Elimination Rate Constant Research Articles

Comparison of amikacin lung delivery between AKITA® and eFlow rapid® nebulizers in healthy controls and patients with CF: A randomized cross-over trial

IntroductionNebulization plays a key role in the treatment of cystic fibrosis. The Favorite function couple to jet nebulizers (AKITA®) emerged recently. The aim of this study was to assess the efficiency of the lung delivery by the AKITA® by comparing the urinary concentration of amikacin after nebulization with the AKITA® and the eFlow rapid®, in healthy subjects and patients with CF (PwCF). MethodThe two samples (healthy subjects and PwCF) were randomized (cross-over 1:1) for two nebulizations (500 mg of amikacin diluted in 4 mL of normal saline solution), with the AKITA® and with the eFlow rapid®. The primary endpoint was the amount of urinary excretion of amikacin over 24 h. The constant of elimination (Ke) was calculated based on the maximal cumulative urinary amikacin excretion plotted over time. ResultsThe total amount of urinary amikacin excretion was greater when AKITA® was used in PwCF (11.7 mg (8.2–14.1) vs 6.1 mg (3.7–13.3); p = 0.02) but not different in healthy subjects (14.5 mg (11.7–18.5) vs 12.4 mg (8.0–17.1); p = 0.12). The duration of the nebulization was always shorter with eFlow rapid® than with AKITA® (PwCF: 6.5 ± 0.6 min vs 9.2 ± 1.8 min; p = 0.001 – Healthy: 4.7 ± 1.3 min vs 9.7 ± 1.6 min; p = 0.03). The constant of elimination was similar between the two modalities in CF subjects (0.153 (0.071–0.205) vs 0.149 (0.041–0.182); p = 0.26) and in healthy subjects (0.166 (0.130–0.218) vs 0.167 (0.119–0.210), p = 0.25). Conclusionthe Favorite inhalation is better to deliver a specific amount of drug than a mesh nebulizer (eFlow rapid®) in PwCF but not in healthy subjects.

Carrier-Mediated Process of Putrescine Elimination at the Rat Blood-Retinal Barrier.

Putrescine is a bioactive polyamine. Its retinal concentration is strictly controlled to maintain a healthy sense of vision. The present study investigated putrescine transport at the blood-retinal barrier (BRB) to gain a better understanding of the mechanisms of putrescine regulation in the retina. Our microdialysis study showed that the elimination rate constant during the terminal phase was significantly greater (1.90-fold) than that of [14C]D-mannitol, which is a bulk flow marker. The difference in the apparent elimination rate constants of [3H]putrescine and [14C]D-mannitol was significantly decreased by unlabeled putrescine and spermine, suggesting active putrescine transport from the retina to the blood across the BRB. Our study using model cell lines of the inner and outer BRB showed that [3H]putrescine transport was time-, temperature-, and concentration-dependent, suggesting the involvement of carrier-mediated processes in putrescine transport at the inner and outer BRB. [3H]Putrescine transport was significantly reduced under Na+-free, Cl--free, and K+-replacement conditions, and attenuated by polyamines or organic cations such as choline, a choline transporter-like protein (CTL) substrate. Rat CTL1 cRNA-injected oocytes exhibited marked alterations in [3H]putrescine uptake, and CTL1 knockdown significantly reduced [3H]putrescine uptake in model cell lines, suggesting the possible participation of CTL1 in putrescine transport at the BRB.

Effects of nanoplastics on clam Ruditapes philippinarum at environmentally realistic concentrations: Toxicokinetics, toxicity, and gut microbiota

Nanoplastics are ubiquitous in marine environments, understanding to what extent nanoplastics accumulate in bivalves and the adverse effects derived from their retention is imperative for evaluating the detrimental effects in the benthic ecosystem. Here, using palladium-doped polystyrene nanoplastics (139.5 nm, 43.8 mV), we quantitatively determined nanoplastic accumulation in Ruditapes philippinarum and investigated its toxic effects by combining physiological damage assessments with a toxicokinetic model and 16 S rRNA sequencing. After a 14 days exposure, significant nanoplastic accumulation was observed, up to 17.2 and 137.9 mg·kg−1 for the environmentally realistic (0.02 mg·L−1) and ecologically (2 mg·L−1) relevant groups, respectively. Ecologically relevant nanoplastic concentrations evidently attenuated the total antioxidant capacity and stimulated excessive reactive oxygen species, which elicited lipid peroxidation, apoptosis, and pathological damage. The modeled uptake (k1) and elimination (k2) rate constants (from physiologically based pharmacokinetic model) were significantly negatively correlated with short-term toxicity. Although no obvious toxic effects were found, environmentally realistic exposures notably altered the intestinal microbial community structure. This work increases our understanding of how the accumulation of nanoplastics influences their toxic effects in terms of the toxicokinetics and gut microbiota, providing further evidence of their potential environmental risks.

Pharmacokinetics comparison of vardenafil as administered by an intranasal spray formulation vs a 10-mg oral tablet.

Oral vardenafil (VDF) tablet is an effective treatment for erectile dysfunction (ED), but intranasal administration with a suitable formulation can lead to a faster onset of action and offer more convenient planning for ED treatment. The primary purpose of the present pilot clinical study was to determine whether intranasal VDF with an alcohol-based formulation can result in more "user-friendly pharmacokinetics" as compared with oral tablet administration. This single-dose randomized crossover study was conducted in 12 healthy young volunteers receiving VDF as a 10-mg oral tablet or 3.38-mg intranasal spray. Multiple blood concentrations were obtained, and VDF concentrations were determined with a liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters following each treatment were compared and adverse events assessed. Pharmacokinetic parameters were obtained: apparent elimination rate constant, elimination half-life, peak concentration, peak time, total area under the curve, and relative bioavailability. Although mean apparent elimination rate constant, elimination half-life, peak concentration, and total area under the curve were similar between intranasal and oral administration, the median peak time from intranasal was much shorter (10vs 58minutes, P < .001, Mann-Whitney U test). The variability of the pharmacokinetic parameters was also less with intranasal than oral administration. The relative bioavailability of intranasal to oral was 1.67. Intranasal VDF caused transient but tolerable local nasal reactions in 50% of subjects. Other adverse events (eg, headache) were similar between the treatments. The incidence of adverse events was, however, significantly less in the second treatment after initial exposure to VDF. No serious adverse events were noted. Intranasal VDF potentially offers a more timely and lower dose for the treatment of ED in patients who can tolerate the transient local adverse reactions. The strength of this study is its randomized crossover design. Because the study was conducted in 12 healthy young subjects, the results may not reflect those observed in elderly patients who may be likely taking VDF for ED. Nevertheless, the changes of pharmacokinetic parameters in the present study are likely a reflection of the differences between intranasal and oral administration of the formulations. Our study indicated that the present VDF formulation, when administered intranasally, can achieve a more rapid but similar plasma concentration with only about one-third dose when compared with the oral administration.

Laboratory-Derived Bioaccumulation Kinetic Parameters for Four Per- and Polyfluoroalkyl Substances in Freshwater Mussels.

Although freshwater mussels are imperiled and identified as key conservation priorities, limited bioaccumulation information is available on these organisms for contaminants of emerging concern. In the present study we investigated the bioaccumulation of per- and polyfluoroalkyl substances (PFAS) in the model freshwater pond mussel Sagittunio subrostratus because mussels provide important ecosystem services and are important components of aquatic systems where PFAS occur. In the present study we selected four representative perfluorinated carboxylic acids and sulfonic acids, then determined the bioaccumulation kinetics of freshwater mussels in a controlled laboratory study. Because uptake (ku ) and elimination (ke ) rate constants and time to steady state are important parameters for food web bioaccumulation models, we derived bioaccumulation kinetic parameters following exposure to perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), and perfluorodecanoic acid (PFDA) at 10 µg/L and perfluoroundecanoic acid (PFUnDA) at 1 µg/L during a 14-day uptake period followed by a 7-day elimination period. Kinetic and ratio-based bioaccumulation factors (BAFs) were subsequently calculated, for example ratio-based BAFs for mussel at day 7 were determined for PFHxS (0.24 ± 0.08 L/kg), PFOS (7.73 ± 1.23 L/kg), PFDA (4.80 ± 1.21 L/kg), and PFUnDA (84.0 ± 14.4 L/kg). We generally observed that, for these four model PFAS, freshwater mussels have relatively low BAF values compared with other aquatic invertebrates and fish. Environ Toxicol Chem 2023;42:1190-1198. © 2023 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes.

Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM). A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups. The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population. Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.

Interspecies calibration for biomonitoring metal contamination in coastal waters using oysters and mussels

Differences in metal bioaccumulation among species make it difficult to compare biomonitoring results obtained using different marine bivalve species. To address this challenge and improve the interpretation of biomonitoring data, we studied the toxicokinetic mechanisms underlying these differences and developed a method to estimate seawater metal concentrations based on metal concentrations in the organisms. We transplanted six common species of oysters and mussels found in Chinese coastal waters into the Jiulong River estuary and monitored metal concentrations in the organisms, water, and suspended particles every three days over a six-week period. A one-compartment first-order toxicokinetic model was used to describe the relationship between metal bioaccumulation and metal concentrations in the environment. The model parameters, including aqueous uptake (ku) and dietary assimilation (kp) rate constants, and elimination rate constant (ke), were estimated using a Markov Chain Monte Carlo fitting method with a priori information from a systematic review we conducted. The toxicokinetic model successfully fitted the temporal changes in metal bioaccumulation in all six bivalve species and explained the interspecies differences. Using the calibrated models, we were able to calculate metal concentrations in the seawater at the bivalve collection sites and enable comparisons of biomonitoring data across multiple species. In conclusion, we have established a toxicokinetic framework to explain interspecies differences in metal bioaccumulation in six commonly found bivalves and provided a useful tool for interpreting biomonitoring data in coastal environments.

Abstract 5426: Multi-omic characterization and predictive features of advanced ovarian cancer patients in a large phase III cohort

Abstract Discovery and validation of biomarkers derived from multi-dimensional clinico-genomic datasets have become critical in precision medicine and oncology drug development. The integration of multi-dimensional genomic and imaging datasets from patients in late-stage oncology clinical trials can be difficult, in part due to limited patient enrollment and sample collection, especially tumor tissue biopsies. The objective of this project was to conduct predictive biomarker discovery on integrated clinico-genomics data spanning tumor genomics, germline genetics, tumor imaging, and circulating blood-based biomarkers for a cohort of 800+ advanced ovarian cancer patients enrolled in the phase III trial of the PARP-1 inhibitor Veliparib (VELIA). Genomic (DNA &amp; RNA) and imaging datasets were generated from 800+ patient-matched tumor biopsies, liquid biopsies and whole blood to enable various biomarker analyses for this study, notably in BRCA-deficient and HRD+ subgroups. Pairwise analysis of individual features with clinical outcomes shows that increased tumor-mutation burden (TMB), RNA-based estimates of immune activity (ICR and MIRACLE scores), CA-125 elimination constant (KELIM score), and image-based estimates tumor-infiltrating lymphocytes (TILs) were each significantly associated with longer PFS and less progressive disease (PD). Similarly, homologous recombination deficiency (HRD) and BRCA alteration were associated with better clinical outcomes, while high CA-125 was associated with worse outcomes. To understand the concerted impact of these features on clinical outcome, we developed multivariate classifiers of PD and regressors (Cox Proportional Hazards) of PFS using XGBoost; using a train-test split of 75/25, we trained the models with 500 rounds of 10-fold cross validation hyperparameter tuning, which resulted in fit models. The PD classifier achieved a validation accuracy of 0.71 and F1-score of 0.78, with high immune activation, high TMB, high KELIM, and HRD and BRCA alteration predicting better outcomes. The PFS survival model achieved a validation C-index of 0.61, with a rank importance of features similar to that of PD classification models; for both models, patients receiving Veliparib had clear benefit relative to that of control arms. Collectively, this study illustrates the value of integrating multi-dimensional datasets with predictive machine learning to identify clinically-relevant biomarkers. CR, DM, PA, BR, JD, TB, PN, JS, XH, and JFW are employees of AbbVie. RLC an employee at The University of Texas MD Anderson Cancer Center and has no funding to disclose. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Cyril Ramathal, David Masica, Peter Ansell, Bridget Riley-Gillis, Jacob Degner, Thanh Bui, Priya Narayanan, Josue Samayoa, Xin Huang, Robert F. Coleman, Jeffrey F. Waring. Multi-omic characterization and predictive features of advanced ovarian cancer patients in a large phase III cohort. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5426.

Determination of coffee extract level in saliva Orthodontic patient

Aim: this study was aimed to find out the pharmacokinetic of caffeine (the active compound in coffee) to determine the elimination half-life, area under the curve and other pharmacokinetic parameters for caffeine after excretion in saliva. Materials and Methods: data were collected from twenty orthodontic patients wearing fixed appliance treated in AL Noor center for at least 2 months. Each patient took one cup of coffee (100 ml), then salivary sample was collected at 0, 10, 20, 30, 45 min, 1, 2 and 3 hr. then the concentration of caffeine was detected in every sample. Results: The pharmacokinetic results for caffeine were, elimination rate constant was (0.69hr-1) by NCOMP and (0.69013hr-1) by equation, elimination half-life (1.00hr) and (1.0041hr), volume of distribution (18.17L\kg) and (17.5265L\kg), rate of clearness (10.32 L-1\hr\kg) and (12.0957 L-1\hr\kg), maximum concentration was (15.52 mg) and (15.521 mg). Conclusion: Caffeine pharmacokinetic study shows that caffeine excretes in saliva and has short half-life equal to one hr.

Warming Affects Bioconcentration and Bioaccumulation of Per- and Polyfluoroalkyl Substances by Pelagic and Benthic Organisms in a Water-Sediment System.

Warming and exposure to emerging global pollutants, such as per- and polyfluoroalkyl substances (PFAS), are significant stressors in the aquatic ecosystem. However, little is known about the warming effect on the bioaccumulation of PFAS in aquatic organisms. In this study, the pelagic organisms Daphnia magna and zebrafish, and the benthic organism Chironomus plumosus were exposed to 13 PFAS in a sediment-water system with a known amount of each PFAS at different temperatures (16, 20, and 24 °C). The results showed that the steady-state body burden (Cb-ss) of PFAS in pelagic organisms increased with increasing temperatures, mainly attributed to increased water concentrations. The uptake rate constant (ku) and elimination rate constant (ke) in pelagic organisms increased with increasing temperature. In contrast, warming did not significantly change or even mitigate Cb-ss of PFAS in the benthic organism Chironomus plumosus, except for PFPeA and PFHpA, which was consistent with declined sediment concentrations. The mitigation could be explained by the decreased bioaccumulation factor due to a more significant percent increase in ke than ku, especially for long-chain PFAS. This study suggests that the warming effect on the PFAS concentration varies among different media, which should be considered for their ecological risk assessment under climate change.

Toxicokinetics and Particle Number-Based Trophic Transfer of a Metallic Nanoparticle Mixture in a Terrestrial Food Chain.

Herein, we investigated to which extent metallic nanoparticles (MNPs) affect the trophic transfer of other coexisting MNPs from lettuce to terrestrial snails and the associated tissue-specific distribution using toxicokinetic (TK) modeling and single-particle inductively coupled plasma mass spectrometry. During a period of 22 days, snails were fed with lettuce leaves that were root exposed to AgNO3 (0.05 mg/L), AgNPs (0.75 mg/L), TiO2NPs (200 mg/L), and a mixture of AgNPs and TiO2NPs (equivalent doses as for single NPs). The uptake rate constants (ku) were 0.08 and 0.11 kg leaves/kg snail/d for Ag and 1.63 and 1.79 kg leaves/kg snail/d for Ti in snails fed with NPs single- and mixture-exposed lettuce, respectively. The elimination rate constants (ke) of Ag in snails exposed to single AgNPs and mixed AgNPs were comparable to the corresponding ku, while the ke for Ti were lower than the corresponding ku. As a result, single TiO2NP treatments as well as exposure to mixtures containing TiO2NPs induced significant biomagnification from lettuce to snails with kinetic trophic transfer factors (TTFk) of 7.99 and 6.46. The TTFk of Ag in the single AgNPs treatment (1.15 kg leaves/kg snail) was significantly greater than the TTFk in the mixture treatment (0.85 kg leaves/kg snail), while the fraction of Ag remaining in the body of snails after AgNPs exposure (36%) was lower than the Ag fraction remaining after mixture exposure (50%). These results indicated that the presence of TiO2NPs inhibited the trophic transfer of AgNPs from lettuce to snails but enhanced the retention of AgNPs in snails. Biomagnification of AgNPs from lettuce to snails was observed in an AgNPs single treatment using AgNPs number as the dose metric, which was reflected by the particle number-based TTFs of AgNPs in snails (1.67, i.e., higher than 1). The size distribution of AgNPs was shifted across the lettuce-snail food chain. By making use of particle-specific measurements and fitting TK processes, this research provides important implications for potential risks associated with the trophic transfer of MNP mixtures.

Toxicokinetics and toxicodynamics of Ag nanomaterials (NM300K) in the soil environment–impact on Enchytraeus crypticus (Oligochaeta)

Silver (Ag) is one of the most used elements in the nanomaterials (NMs) form, which upon release to the environment can be harmful to organisms. We compared the toxicokinetics (TK) and toxicodynamics (TD) of Ag from AgNO3 (0, 15, 45, 135, 405 mg Ag/kg soil) and AgNM300K (0, 75, 150, 300, 600, 1200 mg Ag/kg soil) in the model organism Enchytraeus crypticus. Organisms were exposed in LUFA 2.2 soil, and besides body Ag concentrations, survival and reproduction were determined, in a time series (for 21 days). In the soil, the available (CaCl2 extractable) Ag fraction from Ag NM300K increased from 0 to 21 days but did not consistently change for AgNO3. Internal concentrations reached equilibrium in most exposures to both Ag forms. The organisms were able to internalize and eliminate Ag, but less when exposed to Ag NM300K. The overall uptake rate constants for Ag from AgNO3 and Ag NM300K exposures were 0.05 and 0.06 kg soil/kg organism/day, respectively, the elimination rate constants 0.2 and 0.1 day−1, respectively. For AgNO3 the median lethal concentrations decreased steadily with time, while for Ag NM300K they remained constant during the first 10 days of exposure followed by a 2-fold decline in the last 7 days. The 21-d LC50s for both Ag forms were similar but the LC50inter (based on internal concentrations) were 63 and 121 mg Ag/kg body DW (Dry Weight) for AgNO3 and Ag NM300K, respectively, showing higher toxicity of AgNO3. These results show the importance of assessing time to toxicity, a relevant factor in toxicity assessment, especially for NMs.

Using simulations to explore the potential effect of disease and inflammation on the frequency of violative flunixin residues in cattle.

The US Food and Drug Administration (FDA) assigns a tolerance and withdrawal period when evaluating new drugs for use in food-producing species. Because withdrawal periods are determined from data generated in normal, healthy animals, questions have been raised regarding whether disease and inflammation can be a factor associated with some residue violations. We explored this question using flunixin liver concentrations as a model situation. Using data contained in the flunixin FOI Summary (NADA 101-479) and Monte Carlo simulation, we generated sets of residue depletion data. Our mathematical model was simple linear regression containing the terms alpha (the marker residue back-extrapolated to time zero, which equals ) and beta (the elimination rate constant which equals ). By modifying alpha and beta means and variances, we determined the smallest change in these parameters that would result in the presence of violative residues above the statistically determined expected frequency of 1%. The results of this in silico study indicated that the magnitude of change in alpha and beta needed to generate violative residues exceeds that likely to occur due to disease or inflammation when flunixin is used in accordance with the approved product label.

Pharmacokinetics and Target Attainment of ß-lactam Antibiotics in Older People: A Systematic Review of Current Literature

(Patho)physiological changes in older people may influence the pharmacokinetics (PK), and consequently the target attainment, of ß-lactam antibiotics using standard dosing regimens. This systematic review compiles the current knowledge on the PK and target attainment of ß-lactam antibiotics in older people, with the aim to identify priorities for dose optimization in this patient population. A systematic literature search of the PubMed and EMBASE databases was conducted. Relevant articles published prior to 1 December 2021 were identified as eligible when they included data on the PK of ß-lactam antibiotics in adults ≥65 years of age. Extracted information included reported PK parameters (volume of distribution, clearance [CL], elimination rate constant, intercompartmental CL, elimination half-life, area under the concentration-time curve, maximum and trough concentration), covariates on PK parameters, target attainment rate, and dosing recommendations. Ninety-one relevant articles were included in this review. Four main ß-lactam subclasses were represented: 59.3% on cephalosporins + cephamycins, 25.3% on penicillins, 15.4% on carbapenems, and 3.3% on monobactams; 65.9% of articles involved intravenous administration, 16.5% mixed administration routes, 12.1% oral administration, and 5.5% intramuscular administration. The majority of studies had a small sample size, often did not include detailed information on the study population and methods, and were fairly old. CL was, on average, decreased, while elimination half-life was prolonged in aged subjects compared with young subjects. Volume of distribution was generally similar between age groups. Most studies identified renal function as the most important contributor to altered drug CL. In only 30.8% of the articles, target attainment was studied, and in 35.7% of these articles, target attainment was found to be suboptimal. Dosing recommendations were incorporated in 87.9% of articles. Studies frequently fail to provide an evidence-based dosing recommendation for this diverse patient population. Model-based PK studies that address both physiological and disease-related changes are urgently needed. This review identified gaps of knowledge to set priorities for further research.

Toxicokinetics of Ag from Ag2S NP exposure in Tenebrio molitor and Porcellio scaber: Comparing single-species tests to indoor mesocosm experiments

Determining the potential for accumulation of Ag from Ag2S NPs as an environmentally relevant form of AgNPs in different terrestrial organisms is an essential component of a realistic risk assessment of AgNP emissions to soils. The objectives of this study were first to determine the uptake kinetics of Ag in mealworms (Tenebrio molitor) and woodlice (Porcellio scaber) exposed to Ag2S NPs in a mesocosm test, and second, to check if the obtained toxicokinetics could be predicted by single-species bioaccumulation tests. In the mesocosms, mealworms and woodlice were exposed together with plants and earthworms in soil columns spiked with 10 μg Ag g−1 dry soil as Ag2S NPs or AgNO3. The total Ag concentrations in the biota were measured after 7, 14, and 28 days of exposure. A one-compartment model was used to calculate the Ag uptake and elimination rate constants. Ag from Ag2S NPs appeared to be taken up by the mealworms with significantly different uptake rate constants in the mesocosm compared to single-species tests (K1 = 0.056 and 1.66 g dry soil g−1 dry body weight day−1, respectively), and a significant difference was found for the Ag bioaccumulation factor (BAFk = 0.79 and 0.15 g dry soil g−1 dry body weight, respectively). Woodlice did not accumulate Ag from Ag2S NPs in both tests, but uptake from AgNO3 was significantly slower in mesocosm than in single-species tests (K1 = 0.037 and 0.26 g dry soil g−1 dry body weight day−1, respectively). Our results are of high significance because they show that single-species tests may not be a good predictor for the Ag uptake in mealworms and woodlice in exposure systems having greater levels of biological complexity. Nevertheless, single-species tests could be used as a fast screening approach to assess the potential of a substance to accumulate in biota before more complex tests are conducted.

Pharmacokinetics and bioequivalence study of montelukast sodium oral soluble film and chewable tablet in healthy Chinese volunteers: randomized trials under fasting and fed conditions.

The oral soluble film (OSF) is a new drug delivery system. Whether montelukast sodium OSF has similar pharmacokinetic (PK) properties and bioequivalence to chewable tablet (CT) should be investigated. This study, conducted at Haikou People's Hospital, consisted of two trials: a randomized, open-label, single-dose, 3-sequence, 3-period crossover trial under fasting conditions and a randomized, open-label, single-dose, 2-sequence, 2-period crossover trial under fed conditions. Healthy volunteers were randomized 1:1:1 to receive single-dose oral montelukast sodium OSF without water, OSF, or CT with water in the fasting trial, and 1:1 to receive OSF or CT with water in the fed trial in each period, with a 7-day washout period. Randomization was performed according to random number tables generated using computer. Blood samples were collected over a 24-h period. Plasma drug concentrations were tested using high-performance liquid chromatography-tandem mass spectrometry. The primary PK parameters were maximum plasma drug concentration (Cmax), area under the plasma drug concentration-time curve (AUC) from t=0 to the last quantifiable concentration (AUC0-t), and AUC from t=0 to infinity (AUC0-∞). The other PK parameters included time to Cmax (Tmax), terminal elimination rate constant (λz), and half-life (t1/2). Safety was also assessed. Analysis of variance on log-transformed primary PK parameters was applied to analyze the bioequivalence between the OSF and CT. The bioequivalence margin was 80-125%. From November 2018 to January 2019, 30 subjects were included in each trial. The PK parameters between OSF and CT were numerically similar. All 90% confidence intervals (CIs) of the geometric mean ratio (GMR) for the primary PK parameters fell within 80-125%, confirming the bioequivalence of montelukast sodium OSF and CT under fasting and fed conditions. In the fasting trial, 6 (20%) adverse events (AEs) were reported, including 3 (10%) cases after OSF administration without water and 3 (10%) after OSF administration with water, with no serious AEs. No AEs were recorded in the fed trial. Montelukast sodium OSF is bioequivalent to CT, with acceptable safety. The OSF is an alternative option of CT. ClinicalTrials.gov identifiers: NCT05528198 (the fasting trial) and NCT05531994 (the fed trial).

A review of freshwater benthic clams (Corbicula fluminea): Accumulation capacity, underlying physiological mechanisms and environmental applications.

Asian clams (Corbicula fluminea) have been extensively applied in biomonitoring and other environmental fields based on their high enrichment capacity and rapid response to pollutants. This review first summarizes the kinetic process of metals and organic pollutants enriched by C. fluminea and discusses the environmental behavior and application. The accumulation ability of Cu, Zn, and Mn were significantly higher than that of other metals, which were attributed to their high uptake rate constant and low elimination rate constant. The visceral mass was found to be the major burden tissue. However, large knowledge gaps existed regarding the accumulation capacity of C. fluminea for organic pollutants and nanoparticles. Moreover, physiological mechanisms underlying the accumulation of environmental pollutants were proposed. C. fluminea can improve the niche of benthic algae by ingesting pelagic algae, mitigating water eutrophication. It can also remove pathogens and parasites based on the biological assimilation of nonspecific immunity, interrupting disease transmission. The novel insight into the application of C. fluminea in wastewater treatment further broadens the range of pest management strategies and offers the feasibility of blocking the spread of invasive bivalves.

Assessment of Prostate Carcinoma Aggressiveness: Relation to 68Ga-PSMA-11-PET/MRI and Gleason Score.

To test the correlation of 68Ga-PSMA-11 uptake and the expression of PSMA (prostatic specific membrane antigen) with the Gleason score, apparent diffusion coefficient (ADC) and pharmacokinetic parameters obtained from dynamic contrast agent-enhanced MRI/PET. Forty newly diagnosed, therapy naïve patients with prostatic carcinoma (PC) (mean age of 56.7, range=34-79), who were referred for 68Ga-PSMA-11-PET/MRI for primary staging and had undergone radical prostatectomy (RAPE) were included in this prospective study. Their blood samples were tested for serum levels of prostate-specific antigen (PSA) and proPSA. The patients' prostates were evaluated using whole-mount sections, which helped determine the extent and grade of the tumor; tests were performed to determine immunohistochemical PSMA expression. A correlation between PSMA expression and the accumulation of 68Ga-PSMA-11 was found using the Spearman correlation coefficient (p=0.0011). A stronger correlation was found between Gleason patterns 3 or 4 and PSMA expression (p=0.06). Furthermore, the correlation of Gleason score with the overall 68Ga-PSMA-11 accumulation within the tumor or non-tumor tissue was found to be significant (p=0.0157). A significant relation was found only with the Kep elimination rate constant, which was stronger in Gleason pattern 4 than in Gleason pattern 3. A weaker correlation was found between the accumulation of 68Ga-PSMA-11 and Ktrans in Gleason pattern 4: the most significant relation being between ADCmin and Gleason pattern 3 and 4 (p=0.0074). The total size of the tumor correlated with levels of proPSA (p<0.0001), and its extra prostatic extension correlated with levels of proPSA (p<0.0001). 68Ga-PSMA-11 correlates well with the expression of PSMA. Gleason pattern 3 and 4 had a higher correlation with 68Ga-PSMA-11 levels than did Gleason pattern 5. Either no correlation, or a weak correlation, was established with pharmacokinetics.

Evaluation of Ethnicity Effect on Intranasal Esketamine Pharmacokinetics by Population Pharmacokinetic Modeling Using Data From a Japanese Phase 2b Study.

Esketamine is used for the treatment of treatment-resistant depression in many countries. A population pharmacokinetic (popPK) model of esketamine and its metabolite (noresketamine) has been previously developed, which included Asian race and Japanese ethnicity as covariates on their exposures. The present study aimed to update the popPK model by adding new data from a phase 2b study in Japanese patients and reassess intrinsic and extrinsic factors on esketamine and noresketamine exposures. The updated model identified the effects of body weight on the fraction of the esketamine dose absorbed in the nasal cavity and elimination rate constant of esketamine, and Asian race on the apparent clearance of noresketamine. The model predicted that an increase of 30 kg of body weight would decrease esketamine exposures by ≈20%. Noresketamine exposures would be affected by Asian race and body weight. However, those newly identified covariates were not considered to have clinically relevant impacts, and therefore dose adjustments were not necessary. In conclusion, the popPK model of esketamine and noresketamine was successfully updated and suggested that interindividual variability of esketamine exposures can be better explained by body weight, rather than by race/ethnicity. The new findings obtained in this study should be useful information for the further development of esketamine and for clinical practice in the future.

1698. Pharmacokinetics/pharmacodynamics of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor, and High Intracellular Penetration in the Intracellular Hollow Fiber System Model of Mycobacterium avium Complex Lung Disease

Abstract Background Epetraborole (EBO) is a boron-containing, oral inhibitor of bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis; EBO demonstrates potent activity against nontuberculous mycobacteria. Dose-effect studies in the intracellular hollow fiber system model of Mycobacterium avium complex (MAC) lung disease, or HFS-MAC, have demonstrated that EBO is highly bactericidal. In this study we used dose fractionation in the HFS-MAC system to find the best pharmacokinetic/ pharmacodynamic (PK/PD) index that was associated with EBO microbial kill and acquired microbial resistance (AMR). Methods A dose-fractionation design was used to dose 30 HFS-MAC units. ED20, ED50 and ED80 doses were administered as one of 4 dose schedules of twice daily, once daily, twice weekly, or once weekly at a half-life of 10.4h. Total MAC burden and EBO-resistant MAC burden were determined every 7 days by culturing HFS-MAC contents on Middlebrook 7H10 agar. For drug concentrations, the central compartment of each HFS-MAC unit was sampled throughout the 28 days, and after the final dose, intracellular (IC) PK in the MAC-infected monocytes were established. EBO PK/PD index parameters including 0-168h area under the concentrations-time curve (AUC0-168), peak concentration, or % of time concentration persists above the intracellular MIC (%TMIC), which was 0.5 mg/L, were modeled versus total MAC burden using the inhibitory sigmoid maximal effect (Emax) model. The PK/PD index was chosen using Akaike Information Criteria (AIC). For AMR, EBO PK/PD index exposure value versus EBO-resistant MAC burden were modeled using a quadratic function, and the best model was chosen using AIC. Results The measured EBO concentrations demonstrated PKs shown in Figure 1. The median EBO IC versus extracellular (IC/EC) elimination rate constants were 0.018h-1 versus 0.061h-1 (p&amp;lt; 0.0001), which means slower IC EBO elimination, leading to IC/EC to AUC ratio of 11. Based on AIC scores in Table 1, the PK/PD driver for microbial kill was unequivocally AUC on each sampling day. For AMR the PK/PD driver was also AUC. Table 1.Corrected Akaike Information Criteria (AIC) Scores for PK/PD Indicesa-The intracellular EBO MIC was 0.5 mg/LFigure 1.Epetraborole concentrations achieved in the HFS-MAC during the 168-hour dosing interval. Epetraborole concentrations were measured for each of the four dosing schedules, and are shown together with compartmental pharmacokinetics modeling during the 168-hour dosing interval. A. Twice a day dosing. B. Once a day dosing. C. Once every 3.5 days. D. Once every 7 days. Conclusion The PK/PD index best associated with EBO microbial kill and AMR was AUC. Disclosures Shruti Athale, PhD, Praedicare Inc.: Stocks/Bonds Moti Chapagain, MD, PhD, Praedicare Inc.: Stocks/Bonds Jotam Pasipanodya, MD, PhD, Praedicare Inc.: Employee MRK Alley, PhD, ABBOTT LABS: Stocks/Bonds|ABBVIE: Stocks/Bonds|AN2 Therapeutics: Author on epetraborole patent|AN2 Therapeutics: Salary|AN2 Therapeutics: Ownership Interest|AVANOS MED INC: Stocks/Bonds|NABRIVA THERAPEUTICS PLC: Stocks/Bonds|NOVARTIS AG: Stocks/Bonds Tawanda Gumbo, MD, Hydronium Biopharma: Ownership Interest|Hydronium Biopharma: Stocks/Bonds|Praedicare Africa Pvt Ltd: Board Member|Praedicare Africa Pvt Ltd: Ownership Interest|Praedicare Africa Pvt Ltd: Stocks/Bonds|Praedicare Inc.: Patents|Praedicare Inc.: Ownership Interest|Praedicare Inc.: Stocks/Bonds.