Clearance Data Research Articles

Inborn errors of metabolism in neonates and pediatrics on varying dialysis modalities: a systematic review and meta-analysis.

Some inborn errors of metabolism (IEMs) resulting in aberrations to blood leucine and ammonia levels are commonly treated with kidney replacement therapy (KRT). Children with IEMs require prompt treatment, as delayed treatment results in increased neurological and developmental morbidity. Our systematic review in neonates and pediatrics evaluates survival rates and reductions in ammonia and leucine levels across different KRT modalities (continuous KRT (CKRT), hemodialysis (HD), peritoneal dialysis (PD)). A literature search was conducted through PubMed, Web of Science, and Embase databases for articles including survival rate and toxic metabolite clearance data in pediatric patients with IEM undergoing KRT. Cross-sectional, prospective, and retrospective studies with survival rates reported in patients with IEM with an intervention of CKRT, PD, or HD were included. Studies with patients receiving unclear or multiple KRT modalities were excluded. Analysis variables included efficacy outcomes [% reduction in ammonia (RIA) from pre- to post-dialysis and time to 50% RIA] and mortality. The Newcastle Ottawa Risk of Bias quality assessment was used to assess bias. All statistical analyses were performed with MedCalc Statistical Software version 19.2.6. A total of 37 studies (n = 642) were included. The pooled proportion (95% CI) of mortality on CKRT was 24.84% (20.93-29.08), PD was 34.42% (26.24-43.33), and HD 34.14% (24.19-45.23). A lower trend of pooled (95% CI) time to 50% RIA was observed with CKRT [6.5 (5.1-7.8)] vs. PD [14.4 (13.3-15.5)]. A higher mortality was observed with greater plasma ammonia level before CKRT (31.94% for ≥ 1000µmol/L vs. 15.04% for < 1000µmol/L). Despite the limitations in sample size, trends emerged suggesting that CKRT may be associated with lower mortality rates compared to HD or PD, with potential benefits including prevention of rebound hyperammonemia and improved hemodynamic control. While HD showed a trend towards faster achievement of 50% RIA, all modalities demonstrated comparable efficacy in reducing ammonia and leucine levels. CRD42023418842.

Geo-sustainability Challenges and Remediation Strategies: A GIS-based Assessment of Sripur Coalmine Areas, West Bengal, India

This study examines the health, risk, and safety aspects of coal mining in the Sripur area, focusing on the Bhanora West Block, Asansol, West Bengal, India as one of the 14 operational mines of Eastern Coalfields Limited in Asansol. The study addresses the increasing risks of accidents, fires, and subsidence in active, ageing, and closed mines and storage yards. The study’s incorporation of field surveys, satellite imagery, and environmental data ensures that the findings are based on a well-rounded and multi-faceted dataset. The satellite imagery data (GIS and Remote Sensing) are perceived along with available literature and environmental impact compliance reports from time to time, with particular interest in the Bhanora West coal mine, both open cast and underground. The aspect, Hill shade, LULC and stream order maps of the Damodar are generated using Q-GIS, 3.28.7. The environmental clearance data, accident data, subsidence area, and landslide data are analysed. A vast area in Sripur is observed to be under subsidence, with cracks appearing even near residential areas. The flow of the Nunia nallah is nearby, and old closed mines are not adequately backfilled, so the chance of seepage cannot be neglected though regularly attended. Pneumoconiosis (CWP), a lung disease (black lung), chronic obstructive pulmonary disease (COPD), and silicosis are common in Sripur due to dust and substandard water. Effective and riskless mining extractions using proper technologies can avoid mining hazards, such as subsidence, the influx of water in underground mines, health hazards, air/water pollution, mine fire, and intact physical landscape and observing criteria of sustainable Development Goal SDG-1 SDG-3, SDG-6, SDG 12, SDG-13, and SDG 16.

Predicting improvement in biofeedback gait training using short-term spectral features from minimum foot clearance data.

Stroke rehabilitation interventions require multiple training sessions and repeated assessments to evaluate the improvements from training. Biofeedback-based treadmill training often involves 10 or more sessions to determine its effectiveness. The training and assessment process incurs time, labor, and cost to determine whether the training produces positive outcomes. Predicting the effectiveness of gait training based on baseline minimum foot clearance (MFC) data would be highly beneficial, potentially saving resources, costs, and patient time. This work proposes novel features using the Short-term Fourier Transform (STFT)-based magnitude spectrum of MFC data to predict the effectiveness of biofeedback training. This approach enables tracking non-stationary dynamics and capturing stride-to-stride MFC value fluctuations, providing a compact representation for efficient processing compared to time-domain analysis alone. The proposed STFT-based features outperform existing wavelet, histogram, and Poincaré-based features with a maximum accuracy of 95%, F1 score of 96%, sensitivity of 93.33% and specificity of 100%. The proposed features are also statistically significant (p 0.001) compared to the descriptive statistical features extracted from the MFC series and the tone and entropy features extracted from the MFC percentage index series. The study found that short-term spectral components and the windowed mean value (DC value) possess predictive capabilities regarding the success of biofeedback training. The higher spectral amplitude and lower variance in the lower frequency zone indicate lower chances of improvement, while the lower spectral amplitude and higher variance indicate higher chances of improvement.

Association between measures of resuscitation in the critical care resuscitation unit and in-hospital mortality among patients with sepsis.

We hypothesized that lactate clearance and reduction of the Sequential Organ Failure Assessment (SOFA) score during patients' critical care resuscitation unit (CCRU) stay would be associated with lower in-hospital mortality. This was a retrospective study of adult patients who had sepsis diagnoses and were admitted to the CCRU in 2018. Multivariable logistic regression analysis was performed to assess the association of clinical factors, lactate clearance, and SOFA reduction with hospital mortality. A total of 401 patients with lactate clearance data and 455 patients with SOFA score data were included in the study. The mean (SD) lactate and SOFA score on admission were 2.2 (1.8) mmol/L and 4.4 (4.3), respectively. Average lactate clearance was 0.1 (2.6) mmol/L, and average SOFA score reduction was 0.65 (5.9). Patients with a one point reduction in SOFA score during their CCRU stay had a 31% reduction of mortality (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.62-0.77, p<0.001). SOFA score reduction was associated with lower hospital mortality for both surgical patients (OR 0.69, 95% CI 0.58-0.81, p<0.001) and non-surgical patients (OR 0.71 95% CI 0.06-0.83, p<0.001). SOFA score reduction, but not lactate clearance during the CCRU stay, was associated with lower odds of in-hospital mortality. These findings suggest that resuscitative efforts leading to an early improvement in SOFA score may benefit patients with sepsis.

Feasibility of safe outpatient treatment in pediatric patients following intraventricular radioimmunotherapy with 131I-omburtamab for leptomeningeal disease

BackgroundRadiolabeled antibody 131I-omburtamab was administered intraventricularly in patients with leptomeningeal disease under an institutionally approved study (#NCT03275402). Radiation safety precautions were tailored for individual patients, enabling outpatient treatment based on in-depth, evidence-based recommendations for such precautions. The imperative advancement of streamlined therapeutic administration procedures, eliminating the necessity for inpatient isolation and resource-intensive measures, holds pivotal significance. This development bears broader implications for analogous therapies within the pediatric patient demographic.MethodsIntraventricular radioimmunotherapy (RIT) with 925–1850 MBq (25–50 mCi) of 131I-omburtamab was administered via the Ommaya reservoir, in designated rooms within the pediatric ambulatory care center. Dosimeters were provided to staff involved in patient care to evaluate exposure during injection and post-administration. Post-administration exposure rate readings from the patient on contact, at 0.3 m, and at 1 m were taken within the first 30 min, and the room was surveyed after patient discharge. Duration of radiation exposure was calculated using standard U.S. Nuclear Regulatory Commission (US NRC) regulatory guidance recommendations combined with mean exposure rates and whole-body clearance estimates. Exposure rate measurements and clearance data provided patient-specific precautions for four cohorts by age: < 3 y/o, 3–10 y/o, 10–18 y/o, and 18+.ResultsPost-administration exposure rates for patients ranged from 0.16 to 0.46 µSv/hr/MBq at 0.3 m and 0.03–0.08 µSv/hr/MBq at 1 m. Radiation exposure precautions ranged from 1 to 10 days after release for the four evaluated cohorts. Based on the highest measured exposure rates and slowest whole-body clearance, the longest precautions were approximately 78% lower than the regulatory guidance recommendations. Radiation exposure to staff associated with 131I-omburtamab per administration was substantially below the annual regulatory threshold for individual exposure monitoring.Conclusion131I-omburtamab can be administered on an outpatient basis, using appropriate patient-based radiation safety precautions that employ patient-specific exposure rate and biological clearance parameters. This trial is registered with the National Library of Medicine’s ClinicalTrials.gov. The registration number is NCT03275402, and it was registered on 7 September 2017. The web link is included here. https://clinicaltrials.gov/study/NCT03275402.

Commentary: Pharmacokinetic Theory Must Consider Published Experimental Data.

Recently, we have proposed simple methodology to derive clearance and rate constant equations, independent of differential equations, based on Kirchhoff's Laws, a common methodology from physics used to describe rate-defining processes either in series or parallel. Our approach has been challenged in three recent publications, two published in this journal, but notably what is lacking is that none evaluate experimental pharmacokinetic data. As reviewed here, manuscripts from our laboratory have evaluated published experimental data, demonstrating that the Kirchhoff's Laws approach explains (1) why all of the experimental perfused liver clearance data appear to fit the equation that was previously believed to be the well-stirred model, (2) why linear pharmacokinetic systemic bioavailability determinations can be greater than 1, (3) why renal clearance can be a function of drug input processes, and (4) why statistically different bioavailability measures may be found for urinary excretion versus systemic concentration measurements. Our most recent paper demonstrates (5) how the universally accepted steady-state clearance approach used by the field for the past 50 years leads to unrealistic outcomes concerning the relationship between liver-to-blood Kpuu and hepatic availability FH , highlighting the potential for errors in pharmacokinetic evaluations based on differential equations. The Kirchhoff's Laws approach is applicable to all pharmacokinetic analyses of quality experimental data, those that were previously adequately explained with present pharmacokinetic theory, and those that were not. The publications that have attempted to rebut our position do not address unexplained experimental data, and we show here why their analyses are not valid. SIGNIFICANCE STATEMENT: The Kirchhoff's Laws approach to deriving clearance equations for linear systems in parallel or in series, independent of differential equations, successfully describes published pharmacokinetic data that has previously been unexplained. Three recent publications claim to refute our proposed methodology; these publications only make theoretical arguments, do not evaluate experimental data, and never demonstrate that the Kirchhoff methodology provides incorrect interpretations of experimental pharmacokinetic data, including statistically significant data not explained by present pharmacokinetic theory. We demonstrate why these analyses are invalid.

Novel progressive deep learning algorithm for uncovering multiple single nucleotide polymorphism interactions to predict paclitaxel clearance in patients with nonsmall cell lung cancer.

The rate at which the anticancer drug paclitaxel is cleared from the body markedly impacts its dosage and chemotherapy effectiveness. Importantly, paclitaxel clearance varies among individuals, primarily because of genetic polymorphisms. This metabolic variability arises from a nonlinear process that is influenced by multiple single nucleotide polymorphisms (SNPs). Conventional bioinformatics methods struggle to accurately analyze this complex process and, currently, there is no established efficient algorithm for investigating SNP interactions. We developed a novel machine-learning approach called GEP-CSIs data mining algorithm. This algorithm, an advanced version of GEP, uses linear algebra computations to handle discrete variables. The GEP-CSI algorithm calculates a fitness function score based on paclitaxel clearance data and genetic polymorphisms in patients with nonsmall cell lung cancer. The data were divided into a primary set and a validation set for the analysis. We identified and validated 1184 three-SNP combinations that had the highest fitness function values. Notably, SERPINA1, ATF3 and EGF were found to indirectly influence paclitaxel clearance by coordinating the activity of genes previously reported to be significant in paclitaxel clearance. Particularly intriguing was the discovery of a combination of three SNPs in genes FLT1, EGF and MUC16. These SNPs-related proteins were confirmed to interact with each other in the protein-protein interaction network, which formed the basis for further exploration of their functional roles and mechanisms. We successfully developed an effective deep-learning algorithm tailored for the nuanced mining of SNP interactions, leveraging data on paclitaxel clearance and individual genetic polymorphisms.

Computational Modeling of Sodium Fluorescein Disposition in Ex Vivo, Machine-Perfused Livers with Ischemia-Reperfusion Injury

Rationale: Quantitation of bile formation machinery activity through biliary sodium fluorescein (SF) clearance is useful for assessing liver viability. Studies have shown that the bile-to-plasma SF ratio is inversely correlated with warm ischemia time (WIT) in rats, which is associated with ischemia-reperfusion injury (IRI)-induced intracellular internalization of the multidrug resistance protein 2 (MRP2) transporter (doi: 10.1152/ajpgi.00038.2022). Computational modeling studies by Monti et al. have demonstrated the sensitivity of biliary SF clearance to MRP2 transporter activity in vivo (doi: 10.48550/arXiv.2302.05511). In vivo experimentation is pertinent for establishing physiological variations occurring during IRI, but transplantation often requires a period of ex vivo machine perfusion (MP). The effects of total hepatectomy, WIT, cold ischemia time (CIT), and MP on biliary function remain unclear. We aim to develop a model for quantitative interpretation of biliary SF clearance kinetics in MP livers to estimate parameters descriptive of the dominant processes determining hepatic SF uptake kinetics in MP livers subjected to different periods of WIT. We hypothesize that increasing WIT will lead to a decrease in the maximal transport velocity (Vmax) parameter for MRP2, which is reflective of decreased biliary SF clearance and diminished liver viability. Methods: Using established protocols (doi: 10.3389/frtra.2023.1215182), livers (n = 3-5) were obtained from anesthetized, male, Sprague-Dawley rats and subjected to 0-, 10-, 20-, or 30-min WIT through ligation of the portal vein and hepatic artery. Livers were removed and subjected to 3 hours of CIT on ice. Livers were attached to a custom normothermic MP system, 0.4 mg/kg SF were added to the MP system’s perfusate-containing reservoir, and SF fluorescence measurements in perfusate and bile were obtained and converted to concentration measurements using standard curves. We modified the liver-centric model described in Monti et al. to account for MP by replacing the liver input functions with ordinary differential equations for SF and its conjugate SF glucuronide (SFG) kinetics in the MP system’s reservoir. The model also accounts for three liver regions (sinusoid, hepatocytes, bile) and major processes, including hepatic transporter kinetics and SF metabolism into SFG, which govern SF dynamics in different model regions. We fit the model solutions using a pseudo-Monte Carlo parameter estimation strategy to each of the datasets by allowing the Vmax parameters to vary, while others were fixed to physiologic values. Results: Time course data for IRI conditions showed a modest decrease in biliary SF with 10- and 20-min WIT and a marked change in biliary SF kinetics with 30-min WIT when compared to control. The MP model was fit to each dataset individually and the model was able to provide a good fit to each dataset. Comparison of Vmax parameters estimated from fitting showed a decrease in MRP2’s Vmax with increasing WIT relative to control. Sensitivity analysis supported our finding by demonstrating that MRP2’s Vmax­ was the most sensitive model parameter. Conclusions: We modified an existing in vivo biliary SF clearance model to account for MP livers and fit the new model to biliary SF clearance data for ex vivo MP livers with varying amounts of WIT. We found that the new model was able to fit biliary SF clearance data for ex vivo MP livers and that the Vmax for MRP2 decreased during MP with increasing WIT. Funded in part by 1F30AI179084-01 to C.M. and NSF DMS 2153387 to R.D. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

STUDY OF THE FACTORS AFFECTING DIFFICULT ENDOTRACHEAL INTUBATION WHO PRESENTED TO EMERGENCY DEPARTMENT IN RAMKRISHNA CARE HOSPITAL, RAIPUR, CHHATTISGARH

Background: A thorough but brief airway assessment is important and challenging for patients requiring advanced airway assessment. The study aimed to provide knowledge about the factors leading to difficult endotracheal intubation, reduce the number of attempts which will lead to more successful intubation and improve the overall quality of the procedure. Material Methods: A total of 293 patients were selected based on consecutive sampling methods. After ethical committee clearance data was collected using a data collection form. Age, gender, obesity,pre-existing medical conditions, and facial malformations were recorded for each participant. Airway assessment tests such as mouth opening, thyromental distance, hyomental distance, short neck, and Mallampati classes were conducted by investigators. Inclusion criteria were based on 1. The patient who is alive 2. The patient who needs advanced airway management The exclusion criteria were 1. The patient presented in the emergency department with ventilator support 2. Patient who didnt give consent 3. Patients below 14 years of age(pediatric age group) Data was initially entered into an Excel data sheet and then exported to SPSS Statistics version 22 for analysis. Results:From July 2022 to Aug 2023, a total of 293 patients were included in the study. Of these, 170 were male and 123 were female. Under 65 years of age 40 (43.5%) had difficult intubation whereas above 65 years 52(56.5%) had difficult intubation. 134 patients were obese resulting in difficult intubation. Female patients, those suffering from systemic diseases and facial malformation or fracture were found to be more difficult to intubate. We recognized that Mallampati classes ≥3, mouth opening &lt; 4cm, short thyromental distance, and hyomental distance, were also associated with difficult intubation. Multiple logistic regression analysis of the related factors determined that the odds ratio was highest for mouth opening &lt;4 cm (OR = 3.613) and Thyromental distance &lt;6cm (OR = 3.157) Conclusion: Factors affecting difficult intubation were constructed from the patients demographic characteristics and clinical examination. This may help in discriminating against difficult intubation.This will also help in the overall success rate of first attempts of endotracheal intubation in the emergency department.

Introducing the Dynamic Well-Stirred Model for Predicting Hepatic Clearance and Extraction Ratio

The well-stirred model (WSM) incorporating the fraction of unbound drug (fu) to account for the effect of plasma binding on intrinsic clearance has been widely used for predicting hepatic clearance under the assumption that drug protein binding reaches equilibrium instantaneously. Our theoretical analysis reveals that the effect of protein binding on intrinsic clearance is better accounted for with the dynamic free fraction (fD), a measure of drug protein binding affinity, which leads to a putative dynamic well-stirred model (dWSM) without the instantaneous equilibrium assumption. Using recombinant CYP3A4 as the in vitro clearance system, we demonstrate that the binding effect of albumin on the intrinsic clearance of both highly bound midazolam and highly free verapamil is fully corrected by their corresponding fD values, respectively. On the other hand, fu only corrects the binding effect of albumin on the intrinsic clearance of verapamil, and yields severe over-correction of the intrinsic clearance of midazolam. The results suggest that the traditional WSM is suitable for highly free drugs like verapamil but not necessarily for highly bound drugs such as midazolam due to the violation of the instantaneous equilibrium assumption or under-estimating the true free drug concentration. In comparison, the dWSM incorporating fD holds true as long as drug elimination follows steady-state kinetics, and hence, it is more broadly applicable to drugs with different protein binding characteristics. Here we demonstrate with 36 diverse drugs, that the dWSM significantly improves the accuracy of predicting human hepatic clearance and liver extraction ratio from in vitro microsomal clearance data, highlighting the importance of drug plasma protein binding kinetics in addressing the under-prediction of hepatic clearance by the WSM.

Continuous renal replacement therapy and survival in acute liver failure: A systematic review and meta-analysis

ObjectiveAcute liver failure (ALF) is a rare syndrome leading to significant morbidity and mortality. An important cause of mortality is cerebral edema due to hyperammonemia. Different therapies for hyperammonemia have been assessed including continuous renal replacement therapy (CRRT). We conducted a systematic review and meta-analysis to determine the efficacy of CRRT in ALF patients. Materials and methodsWe searched MEDLINE, EMBASE, Cochrane Library, and Web of Science. Inclusion criteria included adult patients admitted to an ICU with ALF. Intervention was the use of CRRT for one or more indications with the comparator being standard care without the use of CRRT. Outcomes of interest were overall survival, transplant-free survival (TFS), mortality and changes in serum ammonia levels. ResultsIn total, 305 patients underwent CRRT while 1137 patients did not receive CRRT. CRRT was associated with improved overall survival [risk ratio (RR) 0.83, 95% confidence interval (CI) 0.70–0.99, p-value 0.04, I2 = 50%] and improved TFS (RR 0.65, 95% CI 0.49–0.85, p-value 0.002, I2 = 25%). There was a trend towards higher mortality with no CRRT (RR 1.24, 95% CI 0.84–1.81, p-value 0.28, I2 = 37%). Ammonia clearance data was unable to be pooled and was not analyzable. ConclusionUse of CRRT in ALF patients is associated with improved overall and transplant-free survival compared to no CRRT.

Insights into pharmacokinetic properties for exposure chemicals: predictive modelling of human plasma fraction unbound (fu) and hepatocyte intrinsic clearance (Clint) data using machine learning

We have developed regression-based models with the protein fraction unbound (fu) human data set and a classification-based model with the hepatocyte intrinsic clearance (Clint) human data set collected from the recently published ICE database.

Numerical and experimental analysis of blade-tower clearance for large-scale wind turbines

With the increase of the rotor diameter and the flexibility of the blade, the efficient blade-tower clearance control becomes increasingly important. As a widely used strategy in the wind power industry to increase the blade-tower clearance, the fine pitch strategy still has the problem of power de-rating under typical operating conditions. Therefore, a novel coupled blade-tower clearance control strategy is proposed, combining the fine pitch strategy with a revised LiDAR monitoring system. Incorporating the LiDAR's characteristics and the operation modes of wind turbines, the LiDAR is designed to be installed at the front of the nacelle to monitor the real-time blade-tower clearance and feed back to adjust the pitch angle, allowing for safe operation of the wind turbine and maximizing output power. The reliability of the proposed strategy and the influence of weather on the strategy are verified through 22-day all-weather field tests on numerous wind turbines in a wind farm in China, nearly 100% of the efficiency can be achieved if conditions permit. Additionally, the strategy’s two trigger modes—the clearance threshold and data validity protection mechanism—are exemplified, demonstrating the efficiency of the proposed coupled blade-tower clearance control strategy.

Incense smoke (IS) inhalation exposure system: Physicochemical characterization, IS particle deposition and clearance in human airway using MPPD model

Incense smoke (IS) is source of indoor air pollution and key risk for diverse human diseases. Less information is available regarding controlled IS rodent inhalation exposure system and IS particulate matter (PM) deposition in human airways. Study aimed to demonstrate stable ISPM physicochemical parameters of 10 incense products inside the customized whole body inhalation exposure chamber (without animal) connected to smoke generation unit via aerosol mixing device. IS analyzed for size segregated PM emission, ISPM in vitro aerodynamics (MMAD and GSD determination), fine and ultrafine particle's SEM, SEM-EDX and PAH analysis. Using real life exposure scenario by utilizing MMAD, GSD and PM concentration after Tier 1 exposure assessment as key input parameters, ISPM dosimetry in infant (3 months) and adult (21 years male and female) human airways was calculated using multiple-path particle dosimetry (MPPD 3.04) modeling. Mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) ranged between 0.55 and 2.10 μm and 1.22 to 1.77 (polydisperse) respectively. PM1.0 and PM0.1 showed multiple morphology and presence of heavy and trace elements. PAH like acenaphthylene, anthracene, fluorene, naphthalene and phenanthrene were detected (0.84–143.17 μg/g). MPPD results showed higher ISPM deposition in pulmonary region and lowest in trachea bronchial region. ISPM deposition in tissue was higher in lower, peripheral lung as compared to upper and central lung tissue. Whole body inhalation exposure system showed stable IS atmosphere (physicochemical parameters) indicating the device suitability in future inhalation studies. MPPD ISPM deposition fraction and clearance data showed deep lung penetrating and retention behavior with higher risk in infant followed by female and then male. These modeled particle deposition and clearance data may be useful in risk assessment analysis of IS.

Investigations Using Albumin Binders to Modify the Tissue Distribution Profile of Radiopharmaceuticals Exemplified with Folate Radioconjugates.

Introducing an albumin-binding entity into otherwise short-lived radiopharmaceuticals can be an effective means to improve their pharmacokinetic properties due to enhanced blood residence time. In the current study, DOTA-derivatized albumin binders based on 4-(p-iodophenyl)butanoate (DOTA-ALB-1 and DOTA-ALB-3) and 5-(p-iodophenyl)pentanoate entities (DOTA-ALB-24 and DOTA-ALB-25) without and with a hydrophobic 4-(aminomethyl)benzoic acid (AMBA) linker unit, respectively, were synthesized and labeled with lutetium-177 for in vitro and in vivo comparison. Overall, [177Lu]Lu-DOTA-ALB-1 demonstrated ~3-fold stronger in vitro albumin-binding affinity and a longer blood residence time (T50%IA ~8 h) than [177Lu]Lu-DOTA-ALB-24 (T50%IA ~0.8 h). Introducing an AMBA linker enhanced the albumin-binding affinity, resulting in a T50%IA of ~24 h for [177Lu]Lu-DOTA-ALB-3 and ~2 h for [177Lu]Lu-DOTA-ALB-25. The same albumin binders without or with the AMBA linker were incorporated into 6R- and 6S-5-methyltetrahydrofolate-based DOTA-conjugates (177Lu-RedFols). Biodistribution studies in mice performed with both diastereoisomers of [177Lu]Lu-RedFol-1 and [177Lu]Lu-RedFol-3, which comprised the 4-(p-iodophenyl)butanoate moiety, demonstrated a slower accumulation in KB tumors than those of [177Lu]Lu-RedFol-24 and [177Lu]Lu-RedFol-25 with the 5-(p-iodophenyl)pentanoate entity. In all cases, the tumor uptake was high (30-45% IA/g) 24 h after injection. Both diastereoisomers of [177Lu]Lu-RedFol-1 and [177Lu]Lu-RedFol-3 demonstrated high blood retention (3.8-8.7% IA/g, 24 h p.i.) and a 2- to 4-fold lower kidney uptake than the corresponding diastereoisomers of [177Lu]Lu-RedFol-24 and [177Lu]Lu-RedFol-25, which were more rapidly cleared from the blood (<0.2% IA/g, 24 h after injection). Kidney retention of the 6S-diastereoisomers of all 177Lu-RedFols was consistently higher than that of the respective 6R-diastereoisomers, irrespective of the albumin binder and linker unit used. It was demonstrated that the blood clearance data obtained with 177Lu-DOTA-ALBs had predictive value for the blood retention times of the respective folate radioconjugates. The use of these albumin-binding entities without or with an AMBA linker may serve for fine-tuning the blood retention of folate radioconjugates and also other radiopharmaceuticals and, hence, optimize their tissue distribution profiles. Dosimetry estimations based on patient data obtained with one of the most promising folate radioconjugates will be crucial to identify the dose-limiting organ, which will allow for selecting the most suitable folate radioconjugate for therapeutic purposes.

Comprehensive utilization and biomedical application of MXenes - A systematic review of cytotoxicity and biocompatibility

MXenes are the two-dimensional single-layer atomic nanosheets derived from MAX-phase ceramics. Currently, 2D MXene nanomaterials are extensively studied owing to their multifunctional properties. In a systematic review, we found several studies on the cytotoxicity and biocompatibility of surface-modified or functionalized MXene materials for drug delivery against cancer, tissue engineering, antimicrobial activity, bioimaging, photothermal therapy, advanced sensing, and patient monitoring. Further, more than 10 MXenes have been recently studied as in vitro and in vivo models for biomedical applications are reviewed. Recently, the toxicology and biodegradability of unmodified MXene materials have been well studied, possibly with the existing state-of-the-art research as MXenes can reach clinical trials. Relevant concerns and issues arising from the cytotoxicity and drug clearance data available for MXene materials are highlighted, with an emphasis on the regulatory concerns required for the commercial utilization of MXenes in medical devices or drug delivery.

An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria.

The artemisinins are potent and widely used antimalarial drugs that are eliminated rapidly. A simple concentration-effect pharmacometric model does not explain why dosing more frequently than once daily fails to augment parasite clearance and improve therapeutic responses in vivo. Artemisinins can induce a temporary non-replicative or 'dormant' drug refractory state in Plasmodium falciparum malaria parasites which may explain recrudescences observed in clinical trials despite full drug susceptibility, but whether it explains the dosing-response relationship is uncertain. To propose a revised model of antimalarial pharmacodynamics that incorporates reversible asexual parasite injury and temporary drug refractoriness in order to explain the failure of frequent dosing to augment therapeutic efficacy in falciparum malaria. The model was fitted using a Bayesian Markov Chain Monte Carlo approach with the parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from western Cambodia and 40 patients from northwestern Thailand reported previously. The revised model captured the dynamics of parasite clearance data. Its predictions are consistent with observed therapeutic responses. A within-host pharmacometric model is proposed in which it is hypothesized that some malaria parasites enter a temporary drug refractory state after exposure to artemisinin antimalarials, which is followed by delayed parasite death or reactivation. The model fitted the observed sequential parasite density data from patients with acute P. falciparum malaria, and it supported reduced ring stage activity in artemisinin-resistant infections.

Assumptions Underlying Hepatic Clearance Models: Recognizing the Influence of Saturable Protein Binding on Driving Force Concentration and Discrimination Between Models of Hepatic Clearance.

One underlying assumption of hepatic clearance models is often underappreciated. Namely, plasma protein binding is assumed to be nonsaturable within a given drug concentration range, dependent only on protein concentration and equilibrium dissociation constant. However, in vitro hepatic clearance experiments often use low albumin concentrations that may be prone to saturation effects, especially for high-clearance compounds, where the drug concentration changes rapidly. Diazepam isolated perfused rat liver literature datasets collected at varying concentrations of albumin were used to evaluate the predictive utility of four hepatic clearance models (the well-stirred, parallel tube, dispersion, and modified well-stirred model) while both ignoring and accounting for potential impact of saturable protein binding on hepatic clearance model discrimination. In agreement with previous literature findings, analyses without accounting for saturable binding showed poor clearance prediction using all four hepatic clearance models. Here we show that accounting for saturable albumin binding improves clearance predictions across the four hepatic clearance models. Additionally, the well-stirred model best reconciles the difference between the predicted and observed clearance data, suggesting that the well-stirred model is an appropriate model to describe diazepam hepatic clearance when considering appropriate binding models. SIGNIFICANCE STATEMENT: Hepatic clearance models are vital for understanding clearance. Caveats in model discrimination and plasma protein binding have sparked an ongoing scientific discussion. This study expands the understanding of the underappreciated potential for saturable plasma protein binding. Fraction unbound must correspond to relevant driving force concentration. These considerations can improve clearance predictions and address hepatic clearance model disconnects. Importantly, even though hepatic clearance models are simple approximations of complex physiological processes, they are valuable tools for clinical clearance predictions.

Physiologically-based pharmacokinetic (PBPK) modeling of sodium fluorescein (SF) blood clearance for assessing hepatic ischemia-reperfusion injury (IRI)

Rationale: Quantitative analysis of bile formation machinery has potential to assess the viability of a liver for transplantation. Recently, we demonstrated the utility of the fluorescent dye SF by showing that the bile-to-plasma fluorescence ratio inversely correlated with warm ischemia time in rats and associated this finding with IRI-induced intracellular internalization of the MRP2 transporter (PMID: 35700191). However, it is unclear how much SF is cleared by active MRP2 in relation to other contributing factors associated with complex in vivo physiology. We hypothesize that PBPK modeling can account for dominant vascular, tissue, and biochemical processes contributing to SF clearance, including MRP2 activity, and simulate diminished liver function in IRI leading to decreased disposition of SF in the bile. Methods: We considered previously published data of SF fluorescence intensity in blood, plasma, and bile over time in rats under control and IRI conditions. To model these data, we performed SF calibration experiments and converted these data from fluorescence to concentration using standard curves generated from nonlinear regression. We fit an empirical triple-exponential function to the calibrated control blood SF concentration data and used this function as an input for a mechanistic liver-centric PBPK model. The PBPK model accounts for three regions in the liver (blood, hepatocytes, bile) and major physiological processes, including kinetics of basolateral and canalicular transporters governing SF dynamics in different liver regions. We fit this model to the control SF concentration data in the bile using a pseudo-Monte Carlo strategy. Model parameters relating to maximal velocity for the transporters were allowed to vary, while all others were fixed to physiologic values. Results: The PBPK model was able to provide a good fit to control bile SF concentration data. The input model for blood SF concentration was able to predict plasma SF concentration related by a variable partition coefficient, which led to a large difference between plasma and blood SF concentrations at high SF concentrations but diminished at lower concentrations. We simulated the IRI condition by decreasing MRP2 activity, which showed that SF blood clearance through hepatocytes into bile is highly sensitive to changes in the activity of MRP2, consistent with our hypothesis that SF clearance data and PBPK modeling could quantify the effect of IRI on MRP2 activity. These simulations showed a larger decrease in SF concentration in bile relative to the increase in blood resulting in a lower bile-to-blood SF ratio. Conclusions: Based on our experimental data, we developed a liver-centric PBPK model for the blood clearance of SF through hepatocytes and bile and used this model to simulate the contribution of MRP2 to diminished secretion of SF into the bile as measured following IRI. MCW/BME-FP00022381 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Clearance as an Early Indicator of Efficacy for Therapeutic Monoclonal Antibodies: Circumventing Dose Selection Challenges in Oncology.

The designs of first-in-human (FIH) studies in oncology (e.g., 3+3 dose escalation design) usually do not provide a sufficient sample size to determine the dose-response relationship for efficacy. This study aimed to assess the feasibility of using monoclonal antibody (mAb) clearance as a biomarker for efficacy to facilitate the identification of potentially efficacious doses across cancer types and drug targets. We performed electronic searches of the Drugs@FDA website, the European Medicines Agency website, and PubMed to identify reports of FIH trials of approved mAbs in oncology. The clearance, half-life, and overall response rate (ORR) data for the mAbs at different dose levels were extracted. Twenty-five approved mAbs were included in this study. As expected, due to the small sample sizes in FIH studies, there was no clear dose-response for ORR. However, we found a clear negative association between mAb clearance and ORR across tumors/drug targets, and a clear negative dose-clearance relationship, with clearance decreasing and saturated at high dose levels. The approved mAb doses (1-25 mg/kg) are approximately 2-fold the saturation doses (1-10 mg/kg). The associated clearance values at the approved doses vary across different cancers and drug targets (0.17-1.56 L/day), while tend to be similar within a disease/drug target. Anti-CD20 mAbs for B-cell lymphomas show a higher clearance (~ 1 L/day) than other cancers and targets (e.g., ~0.3 L/day for anti-PD-1). Clearance of mAbs can be a tumor/drug target-agnostic biomarker for potential anti-tumor activity as clearance decreases with increasing ORR. Our findings shed important insights into target clearance values that may lead to desired efficacy for different cancers and drug targets, which can be used to guide dose selection for the future development of mAbs during FIH oncology studies.