Volume Of Distribution Research Articles

#811 Effect of GLP-1 receptor agonists on the weight, urea distribution volume and blood pressure of hemodialysis (HD) patients

Abstract Background and Aims Glucagon-like-peptide-1 receptor agonists (GLP-1) drugs are a class of medications commonly used to treat type-2 diabetes. Diabetes is prevalent in almost 60% of the end stage kidney disease (ESKD) patients and an increasing number of dialysis patients use GLP-1 drugs. It is important to note that GLP-1 drugs may have additional benefits such as weight loss and potential cardiovascular benefits. However, little is known about the effects of these drugs in dialysis patients. We analysed the changes in body weight and blood pressure in hemodialysis (HD) patients who start using these drugs. We also analysed whether there are changes in patients’ urea distribution volume, a proxy of lean body mass, to understand whether these medications affect muscle mass. Method We retrospectively evaluated 236 ESKD patients who were prescribed GLP-1 drugs as part of routine clinical care in October of 2023 at clinics in a large dialysis organization. All patients received dialysis for at least 60 days before and after they started using the medication. We looked at the changes in the average post dialysis weight, urea distribution volume, and pre dialysis systolic blood pressure (pre-SBP) between the 60 days before using GLP-1 drugs (pre-GLP1 period) and 60 days after initiating the drug (post-GLP1 phase). For each metric, we performed a paired t-test to evaluate the changes between pre-GLP1 and post-GLP1. Results The average post dialysis weight pre-GLP1 was 103.98 kg and the average post dialysis weight post-GLP1 was 102.02 kg (difference: −1.96 kg, 95% CI :1.37 to 4.27, p-value <0.001). The average urea distribution volume was 36.0 L pre-GLP1, and 35.6 L post-GLP1 (difference: −0.47 L, 95% CI: −0.99 to 3.56, p-value=0.07). The mean pre-SBP was 147.83 mmHg pre-GLP1 and 149.67 mmHg post-GLP1 (difference: 1.85 mmHg, 95% CI: −5.49 to 24.93, p=0.29). Conclusion Our analysis showed a significant decrease in the average post dialysis weight of HD patients using GLP-1 drugs. While the decline in patients' urea distribution volume, which can be considered as a proxy for lean tissue mass, was not statistically significant, it may be clinically meaningful. We do not see a significant change in pre-SBP. Reductions in weight may suggest reduction in fat and muscle mass but can also be due to “regression to the mean” phenomena as patients who were on these medications tended to be larger. Further studies are necessary to evaluate this association.

Population pharmacokinetics and dose rationale for aciclovir in term and pre-term neonates with herpes.

Aciclovir is considered the first-line treatment against Herpes simplex virus (HSV) infections in new-borns and infants. As renal excretion is the major route of elimination, in renally-impaired patients, aciclovir doses are adjusted according to the degree of impairment. However, limited attention has been given to the implications of immature renal function or dysfunction due to the viral disease itself. The aim of this investigation was to characterize the pharmacokinetics of aciclovir taking into account maturation and disease processes in the neonatal population. Pharmacokinetic data obtained from 2 previously published clinical trials (n = 28) were analyzed using a nonlinear mixed effects modeling approach. Post-menstrual age (PMA) and creatinine clearance (CLCR) were assessed as descriptors of maturation and renal function. Simulation scenarios were also implemented to illustrate the use of pharmacokinetic data to extrapolate efficacy from adults. Aciclovir pharmacokinetics was described by a one-compartment model with first-order elimination. Body weight and diagnosis (systemic infection) were statistically significant covariates on the volume of distribution, whereas body weight, CLCR and PMA had a significant effect on clearance. Median clearance varied from 0.2 to 1.0 L/h in subjects with PMA <34 or ≥34 weeks, respectively. Population estimate for volume of distribution was 1.93 L with systemic infection increasing this value by almost 3-fold (2.67 times higher). A suitable model parameterization was identified, which discriminates the effects of developmental growth, maturation, and organ function. Exposure to aciclovir was found to increase with decreasing PMA and renal function (CLCR), suggesting different dosing requirement for pre-term neonates.

Science mapping of the knowledge base on teacher autonomy: a bibliometric study

PurposeThis research sought to document the volume, development trend and geographical distribution of the research on teacher autonomy, identify high-impact journals, authors and documents and reveal the intellectual structure of the field.Design/methodology/approachThis paper analyzed the articles published on the related subject in the Web of Science (WoS) and/or Scopus. Based on certain exclusion criteria, analyses were conducted on a total of 259 articles. The data were then subjected to descriptive analyses and bibliometric analyses.FindingsThe review found that the teacher autonomy knowledge base has grown dramatically since 2004. In the co-citation analysis, it was determined that four clusters focused on the themes of professionalism and professional development, leadership and self-efficacy, autonomy in language teaching and learning and self-determination theory. According to the co-word analysis in this review, the most co-occurring keywords were revealed to be “teacher autonomy,” “autonomy,” “teachers,” “teacher professionalism” and “professional development.”Originality/valueDespite increasing numbers of systematic reviews focusing on educational administration and leadership, this paper represents the first bibliometric review conducted to reveal the development of research on teacher autonomy using both the WoS and Scopus databases. Teacher autonomy can be regarded as an emerging field of study backed up by a theoretical background. Although there are some distinct prominent scholars in the research area, autonomy research still needs more scholars to specialize in the field.

Population pharmacokinetics of ravidasvir in adults with chronic hepatitis C virus infection and impact of antiretroviral treatment.

Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%-60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.

Development of a Web Application for Simulating Plasma Drug Concentrations in Patients with Zolpidem Intoxication.

Zolpidem is a widely prescribed hypnotic Z-drug used to treat short-term insomnia. However, a growing number of individuals intentionally overdose on these drugs. This study aimed to develop a predictive tool for physicians to assess patients with zolpidem overdose. A population pharmacokinetic (PK) model was established using digitized data obtained from twenty-three healthy volunteers after a single oral administration of zolpidem. Based on the final PK model, a web application was developed using open-source R packages such as rxode2, nonmem2rx, and shiny. The final model was a one-compartment model with first-order absorption and elimination with PK parameters, including clearance (CL, 16.9 L/h), absorption rate constant (Ka, 5.41 h-1), volume of distribution (Vd, 61.7 L), and lag time (ALAG, 0.394 h). Using the established population PK model in the current study, we developed a web application that enables users to simulate plasma zolpidem concentrations and visualize their profiles. This user-friendly web application may provide essential clinical information to physicians, ultimately helping in the management of patients with zolpidem intoxication.

Impacts of permeability and effective diffusivity of porous scaffolds on bone ingrowth: In silico and in vivo analyses

The permeability and the effective diffusivity of a porous scaffold are critical in the bone-ingrowth process. However, design guidelines for porous structures are still lacking due to inadequate understanding of the complex physiological processes involved. In this study, a model integrating the fundamental biological processes of bone regeneration was constructed to investigate the roles of permeability and effective diffusivity in regulating bone deposition in scaffolds. The in silico analysis results were confirmed in vivo by examining bone depositions in three diamond lattice scaffolds manufactured using selective laser melting. The findings show that the scaffolds with better permeability and effective diffusivity had deeper bone ingrowth and greater bone volume. Compared to permeability, effective diffusivity exhibited greater sensitivity to the orientation of porous structures, and bone ingrowth was deeper in the directions with higher effective diffusivity in spite of identical pore size. A 4.8-fold increase in permeability and a 1.6-fold increase in effective diffusivity by changing the porous structure led to a 1.5-fold increase in newly formed bone. The effective diffusivity of the porous scaffold affects the distribution of osteogenic growth factor, which in turn impacts cell migration and bone deposition through chemotaxis effects. Therefore, effective diffusivity may be a more suitable indicator for porous scaffolds because our study shows changes in this parameter determine changes in bone distribution and bone volume.

Phase-sensitive optical coherence tomography reveals droplet penetration into a powder bed

Understanding the mixing behavior that unfolds when liquid droplets impact on powder beds requires a sub-surface dynamic imaging method that provides high spatial and temporal resolution. In this study, a high-resolution phase-sensitive optical coherence tomography (PhS-OCT) technique was introduced to provide in-depth insights into the interaction of droplets and powder beds. A theoretical model correlating changes in the optical path differences (OPD) of the OCT signal with physical properties of the powder bed was presented. Experiments were conducted on three powders with median particle diameters, i.e., the size corresponding to the 50th percentile of the cumulative volume distribution, of 3 µm (mannitol), 4 µm (mannitol) and 109 µm (SV010). Water and ethanol droplets were used to illustrate the technique. The results demonstrated that OPD maps can qualitatively resolve the liquid-powder mixture region, both temporally and spatially, as the droplet diffuses into the powder bed, allowing for a quantitative description of diffusion behavior. A comparison of lactose and mannitol powder samples revealed varying diffusion rates, potentially attributed to differences in porosity, particle size, and agglomeration. Additionally, water and ethanol droplets exhibited significantly different (p = 0.005) diffusion profiles for the same powder properties. In general, the findings indicate the potential of the proposed PhS-OCT technique for evaluating the mixing behavior of multi-phase mixtures, holding promise in applications such as pharmaceutical drug formulations and additive manufacturing.

Selected Chromatographic Methods for Determining the Biological Activity of Substances

This paper presents various aspects of the use of chromatography to determine the biological activity of substances. On the one hand, the use of chromatography to determine the lipophilicity of a substance, a property that affects all LADME steps in various biomimetic systems, is presented, using various descriptors such as the retention factor in pure water (or buffer with physiological plasma pH), the CHI value, and Chrom logD. The use of chromatography in biomimetic systems to determine the interaction of substances with phospholipids (IAM stationary phases) and transport proteins (stationary phases with immobilised proteins) is also discussed. On the basis of the retention data obtained in these systems, the volume of distribution of the substance and the degree of binding of the substance with the proteins in question can be determined. Chromatography is also a method used to determine the interaction of substances with specific membrane receptors at their site of action using membrane chromatography (MCM). Thanks to biological detection, chromatography can also be used to determine the antimicrobial activity (bioautography) of substances and the effect of substances on biochemical reactions taking place in organisms, such as antioxidant properties and the inhibitory activity of various enzymes (biological assay).

Uncertain programming model for designing multi-objective reverse logistics networks

Given the contradiction between the rapid growth of products and the modest recovery rate of end-of-life products, there is a pressing need to understand the societal significance of establishing a reverse logistics network for end-of-life products. This research constructs an open-loop five-tier reverse logistic network model encompassing customers, centres for collection, disassembly and inspection, remanufacturing, and disposal. A multi-objective mixed-integer nonlinear programming model under uncertainty has been developed. Unlike previous research, this model accounts for surrounding residents' disutility of facilities while simultaneously minimizing economic costs and environmental impact. Besides, uncertainty theory is introduced in solving the proposed model. More specifically, the formulated model converts all uncertain variables into uncertain distributions by implementing the uncertain multi-objective programming method. Furthermore, a customised non-dominated sorting genetic algorithm III (NSGA-III) is proposed and is employed for the first time to address facility selection and recycling volume distribution within the network. The model is then validated using a real-life case study focusing on end-of-life vehicles in Changchun, China. This research could assist decision-makers in both governmental and private sectors in achieving a balanced approach to the interests of the economy, environment, and local communities comprehensively when designing reverse supply chains.

Research on Vegetables Sales Profit Based on Machine Learning

The sales volume of different vegetables in supermarkets is different, and the profit is different. The research on the profit of each category of vegetables can help supermarkets predict the sales revenue more accurately to improve inventory management, purchasing plans, and sales strategy. This can help the supermarket avoid excess or insufficient inventory, improve profits, and help the supermarket identify potential sales risks. The research team obtained daily sales data for various categories of vegetables from a supermarket on the Internet for some time. First, according to the "cost plus pricing" method of vegetables, regression analysis was conducted on the total cost and total profit of various categories of vegetables, and it was found that there was a strong linear relationship, and the profit rate of various categories of vegetables was relatively fixed. They were [0.6629, 0.5915, 0.4663, 0.5121, 0.5596, 0.5381]. Since the sales volume of vegetables has seasonal characteristics, this paper established the ARIMA model to forecast the sales volume of each category of vegetables; and obtained the sales volume distribution of each category of vegetables from July 1 to 7, 2023. The BP neural network model with 22 layers of hidden layers was established, and the purchase unit price data could be obtained according to the known sales data. The R square of the model was greater than 0.7, and the goodness of fit was high. According to the known correlation, considering the impact of the loss rate on the profit and the rationality of the data, a multivariate linear programming model is established to give the replenishment volume and pricing strategy from July 1 to 7, 2023. It is concluded that the maximum profit of the supermarket in these seven days is [845.1835, 870.5028,861.6210, 858.8551, 839.4595, 864.7580, 892.9897]. Through the sensitivity analysis of the profit rate of each category of vegetables, it is concluded that the profit rate increases by 1%, the income will increase by about 1.1%, and the model is robust.

Research on Pricing and Replenishment of Vegetables Based on Grey Relational Model and Seasonal Index Prediction Model

This article mainly studies the problem of automatic pricing and replenishment decisions for vegetable products in supermarkets. A grey correlation model and ARIMA time series model are comprehensively established, and based on clustering analysis and regression analysis methods, the distribution patterns of sales volume for each vegetable category and item over time, as well as the relationship with cost plus pricing and mutual correlation, are analyzed to make reasonable predictions for future sales volume. In order to make decisions on product pricing, sales combination, and replenishment, and maximize supermarket profits, the data is preprocessed through normal test and quartile method. Through screening and sorting analysis, the distribution patterns of sales volume for each vegetable category and item over time are obtained; In order to analyze the relationship between different categories of vegetables and between different single products, a grey correlation model is established to determine the analysis sequence, and the correlation coefficients between each category and each single product are calculated to analyze the mutual relationship. And combined with the hierarchical clustering analysis method, the vegetable categories were divided into three sales types: high, medium, and low, expanding the relationship between categories. At the same time, a periodic chart was drawn to determine the periodicity of sales volume distribution in each category. Then, statistical analysis was conducted on the data to determine the linear correlation between sales volume and cost plus pricing. Based on this, a linear regression model was established to analyze the linear relationship between sales volume and cost plus pricing for the six categories; In order to provide the total daily replenishment amount and pricing strategy for the next week, this article establishes a seasonal index prediction model for sales forecasting. Combining the seasonal distribution of each category, the seasonal index is used to predict the sales volume for the next week. Considering the goal of maximizing profits, the target function is listed to comprehensively analyze the replenishment and pricing strategy for the next week.

Gentamicin concentration and acute kidney injury in term neonates treated for neonatal sepsis with gentamicin and ampicillin-cloxacillin combination.

Gentamicin is widely used to treat neonatal infections caused by both Gram-negative and Gram-positive bacteria, and the WHO recommends its use while monitoring serum creatinine and gentamicin concentrations to avoid drug-induced nephrotoxicity and ototoxicity. Yet in some resource-limited settings, the drug is used without monitoring. A population pharmacokinetics study involving term neonates with neonatal infection admitted to a neonatal unit. Participants were started on intravenous gentamicin 5 mg/kg once a day in combination with ampicilin-cloxacillin. Blood samples for serum gentamicin concentration were taken at 0.25, 0.5, 1, 2, 3, 5, 6, 8, 10, 12, 14, 16, 18, 20, 23, and 24 hours after the initial dose, each participant contributing two samples to the 24 hour sampling schedule. An additional sample for trough concentration was taken from each participant just before the third gentamicin dose while serum creatinine concentration was measured before and after treatment. Twenty-four participants were enrolled into the study and included in the final analysis. Mean (SD) peak and trough serum gentamicin concentrations were 16.66 (0.64) µg/mL and 3.28 (0.70) µg/mL, respectively. Gentamicin clearance (CL) was 0.40 mL min-1 kg-1 and volume of distribution (VD) was 0.31 L kg-1. Mean (SD) serum creatinine level after treatment was 209.7 (70.4) µmol/L compared to 103.3 (23.6) µmol/L before treatment [mean difference (106.4 ± 67.1; 95% confidence interval (CI): 78.1; 134.7 µmol/L; t (23) = 7.77; P < 0.001]. All participants fulfilled the Kidney Disease Improving Global Outcomes (KDIGO) criteria for acute kidney injury after treatment. Treatment of neonatal infection with antimicrobial regimen containing gentamicin, without renal function and gentamicin concentration monitoring, carries a significant risk for drug-induced acute kidney injury.

Hourglass cascaded recurrent stereo matching network

Stereo matching acts a crucial role in computer vision and robotics applications. An accurate cost volume and robust disparity regression method are essential for stereo matching of high accuracy. Following GCNet and PSMNet, constructing 4D cost volume and then using the soft argmin method to regress has been dominated. However, it will encounter many difficulties due to the multi-modal distribution of cost volume. One of the reasons for this multi-modal distribution is the occlusion area which not be possible to find a matching region on the reference image and rarely discussed. In this paper, we propose to use global context information could improve the performance of model in occluded regions. Recently, novel recurrent neural network regression methods are proposed, but most of them regress disparity maps from 3D cost volume. In this paper, we propose the new combinatorial paradigm that combine stacked hourglass modules and recurrent neural networks to further aggregate 4D cost volume and regress disparity respectively. The proposed method can be seamlessly integrated into most stereo matching networks, we improved the accuracy by 45% for PSMNet and 38% for GwcNet in our experiment. Experimental results on Scene Flow, KITTI2012, KITTI2015, and ETH3D datasets show our method is competitive. The code is available at: https://github.com/truman1211/HCRnet.

Preclinical pharmacokinetic studies of villocarine A, an active Uncaria alkaloid.

Villocarine A is a bioactive indole alkaloid isolated from the Uncaria genus. It has demonstrated vasorelaxation activity and potential to protect the central nervous system. To identify the pharmacokinetic properties of villocarine A, a series of in vitro and in vivo studies have been performed. Villocarine A was found to be highly permeable (15.6 ± 1.6*10-6cm/s) across human colorectal adenocarcinoma cell monolayer with high protein binding (>91%) in both rat and human plasma. Hepatic extraction ratio of villocarine A was 0.1 in pooled rat liver and 0.2 in human liver microsomes and was found stable in rat plasma at 37°C. Due to the high permeability and low rate of metabolism properties, villocarine A was initially considered suitable for preclinical development and an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification (linearity: 1-150 ng/ml) in rat plasma was developed and validated for in vivo studies. Essential pharmacokinetic parameters included the volume of distribution and clearance of villocarine A, which were found to be 100.3 ± 15.6L/kg and 8.2 ± 1.1L/h/kg, respectively, after intravenous administration in rats. Following oral dosing, villocarine A exhibited rapid absorption as the maximum plasma concentration (53.2 ± 10.4ng/ml) occurred at 0.3 ± 0.1h, post-dose. The absolute oral bioavailability of villocarine A was 16.8 ± 0.1%. To our knowledge, this was the first pharmacokinetic study of villocarine A, which demonstrated the essential pharmacokinetic properties of villocarine A: large volume distribution, high clearance, and low oral bioavailability in rats.

Pharmacokinetics of N-acetyl-l-cysteine in chickens.

N-acetyl-l-cysteine (NAC) has been suggested as an antioxidant that can alleviate the negative effects of stress conditions in broilers. However, knowledge of its pharmacokinetics (PK) in this avian species is very limited. Therefore, the study aimed to shed more light on the PK properties of NAC in chickens. Broilers were subjected to single intravenous (i.v.) or oral (p.o.) treatment or multiple NAC administrations via the feed. Drug concentrations were determined by LC-MS/MS, and the data were subjected to non-compartmental analysis and modeled by non-linear mixed effect approach. NAC was eliminated in a short time after i.v. treatment, with a t1/2el of 0.93 (0.59-2.09) h. It showed limited distribution with population mean of volumes of distribution in the central and peripheral compartments V1 of 0.148 L/kg and V2 of 0.199 L/kg, respectively, and Vdarea of 0.39 (0.258-0.635) L/kg. The value of MRT was 1.76 h (range of 0.96-2.69, p < .05) after single p.o. treatment, indicating a twofold increase if compared to i.v. administration (0.87 h, 0.55-1.78). Both methods of Pk analysis revealed very limited bioavailability, <10%. Feeding behavior led to a later achievement of lower maximum plasma concentrations (5.74, range of 3.44-9.32 μg/mL, p < .05), which were maintained during the 5 days of treatment.

Population Pharmacokinetic Modeling of Unbound Meropenem in Patients Undergoing Continuous Renal Replacement Therapy: An Observational Cohort Study.

The most effective dosing strategy of meropenem for patients undergoing continuous renal replacement therapy (CRRT) remains uncertain. This study aimed to analyze the population pharmacokinetics (popPKs) of unbound meropenem and establish an appropriate dosing approach. This prospective study involved 19 patients for the development of a popPK model and an additional 10 for its validation. Ethical approval was obtained. The clearance of unbound meropenem was influenced by the sequential organ failure assessment (SOFA) score [=2.22 × (SOFA score/12)^1.88] and the effluent flow rate from the CRRT device, with an interindividual variability of 44.5%. The volume of distribution was affected by the simplified acute physiology score II [=23.1 × (simplified acute physiology score II/52)^1.54]. Monte Carlo simulations suggested meropenem doses ranging from 1.0 to 3.0 g/d using continuous infusion to achieve a target time above the 4 times of minimum inhibitory concentration of the unbound form (%fT>4×MIC) of 100% for definitive therapy. For empirical therapy, a dose of 1.0 g/d using continuous infusion was recommended to target %fT>MIC of 100%. This study developed a popPK model for unbound meropenem in patients undergoing CRRT and formulated dosing guidelines. UMIN000024321.

Glutamate Signaling in Patients With Parkinson Disease With REM Sleep Behavior Disorder.

Clinical heterogeneity of patients with Parkinson disease (PD) is well recognized. PD with REM sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher nonmotor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning imbalances in neurotransmitter systems remain elusive. Combining magnetic resonance (MR) spectroscopy and [11C]ABP688 PET on a PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with PD. Patients were grouped according to their RBD status in overnight video-polysomnography and compared with age-matched and sex-matched healthy control (HC) participants. Total volumes of distribution (VT) of [11C]ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between 45 and 60 minutes of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single-voxel stimulated echo acquisition mode MR spectroscopy of the left basal ganglia. We measured globally elevated VT of [11C]ABP688 in 16 patients with PD and RBD compared with 17 patients without RBD and 15 HC participants (F(2,45) = 5.579, p = 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VT of [11C]ABP688. VT of [11C]ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600, p = 0.023) and with dopaminergic treatment response in patients with PD (F(1,30) = 5.823, p = 0.022). Our results suggest that patients with PD and RBD exhibit altered glutamatergic signaling indicated by higher VT of [11C]ABP688 despite unaffected glutamate levels. The imbalance of glutamate receptors and MR spectroscopy glutamate metabolite levels indicates a novel mechanism contributing to the heterogeneity of PD and warrants further investigation of drugs targeting mGluR5.

Enhancing Housing Finance for Socio-Economic Stability in Uzbekistan

Enhancing Housing Finance for Socio-Economic Stability in Uzbekistan

Mechanistic Account of Distinct Change in Organic Anion Transporting Polypeptide 1B (OATP1B) Substrate Pharmacokinetics during OATP1B-Mediated Drug-Drug Interactions Using Physiologically Based Pharmacokinetic Modeling.

The role of transporters in drug clearance is widely acknowledged, directly and indirectly by facilitating tissue/enzyme exposure. Through the latter, transporters also affect volume of distribution. Drug-drug interactions (DDIs) involving organic anion transporting polypeptides (OATPs) 1B1/1B3 and SLCO1B1 pharmacogenetics lead to altered pharmacokinetics of OATP1B substrates; however, several factors may confound direct interpretation of pharmacokinetic parameters from these clinical studies using noncompartmental analysis (NCA). A review of clinical data herein indicates a single dose of OATP1B inhibitor rifampin almost never leads to increased substrate half-life but often a decrease and that most clinical OATP1B substrates are CYP3A4 substrates and/or undergo enterohepatic cycling (EHC). Using hypothetically simple OATP1B substrate physiologically based pharmacokinetic (PBPK) models, simulated effect of rifampin differed from specific OATP1B inhibition due to short rifampin half-life causing dissipation of OATP1B inhibition over time combined with CYP3A4 induction. Calculated using simulated tissue data, volume of distribution indeed decreased with OATP1B inhibition and was expectedly limited to the contribution of liver volume. However, an apparent and counterintuitive effect of rifampin on volume greater than that on clearance resulted for CYP3A4 substrates using NCA. The effect of OATP1B inhibition and rifampin on OATP1B substrate models incorporating EHC plus or minus renal clearance was distinct compared with simpler models. Using PBPK models incorporating reversible lactone metabolism for clinical OATP1B substrates atorvastatin and pitavastatin, DDIs reporting decreased half-life with rifampin were reproduced. These simulations provide an explanation for the distinct change in OATP1B substrate pharmacokinetics observed in clinical studies, including changes in volume of distribution and additional mechanisms. SIGNIFICANCE STATEMENT: Transporters are involved in drug clearance and volume of distribution, and distinct changes in OATP1B substrate pharmacokinetics are observed with OATP1B inhibitor rifampin. Using hypothetical and validated PBPK models and simulations, this study addresses the limitations of single-dose rifampin and complicated clinical OATP1B substrate disposition in evaluating the pharmacokinetic parameters of OATP1B substrates during rifampin drug-drug interactions (DDIs). These models account for change in volume of distribution and identify additional mechanisms underlying apparent pharmacokinetic changes in OATP1B DDIs.

Pooled Population Pharmacokinetic Analysis and Dose Recommendations for Ciprofloxacin in Intensive Care Unit Patients with Obesity.

Recent studies have explored the influence of obesity and critical illness on ciprofloxacin pharmacokinetics. However, variation across the subpopulation of individuals with obesity admitted to the intensive care unit (ICU) with varying renal function remains unexamined. This study aims to characterize ciprofloxacin pharmacokinetics in ICU patients with obesity and provide dose recommendations for this special population. Individual patient data of 34 ICU patients with obesity (BMI >30 kg/m2) from four studies evaluating ciprofloxacin pharmacokinetics in ICU patients were pooled and combined with data from a study involving 10 individuals with obesity undergoing bariatric surgery. All samples were collected after intravenous administration. Non-linear mixed effects modeling and simulation were used to develop a population pharmacokinetic model and describe ciprofloxacin exposure in plasma. Model-based dose evaluations were performed using a pharmacokinetic/pharmacodynamic target of AUC/MIC >125. The data from patients with BMI ranging from 30.2 to 58.1 were best described by a two-compartment model with first-order elimination and a proportional error model. The inclusion of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as a covariate on clearance reduced inter-individual variability from 57.3% to 38.5% (P <.001). Neither body weight nor ICU admission significantly influenced clearance or volume of distribution. Renal function is a viable predictor for ciprofloxacin clearance in ICU patients with obesity, while critical illness and body weight do not significantly alter clearance. As such, body weight and critical illness do not need to be accounted for when dosing ciprofloxacin in ICU patients with obesity. Individuals with CKD-EPI >60 mL/min/1.73 m2 may require higher dosages for the treatment of pathogens with minimal inhibitory concentration ≥0.25 mg/L.