug injection into the liver compartment, hepatic extraction alone could be evaluated, further enhancing our estimation of intestinal availability. In a study on midazolam (MDZ), PFPE-based chips showed more than 20-times the appearance of intact MDZ in the liver compartment effluent compared to PDMS-based counterparts. Notably, saturation of hepatic metabolism at higher concentrations was confirmed by observations when the dose was reduced from 200 μM to 10 μM. This result was further emphasized when the metabolism was significantly inhibited by the coadministration of ketoconazole. Our chip, which is designed to minimize the dead volume between the gut and liver compartments, is adept at sensitively observing the saturation of metabolism and the effect of inhibitors. Using genome-edited CYP3A4/UGT1A1-expressing Caco-2 cells, the estimates for intestinal and hepatic availabilities were 0.96 and 0.82, respectively; these values are higher than the known human in vivo values. Although the metabolic activity in each compartment can be further improved, this gut-liver-on-a-chip can not only be used to evaluate oral bioavailability but also to carry out individual assessment of both intestinal and hepatic availability.

A Semi-Mechanistic Population Pharmacokinetic Model of Noscapine in Healthy Subjects Considering Hepatic First-Pass Extraction and CYP2C9 Genotypes.

Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability. This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability. Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately. Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (<0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3). The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at "Deutsches Register Klinischer Studien" under registration no. DRKS00017760.

Integrating Clopidogrel's First-Pass Effect in a Joint Semi-Physiological Population Pharmacokinetic Model of the Drug and Its Inactive Carboxylic Acid Metabolite.

Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85-90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, with most focusing on CLO-TH. Although CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. This study aimed to characterize the process of the absorption of CLO and its conversion to CLO-CA via developing a population pharmacokinetic model. Individual participants' data from two bioequivalence studies were utilized. Extensive blood samples were collected at predetermined intervals, including 841 concentrations of CLO and 1149 of CLO-CA. A nonlinear, mixed-effects modelling approach using NONMEM® software (v 7.5) was applied. A one-compartment model was chosen for CLO, while a two-compartment proved optimal for CLO-CA. Absorption from the depot compartment was modeled via two transit compartments, incorporating transit rate constants (Ktr). A semi-physiological model explained the first-pass effect of CLO, integrating a liver compartment. The estimated mean transit times (MTTs) for the studies were 0.470 and 0.410 h, respectively. The relative bioavailability for each study's generic medicine compared to the reference were 1.08 and 0.960, respectively. Based on the estimated parameters, the fractions metabolized to inactive metabolites (FiaM_st1 and FiaM_st2) were determined to be 87.27% and 86.87% for the two studies, respectively. The appropriateness of the final model was confirmed. Our model offers a robust framework for elucidating the pharmacokinetic profiles of CLO and CLO-CA.

Improving HCC Prognostic Models after Liver Resection by AI-Extracted Tissue Fiber Framework Analytics.

Despite advances in diagnostic and treatment technologies, predicting outcomes of patients with hepatocellular carcinoma (HCC) remains a challenge. Prognostic models are further obscured by the variable impact of the tumor properties and the remaining liver parenchyma, often affected by cirrhosis or non-alcoholic fatty liver disease that tend to precede HCC. This study investigated the prognostic value of reticulin and collagen microarchitecture in liver resection samples. We analyzed 105 scanned tissue sections that were stained using a Gordon and Sweet's silver impregnation protocol combined with Picric Acid-Sirius Red. A convolutional neural network was utilized to segment the red-staining collagen and black linear reticulin strands, generating a detailed map of the fiber structure within the HCC and adjacent liver tissue. Subsequent hexagonal grid subsampling coupled with automated epithelial edge detection and computational fiber morphometry provided the foundation for region-specific tissue analysis. Two penalized Cox regression models using LASSO achieved a concordance index (C-index) greater than 0.7. These models incorporated variables such as patient age, tumor multifocality, and fiber-derived features from the epithelial edge in both the tumor and liver compartments. The prognostic value at the tumor edge was derived from the reticulin structure, while collagen characteristics were significant at the epithelial edge of peritumoral liver. The prognostic performance of these models was superior to models solely reliant on conventional clinicopathologic parameters, highlighting the utility of AI-extracted microarchitectural features for the management of HCC.

Single-cell RNA sequencing of liver fine-needle aspirates captures immune diversity in the blood and liver in chronic hepatitis B patients.

HBV infection is restricted to the liver, where it drives exhaustion of virus-specific T and B cells and pathogenesis through dysregulation of intrahepatic immunity. Our understanding of liver-specific events related to viral control and liver damage has relied almost solely on animal models, and we lack useable peripheral biomarkers to quantify intrahepatic immune activation beyond cytokine measurement. Our objective was to overcome the practical obstacles of liver sampling using fine-needle aspiration and develop an optimized workflow to comprehensively compare the blood and liver compartments within patients with chronic hepatitis B using single-cell RNA sequencing. We developed a workflow that enabled multi-site international studies and centralized single-cell RNA sequencing. Blood and liver fine-needle aspirations were collected, and cellular and molecular captures were compared between the Seq-Well S 3 picowell-based and the 10× Chromium reverse-emulsion droplet-based single-cell RNA sequencing technologies. Both technologies captured the cellular diversity of the liver, but Seq-Well S 3 effectively captured neutrophils, which were absent in the 10× dataset. CD8 T cells and neutrophils displayed distinct transcriptional profiles between blood and liver. In addition, liver fine-needle aspirations captured a heterogeneous liver macrophage population. Comparison between untreated patients with chronic hepatitis B and patients treated with nucleoside analogs showed that myeloid cells were highly sensitive to environmental changes while lymphocytes displayed minimal differences. The ability to electively sample and intensively profile the immune landscape of the liver, and generate high-resolution data, will enable multi-site clinical studies to identify biomarkers for intrahepatic immune activity in HBV and beyond.

Optimizing Moxifloxacin Dose in MDR-TB Participants with or without Efavirenz Coadministration Using Population Pharmacokinetic Modeling.

Moxifloxacin is included in some treatment regimens for drug-sensitive tuberculosis (TB) and multidrug-resistant TB (MDR-TB). Aiming to optimize dosing, we described moxifloxacin pharmacokinetic and MIC distribution in participants with MDR-TB. Participants enrolled at two TB hospitals in South Africa underwent intensive pharmacokinetic sampling approximately 1 to 6 weeks after treatment initiation. Plasma drug concentrations and clinical data were analyzed using nonlinear mixed-effects modeling with simulations to evaluate doses for different scenarios. We enrolled 131 participants (54 females), with median age of 35.7 (interquartile range, 28.5 to 43.5) years, median weight of 47 (42.0 to 54.0) kg, and median fat-free mass of 40.1 (32.3 to 44.7) kg; 79 were HIV positive, 29 of whom were on efavirenz-based antiretroviral therapy. Moxifloxacin pharmacokinetics were described with a 2-compartment model, transit absorption, and elimination via a liver compartment. We included allometry based on fat-free mass to estimate disposition parameters. We estimated an oral clearance for a typical patient to be 17.6 L/h. Participants treated with efavirenz had increased clearance, resulting in a 44% reduction in moxifloxacin exposure. Simulations predicted that, even at a median MIC of 0.25 (0.06 to 16) mg/L, the standard daily dose of 400 mg has a low probability of attaining the ratio of the area under the unbound concentration-time curve from 0 to 24 h to the MIC (fAUC0-24)/MIC target of >53, particularly in heavier participants. The high-dose WHO regimen (600 to 800 mg) yielded higher, more balanced exposures across the weight ranges, with better target attainment. When coadministered with efavirenz, moxifloxacin doses of up to 1,000 mg are needed to match these exposures. The safety of higher moxifloxacin doses in clinical settings should be confirmed.

Simplification of dosimetry in 90Y-radioembolization therapy by dual planar images.

The purpose was to provide apractical and effective method for performing reliable 90Y dosimetry based on 99mTc-MAA and SPEC/CT. The impact of scatter correction (SC) and attenuation correction (AC) on the injected 90Y activity, lung shunt fraction (LSF) and the delivered dose to lung and liver compartments was investigated within the scope of the study. Eighteen eligible patients (F: 3, M: 15) were subjected to 90Y therapy. 99mTc-MAA (111-222 MBq) was injected into the targeted liver, followed by whole-body scan (WBS) with peak-window at 140 keV (15% width) and one down-scatter window. SPECT/CT scan was subsequently acquired encompassing lung and liver regions. The LSFs were fashioned from standard WBS LSFwb (St), scatter corrected WBS LSFwb (Sc), only scatter corrected SPECT LSFspect (NoAC-SC) and SPECT/CT with attenuation and scatter correction LSFspect (AC-SC). The absorbed doses that would be delivered to tumor and injected healthy liver were estimated using different calculation modes involving AC-SC (SPECT/CT), NoAC-SC (SPECT), NoAC-NoSC+LSFwb (SC), AC-SC + LSFwb (St), and NoAC-NoSC+LSFwb (St). The average deviations (range) in LSF values between standard LSFwb (St) and those from SPECT/CT (AC-SC), SPECT (NoAC-SC), and LSFwb (SC) were - 50% (- 29/- 71), - 32% (- 8/- 67), and - 45% (- 13/80), respectively. The suggested 90Y activity (GBq/Gy) was decreased within a range of 2-11%, 1-9%, and 2-7% by using LSFspect (AC-SC), LSFspect (NoAC-SC), and LSFwb (SC), respectively. Overall, two-sample t-test yielded no statistically significant difference (p < 0.05) in the absorbed doses to tumor and injected healthy liver between AC-SC (SPECT) and the rest of approaches with/and without AC and SC. However, a statistically significant difference (p < 0.05) was demonstrated in the lung shunt fractions and lung doses due to AC and SC. The LSFs from scatter corrected planar images LSFwb (SC) exhibited well agreement (R2 = 0.92) with SPECT/CT (AC-SC) and there was no statistically significant difference (Pvalue > 0.05) between both methods. It was deduced that SPECT/CT with attenuation and scatter correction plays a crucial role in the measurements of lung shunt fraction and dose as well as the total number of 90Y treatments. However, the absorbed dose to tumors and injected healthy liver was minimally affected by AC and SC. Besides, a good agreement was observed between LSF datasets from SPECT/CT versus scatter corrected WBS that can be alternatively and effectively used in 90Y dosimetry.

Plasma and Liver Pharmacokinetics of the N-Acetylgalactosamine Short Interfering RNA JNJ-73763989 in Recombinant Adeno-Associated-Hepatitis B Virus-Infected Mice.

JNJ-73763989 is an N-acetylgalactosamine conjugated short interfering RNA combination product consisting of two triggers in clinical development for chronic hepatitis B virus (HBV) infection treatment that induces a selective degradation of all HBV mRNA transcripts. Our aim is to characterize the plasma and liver pharmacokinetics (PK) of JNJ-73763989 after intravenous and subcutaneous administration in recombinant adeno-associated (rAAV) HBV infected mice. Forty-two male rAAV-HBV infected C57Bl/6 mice received JNJ-73763989 doses of 10 mg/kg i.v. or 1, 3 and 10 mg/kg s.c. Plasma and liver concentrations were analyzed simultaneously using nonlinear mixed-effects modeling with the NONMEM 7.4. A population PK model consisting of a two-compartment disposition model with transporter-mediated drug disposition, including internalization to the liver compartment, linear elimination from plasma and liver, and first-order absorption following subcutaneous administration, was suitable to describe both plasma and liver PK. After subcutaneous dosing, absolute bioavailability was complete and flip-flop kinetics were observed. JNJ-73763989 distributes from plasma to liver via transporter-mediated liver internalization in less than 24 hours, with sustained (&gt;42 days) liver exposure. The saturation of transporter-mediated liver internalization was hypothesized to be due to asialoglycoprotein receptor saturation. Increasing the dose decreased the relative liver uptake efficiency in mice for intravenously and, to a lesser extent, subcutaneously administered JNJ-73763989. Lower dose levels administered subcutaneously in mice can maximize the proportion of the dose reaching the liver. SIGNIFICANCE STATEMENT: Pharmacokinetic modeling of JNJ-73763989 liver and plasma concentration-time data in mice indicated that the proportion of JNJ-73763989 reaching the liver may be increased by administering lower subcutaneous doses compared to higher intravenous doses. Model-based simulations can be applied to optimize the dose and regimen combination.

Compartmental model describing the physiological basis for the HepQuant SHUNT test

The HepQuant SHUNT test quantifies hepatic functional impairment from the simultaneous clearance of cholate from the systemic and portal circulations for the purpose of monitoring treatment effects or for predicting risk for clinical outcome. Compartmental models are defined by distribution volumes and transfer rates between volumes to estimate parameters not defined by noncompartmental analyses. Previously, a noncompartmental analysis method, called the minimal model (MM), demonstrated reproducible and reliable measures of liver function (Translational Research 2021). The aim of this study was to compare the reproducibility and reliability of a new physiologically based compartmental model (CM) vs the MM. Data were analyzed from 16 control, 16 nonalcoholic steatohepatitis (NASH), and 16 hepatitis C virus (HCV) subjects, each with 3 replicate tests conducted on 3 separate days. The CM describes transfer of cholates between systemic, portal, and liver compartments with assumptions from measured or literature-derived values and unknown parameters estimated by nonlinear least-squares regression. The CM was compared to the MM for 6 key indices of hepatic disease in terms of intraclass correlation coefficient (ICC) with a lower acceptable limit of 0.7. The CM correlated well with the MM for disease severity index (DSI) with R2 (95% confidence interval) of 0.96 (0.94–0.98, P < 0.001). Acceptable reproducibility (ICC > 0.7) was observed for 6/6 and 5/6 hepatic disease indices for CM and MM, respectively. SHUNT, a measure of the absolute bioavailability, had ICC of 0.73 (0.60–0.83, P = 0.3095) for MM and 0.84 (0.76–0.90, P = 0.0012) for CM. The CM, but not the MM, allowed determination of anatomic shunt and hepatic extraction and improved the within individual reproducibility.

Development of a population pharmacokinetic/pharmacodynamic model for various oral paclitaxel formulations co-administered with ritonavir and thrombospondin-1 based on data from early phase clinical studies

PurposeOrally administered paclitaxel offers increased patient convenience while providing a method to prolong exposure without long continuous, or repeated, intravenous infusions. The oral bioavailability of paclitaxel is improved through co-administration with ritonavir and application of a suitable pharmaceutical formulation, which addresses the dissolution-limited absorption of paclitaxel. We aimed to characterize the pharmacokinetics of different paclitaxel formulations, co-administered with ritonavir, and to investigate a pharmacodynamic relationship between low-dose metronomic (LDM) treatment with oral paclitaxel and the anti-angiogenic marker thrombospondin-1 (TSP-1).MethodsFifty-eight patients treated with different oral paclitaxel formulations were included for pharmacokinetic analysis. Pharmacodynamic data was available for 36 patients. All population pharmacokinetic/pharmacodynamic modelling was performed using non-linear mixed-effects modelling.ResultsA pharmacokinetic model consisting of gut, liver, central, and peripheral compartments was developed for paclitaxel. The gastrointestinal absorption rate was modelled with a Weibull function. Relative gut bioavailabilities of the tablet and capsule formulations, as fractions of the gut bioavailability of the drinking solution, were estimated to be 0.97 (95%CI: 0.67–1.33) and 0.46 (95%CI: 0.34–0.61), respectively. The pharmacokinetic/pharmacodynamic relationship between paclitaxel and TSP-1 was modelled using a turnover model with paclitaxel plasma concentrations driving an increase in TSP-1 formation rate following an Emax relationship with an EC50 of 284 ng/mL (95%CI: 122–724).ConclusionThe developed pharmacokinetic model adequately described the paclitaxel plasma concentrations for the different oral formulations co-administered with ritonavir. This model, and the established pharmacokinetic/pharmacodynamic relationship with TSP-1, may facilitate future development of oral paclitaxel.

Metabolic abnormalities, liver and body fat in American versus Chinese patients with non-alcoholic fatty liver disease.

Background and AimNon‐alcoholic fatty liver disease (NAFLD) is common in the United States and China. We compared prevalence of metabolic syndrome (MS), hepatic steatosis and fibrosis, and quantity and quality of body fat between American versus Chinese patients with NAFLD.MethodsNAFLD patients were prospectively recruited from the University of Michigan Health System (UMHS) in the United States and Peking University Health Sciences Center (PUHSC) in China. All patients had baseline computed tomography (CT), laboratory tests and Fibroscan® controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Comparisons were made for overall cohorts and matched cohorts (matched for sex, age, and body mass index [BMI] category). Logistic regression was performed to identify independent predictors of moderate and severe steatosis and lack of advanced fibrosis.ResultsOne‐hundred and one American and One‐hundred and sixty Chinese patients were included. UMHS patients were older, with higher prevalence of MS, had higher LSM and CAP scores, and more fat in liver, visceral, subcutaneous, and muscle compartments than PUHSC patients. Differences in LSM, visceral fat Hounsfield unit, and subcutaneous fat area (SFA) persisted in the matched cohort. NAFLD patients with MS had significantly higher LSM, and more fat in liver, visceral, subcutaneous and muscle compartments than those without. Moderate or severe steatosis was independently associated with MS, visceral fat quality, and SFA, while the absence of advanced fibrosis was associated with Asian race and not having MS.ConclusionAmerican patients with NAFLD had more liver fibrosis than Chinese patients despite having better quality visceral fat and after matching for age, sex, and BMI category.

166Holmium\u201399mTechnetium dual-isotope imaging: scatter compensation and automatic healthy-liver segmentation for 166Holmium radioembolization dosimetry

BackgroundPartition modeling allows personalized activity calculation for holmium-166 (166Ho) radioembolization. However, it requires the definition of tumor and non-tumorous liver, by segmentation and registration of a separately acquired CT, which is time-consuming and prone to error. A protocol including 166Ho-scout, for treatment simulation, and technetium-99m (99mTc) stannous phytate for healthy-liver delineation was proposed. This study assessed the accuracy of automatic healthy-liver segmentation using 99mTc images derived from a phantom experiment. In addition, together with data from a patient study, the effect of different 99mTc activities on the 166Ho-scout images was investigated. To reproduce a typical scout procedure, the liver compartment, including two tumors, of an anthropomorphic phantom was filled with 250 MBq of 166Ho-chloride, with a tumor to non-tumorous liver activity concentration ratio of 10. Eight SPECT/CT scans were acquired, with varying levels of 99mTc added to the non-tumorous liver compartment (ranging from 25 to 126 MBq). For comparison, forty-two scans were performed in presence of only 99mTc from 8 to 240 MBq. 99mTc image quality was assessed by cold-sphere (tumor) contrast recovery coefficients. Automatic healthy-liver segmentation, obtained by thresholding 99mTc images, was evaluated by recovered volume and Sørensen–Dice index. The impact of 99mTc on 166Ho images and the role of the downscatter correction were evaluated on phantom scans and twenty-six patients’ scans by considering the reconstructed 166Ho count density in the healthy-liver.ResultsAll 99mTc image reconstructions were found to be independent of the 166Ho activity present during the acquisition. In addition, cold-sphere contrast recovery coefficients were independent of 99mTc activity. The segmented healthy-liver volume was recovered fully, independent of 99mTc activity as well. The reconstructed 166Ho count density was not influenced by 99mTc activity, as long as an adequate downscatter correction was applied.ConclusionThe 99mTc image reconstructions of the phantom scans all performed equally well for the purpose of automatic healthy-liver segmentation, for activities down to 8 MBq. Furthermore, 99mTc could be injected up to at least 126 MBq without compromising 166Ho image quality.Clinical trials The clinical study mentioned is registered with Clinicaltrials.gov (NCT02067988) on February 20, 2014.

New Pharmacokinetic Parameters of Imaging Substrates Quantified from Rat Liver Compartments.

Hepatobiliary imaging is increasingly used by pharmacologists to quantify liver concentrations of transporter-dependent drugs. However, liver imaging does not quantify concentrations in extracellular space, hepatocytes, and bile canaliculi. Our study compared the compartmental distribution of two hepatobiliary substrates gadobenate dimeglumine [BOPTA; 0.08 liver extraction ratio (ER)] and mebrofenin (MEB; 0.93 ER) in a model of perfused rat liver. A gamma counter placed over livers measured liver concentrations. Livers were preperfused with gadopentetate dimeglumine to measure extracellular concentrations. Concentrations coming from bile canaliculi and hepatocytes were calculated. Transporter activities were assessed by concentration ratios between compartments and pharmacokinetic parameters that describe the accumulation and decay profiles of hepatocyte concentrations. The high liver concentrations of MEB relied mainly on hepatocyte and bile canaliculi concentrations. In contrast, the three compartments contributed to the low liver concentrations obtained during BOPTA perfusion. Nonlinear regression analysis of substrate accumulation in hepatocytes revealed that cellular efflux is measurable ∼4 minutes after the start of perfusion. The hepatocyte-to-extracellular concentration ratio measured at this time point was much higher during MEB perfusion. BOPTA transport by multidrug resistance associated protein 2 induced an aquaporin-mediated water transport, whereas MEB transport did not. BOPTA clearance from hepatocytes to bile canaliculi was higher than MEB clearance. MEB did not efflux back to sinusoids, whereas BOPTA basolateral efflux contributed to the decrease in hepatocyte concentrations. In conclusion, our ex vivo model quantifies substrate compartmental distribution and transport across hepatocyte membranes and provides an additional understanding of substrate distribution in the liver. SIGNIFICANCE STATEMENT: When transporter-dependent drugs target hepatocytes, cellular concentrations are important to investigate. Low concentrations on cellular targets impair drug therapeutic effects, whereas excessive hepatocyte concentrations may induce cellular toxicity. With a gamma counter placed over rat perfused livers, we measured substrate concentrations in the extracellular space, hepatocytes, and bile canaliculi. Transport across hepatocyte membranes was calculated. The study provides an additional understanding of substrate distribution in the liver.

MODELING THE LONG-TERM RETENTION OF PLUTONIUM IN THE HUMAN RESPIRATORY TRACT USING SCAR-TISSUE COMPARTMENTS.

The respiratory tract tissues of four former nuclear workers with plutonium intakes were radiochemically analyzed post mortem by the United States Transuranium and Uranium Registries. Plutonium activities in the upper respiratory tract of these individuals were found to be higher than those predicted using the most recent biokinetic models described in publications of the International Commission on Radiological Protection. Modification of the model parameters, including the bound fraction, was not able to explain the data in one of the four individuals who had inhaled insoluble form of plutonium. Literature review points to the presence of-and a significant retention of-plutonium in the scar tissues of the lungs. Accordingly, an alternate model with scar-tissue compartments corresponding to larynx, bronchi, bronchioles, alveolar-interstitium and thoracic lymph nodes was proposed. The rates of transfer to the scar tissue compartments were determined using Markov Chain Monte Carlo analysis of data on urinary excretion, lung counts and post-mortem measurements of liver, skeleton and individual respiratory tract compartments, as available. The posterior models predicted that 20-100%-depending on the solubility of the material inhaled-of the activities retained in the respiratory tract were sequestered in the scar tissues.

Concentrations and pharmacokinetic parameters of MRI and SPECT hepatobiliary agents in rat liver compartments

BackgroundIn hepatobiliary imaging, systems detect the total amount of agents originating from extracellular space, bile canaliculi, and hepatocytes. They add in situ concentration of each compartment corrected by its respective volume ratio to provide liver concentrations. In vivo contribution of each compartment to liver concentration is inaccessible. Our aim was to quantify the compartmental distribution of two hepatobiliary agents in an ex vivo model and determine how their liver extraction ratios and cholestasis (livers lacking canalicular transporters) might modify it.MethodsWe perfused labelled gadobenate dimeglumine (Bopta, 200 μM, 7% liver extraction ratio) and mebrofenin (Meb, 64 μM, 94% liver extraction ratio) in normal (n = 18) and cholestatic (n = 6) rat livers. We quantified liver concentrations with a gamma counter placed over livers. Concentrations in hepatocytes and bile canaliculi were calculated. Mann-Whitney and Kruskal-Wallis tests were used.ResultsHepatocyte concentrations were 2,043 ± 333 μM (Meb) versus 360 ± 69 μM (Bopta, p < 0.001). Meb extracellular concentrations did not contribute to liver concentrations (1.3 ± 0.3%). The contribution of Bopta extracellular concentration was 12.4 ± 1.9% (p < 0.001 versus Meb). Contribution of canaliculi was similar for both agents (16%). Cholestatic livers had no Bopta in canaliculi but their hepatocyte concentrations increased in comparison to normal livers.ConclusionHepatocyte concentrations are correlated to liver extraction ratios of hepatobiliary agents. When Bopta is not present in canaliculi of cholestatic livers, hepatocyte concentrations increase in comparison to normal livers. This new understanding extends the interpretation of clinical liver images.