Absorption Rate Constant Research Articles

On the importance and modeling of in-depth spectral radiation absorption in the pyrolysis of black PMMA

In-depth radiation absorption in pyrolysis models is commonly modeled with Beer’s law using a constant absorption coefficient. This approximation neglects the effects of spectral variation of absorption coefficient, material emissions, and directional dependency of penetrated thermal radiation. This research aims to address the importance of these factors in flammability analysis of black poly(methyl methacrylate) (PMMA). Accordingly, a pyrolysis model including the separated full spectrum correlated k-distribution (SFSCK) method for spectral modeling, the ordinate weighting method (OWM) with finite volume method (FVM) for directional distribution of the thermal radiation is introduced as the most detailed model. By gradually simplifying this model, five other pyrolysis models are developed with different levels of details in radiation calculations. Simulations are first done using the optimized thermal conductivity and specific heat capacity for the most detailed model, then by optimizing these parameters for each pyrolysis model separately. The results show that the pyrolysis model with a depth and source temperature-dependent absorption coefficient, two-flux method, and diffuse boundary with a scenario-dependent effective reflectivity can predict the measured mass loss rate and ignition time with accuracy similar to the most detailed model, and can be recommended for future pyrolysis simulations.

Population pharmacokinetic modeling of daridorexant, a novel dual orexin receptor antagonist.

The analysis aimed at identifying subject-specific characteristics (covariates) influencing exposure to daridorexant and quantification of covariate effects to determine clinical relevance. Data from 13 phase I, two phase II, and two phase III studies were pooled to develop a population pharmacokinetic model describing daridorexant concentration over time. Covariate effects were quantified based on model predictions. A two-compartment model with dose-dependent bioavailability, absorption lag time, linear absorption, and nonlinear elimination described the data best. Statistically significant covariates were food status on absorption (lag time and rate constant), time of drug administration (morning, bedtime) on absorption rate constant, lean body weight on central volume of distribution and elimination, fat mass on peripheral volume of distribution and intercompartmental drug transfer, and age and alkaline phosphatase on elimination. Age, lean body weight, fat mass, and alkaline phosphatase influence exposure (area under the curve, time of maximum concentration after dose administration, maximum plasma concentration, and next-morning concentration) to a limited extent, that is, less than 20% difference from a typical subject. Morning administration is not relevant for daridorexant use by insomnia patients. The food effect with simultaneous intake of a high-fat, high-calorie food is an extreme-case scenario unlikely to occur in clinical practice. Body composition, alkaline phosphatase, and age showed clinically negligible effects on exposure to daridorexant. Lean body weight and fat mass described the pharmacokinetics of daridorexant better than other body size descriptors (body weight, height, body mass index), suggesting a convenient physiological alternative to reduce the number of covariates in population pharmacokinetic models. The results indicate that differences between subjects do not require dose adjustments.

Pharmacokinetic Characterization and Exposure-Response Relationship of Crovalimab in the COMPOSER and COMMODORE 3 Trials of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Background Crovalimab is a novel anti-human C5 monoclonal antibody being developed for the treatment of PNH, a rare, life-threatening, acquired hematopoietic stem cell disorder. Crovalimab is a next-generation C5 inhibitor that enables rapid and sustained C5 inhibition with subcutaneous (SC) self-administration every 4 weeks. COMPOSER (NCT03157635) is a 4-part open-label adaptive Phase I/II trial evaluating crovalimab in healthy volunteers and in patients with PNH who were treatment-naive or switched from eculizumab to crovalimab. COMMODORE 3 (NCT04654468) is a multicenter, single-arm, Phase III study evaluating crovalimab in treatment-naive patients with PNH in China. Crovalimab dosing and regimen were optimized in COMPOSER (Sostelly ASH 2019) and are currently being investigated in pivotal studies, including COMMODORE 3. The dose and regimen were: Week 1, Day 1: 1000 mg IV for body weight 40 to <100 kg or 1500 mg IV for weight ≥100 kgWeek 1, Day 2 and Weeks 2, 3, and 4: 340 mg SCWeek 5 onward: 680 mg SC for weight 40 to <100 kg or 1020 mg SC for weight ≥100 kg, Q4W The objectives were to characterize crovalimab's pharmacokinetics (PK) in healthy volunteers and treatment-naive patients with PNH, and to characterize the relationship between crovalimab's exposure parameters and pharmacodynamic (PD) biomarkers, efficacy, and safety, using data from COMPOSER and COMMODORE 3. Methods The legacy population PK model (Sostelly ASH 2019) was updated using data from healthy volunteers and treatment-naive patients from COMPOSER and COMMODORE 3 to characterize the crovalimab PK profile and evaluate impact of potential covariates. Simulations were conducted using the population PK model to evaluate the need for dose adjustment in the population based on the identified significant covariates. The relationships between crovalimab exposure and PD biomarkers, efficacy (normalized lactate dehydrogenase [LDH]), and safety endpoints were graphically explored. PD biomarkers included markers of terminal complement activity (50% hemolytic activity [CH50] as measured by liposome immunoassay [LIA]) and free C5. Safety endpoints included adverse events (AEs) of special interest, related serious AEs, related Grade ≥3 AEs, and any infections. Results Crovalimab PK was best described by a linear two-compartment model with first-order elimination and absorption. After SC administration, bioavailability was estimated to be 73.8% with a typical terminal half-life of 58.7 days (90% CI: 50.7, 74.1). Crovalimab clearances and volumes of distribution were allometrically scaled by body weight; patients with lower weight may experience relatively higher drug exposure vs those with higher weight. Age was found to be negatively correlated with the absorption rate constant without a clinically relevant impact on crovalimab exposure. The PK/PD relationship showed that crovalimab induced a concentration-dependent inhibition of terminal complement activity (Figure 1) and free C5 concentrations. Crovalimab concentrations above approximately 100 μg/mL resulted in inhibition of terminal complement activity as indicated by low CH50 values (LIA close or below the lower limit of quantification [10 U/mL]) and low free C5 (<0.0001 g/L in COMMODORE 3). No relationship was identified between observed steady-state crovalimab concentrations and LDH. For concentrations above approximately 100 μg/mL, no further LDH reduction could be achieved with higher concentrations. The recommended dosing regimen delivered adequate crovalimab concentration to achieve the desired LDH reduction. No relationship between crovalimab exposure and AE occurrence was identified, in line with other C5 inhibitors. Using the recommended dose and regimen, simulations of a representative treatment-naive patient population (based on patient characteristics across studies) showed that the predicted trough concentration at steady state remained above the threshold of 100 µg/mL in >95% of simulated patients (Figure 2). No dose adjustment was required for other intrinsic factors such as ethnicity, anti-drug antibody status, and hepatic or renal impairment. Conclusion PK characterization and exposure-response analyses supported the effectiveness and safety of the weight-based two-tiered crovalimab dosing approach for the treatment of adult and adolescent patients with PNH not currently treated with complement inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Population Pharmacokinetic Analyses of Ravulizumab on-Body Delivery System for Subcutaneous Administration in Patients with Paroxysmal Nocturnal Hemoglobinuria

Background: The efficacy of ravulizumab (intravenous [IV] formulation administered every 8 weeks) for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) has been demonstrated in randomized trials (NCT02946463, NCT03056040, NCT03406507, NCT02949128). Studies of IV ravulizumab have established the target therapeutic pharmacokinetic (PK) threshold of 175 μg/mL for complete and sustained terminal complement inhibition (free C5 < 0.5 µg/mL) in patients with PNH and aHUS; maintenance of serum ravulizumab trough concentration (Ctrough) above this threshold ensures clinical efficacy. In study 303 (NCT03748823), the on-body delivery system for subcutaneous (SUBQ) ravulizumab administration (490 mg self-administered weekly) showed PK non-inferiority to IV ravulizumab after 71 days of treatment in adult patients with PNH weighing ≥ 40 to < 100 kg who were clinically stable on prior IV eculizumab treatment (Yenerel et al. HemaSphere 2021;5:e566). In this study, a population PK (popPK) model was developed to characterize ravulizumab PK following IV or SUBQ ravulizumab treatment in patients with PNH, which was then used to generate model-based dosing simulations to support SUBQ and IV ravulizumab posology. Aims: To develop a popPK model and perform simulations to evaluate model-predicted 1) ravulizumab concentrations following IV and SUBQ administration over 1 year of treatment, 2) ravulizumab exposures following SUBQ administration in patients weighing ≥ 100 kg and 3) impact of switching administration route (from IV to SUBQ ravulizumab and vice versa). Methods: A popPK analysis of ravulizumab was performed using data from patients enrolled in three clinical trials (NCT05288829, NCT05396742, NCT03748823). Concentration-time profiles of ravulizumab following IV and SUBQ administration were simultaneously modeled with a 2-compartment model with linear clearance. Ravulizumab absorption following SUBQ administration was modeled using a first-order rate constant of absorption (Ka), bioavailability and lag time. Model-based analyses for repeated measures PK endpoints were conducted using nonlinear mixed effects modeling. The final popPK model accounted for covariates such as body weight, body mass index, disease status and hemoglobin, and was used to simulate steady state concentration profiles following dosing over 1 year, exposure in virtual patients weighing ≥ 100 kg and the impact of a switch in administration route after differing durations of dosing. Results: In total, 2689 blood samples (SUBQ: 1728; IV: 961) were obtained from 178 participants (129 with PNH and 49 without; 115 treated with SUBQ and 63 IV ravulizumab; 46.6% female; aged 18-79 years; body weight 43.5-98.4 kg). The mean (standard deviation) terminal elimination half-life of ravulizumab after SUBQ dosing was 52.4 (9.72) days. The bioavailable fraction of ravulizumab after SUBQ administration was 79.4%. The model-predicted geometric mean ratio (GMR) of SUBQ compared with IV Ctrough on Day 71 and 351 (steady state) were 1.213 and 1.392, respectively (Figure) and comparable to the Day 71 GMR of 1.257 in study 303, indicating the developed popPK model accurately characterized ravulizumab exposure for the ≥ 40 to < 100 kg body weight range in the trial. Simulations predicted that SUBQ ravulizumab Ctrough both remained above the target PK threshold and was non-inferior to ravulizumab IV for body weights ≥ 100 kg. Simulations describing a switch in ravulizumab formulation (IV to SUBQ or SUBQ to IV) show all concentrations remained within our target exposure range regardless of dosing order, after a single dose or after 6 months of dosing. Conclusions: A popPK model was developed and used to support an expanded indication and unrestricted dosing interchangeability between SUBQ and IV ravulizumab. Simulations using the popPK model predicted that switching SUBQ or IV ravulizumab administration route still maintained ravulizumab concentration within the target exposure range supporting treatment flexibility for patients receiving ravulizumab, and that the studied dose regimen maintained ravulizumab concentrations above the PK threshold for patients with body weight ≥ 100 kg. This study illustrates the utility of popPK modeling and simulation to supplement clinical trial results in expanding the target population and dosing options for patients with rare diseases. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Photothermal effect in macroscopic optomechanical systems with an intracavity nonlinear optical crystal.

Intracavity squeezing is a promising technique that may improve the sensitivity of gravitational wave detectors and cool optomechanical oscillators to the ground state. However, the photothermal effect may modify the occurrence of optomechanical coupling due to the presence of a nonlinear optical crystal in an optical cavity. We propose a novel method to predict the influence of the photothermal effect by measuring the susceptibility of the optomechanical oscillator and identifying the net optical spring constant and photothermal absorption rate. Using this method, we succeeded in precisely estimating parameters related to even minor photothermal effects, which could not be measured using a previously developed method.

Green preparation of robust hydrophobic bio-based epoxy resin with low dielectric constant

Epoxidized soybean oil (ESO) thermosets show poor performance owing to the low cross-linking density and flexibility of their backbone structure. Herein, fully bio-derived benzoxazine (GD) cured ESO thermosets (PGEs) with high-performance were prepared through a green process. As a curing agent, GD improved the cross-linking density and rigidity of ESO resins. Moreover, different types of hydrogen bonds formed in the PGEs, further strengthening the intermolecular interactions. Therefore, the glass transition temperature (Tg) and tensile strength of PGEs attained 93 °C and 34 MPa, respectively, which are higher than those reported for conventional ESO resins. Additionally, PGEs exhibited substantial hydrophobicity and a low dielectric constant, which can be associated with complex intermolecular and intramolecular hydrogen bonds within the thermoset network. Furthermore, as the GD content in PGE increased, the dielectric constant and water absorption of the polymer reduced to 2.72 % and 0.52 %, respectively. Herein, the preparation of novel all-biological ESO thermosets using GD as the curing agent is reported, providing a green and convenient strategy for the design of high-performance ecological materials.

Population pharmacokinetics of sublingually administered tacrolimus in infants and young children with liver transplantation.

Pharmacokinetics of tacrolimus after sublingual administration is not characterized in paediatric liver transplant patients. Therefore, we aimed to develop a population pharmacokinetic model of sublingually administered tacrolimus in patients who cannot swallow the capsules due to their age, sedation status and/or mechanical ventilation during the first weeks post-transplantation. Demographic, clinical and pharmacological variables, including tacrolimus whole blood concentrations obtained from therapeutic drug monitoring and data from dense-sampling pharmacokinetic profiles, were recorded in 26 paediatric patients with biliary atresia who underwent liver transplantation between 2016 and 2021. Population pharmacokinetic analysis was performed with NONMEM v7.4. Disposition of tacrolimus was best characterized by a 2-compartment model with clearance achieving half of the maximum elimination capacity (CLMAX =4.1L/h) at 4.6days post-transplantation (T50 ). Compared to sedated patients, nonsedated status showed an increased first-order absorption rate constant (1.1 vs. 0.1h-1 ) and a 24% reduction in bioavailability (FNS ) at 14 days post-transplant. The model was able to explain the oral absorption pattern in nonsedated patients as the result of gut bioavailability (0.9) and hepatic extraction ratio, with the latter being responsible for first-pass effects. Estimates of interindividual variability remained moderate (25.9% for the gut bioavailability) to high (79.8% for the apparent volume of distribution of the central compartment, and 101% for T50 ). A population pharmacokinetic model of sublingually administered tacrolimus in paediatric patients was developed to characterize different absorption mechanisms. Once the model is externally validated, the effect of post-transplant time on clearance and the sedation status may be considered in routine dosing management.

Population Pharmacokinetic Analysis of Valsartan in Healthy Chinese Subjects.

The study was conducted to establish a population pharmacokinetic (PPK) model of valsartan in Chinese healthy subjects and investigate potential covariate impacts on the pharmacokinetics (PK) parameters. Data from a bioequivalence study with 78 Chinese healthy subjects were retrospectively analyzed to develop a PPK model of valsartan. Phoenix NLME 8.1 was used to build a PPK model and quantify the effects of covariates, such as demographic data and biochemical, on the PK parameters of valsartan. For the healthy Chinese population, valsartan conformed to the two-compartment model with an absorption lag time. In the final PPK model, food affected the absorption rate constant, while aspartate aminotransferase, alanine aminotransferase, and creatinine affected the clearance of the central compartment. The final PPK model was verified to be reproducible, and it can be used to evaluate the PK parameters. This is the first research describing the PPK profile of valsartan in healthy Chinese subjects, and it is expected to provide relevant PK parameters for further study of valsartan.

A Novel Diamine Containing Ester and Diphenylethane Groups for Colorless Polyimide with a Low Dielectric Constant and Low Water Absorption.

In this study, a novel diamine monomer containing ester and phenyl moieties, 1,2-diphenylethane-1,2-diyl bis(4-aminobenzoate) (1,2-DPEDBA), was synthesized through a three-step reaction. Using this diamine, a novel polyimide (PI) film was prepared with 4,4'-(hexafluoroisopropylidene)diphthalic anhydride (6-FDA) as a counter dianhydride through a typical two-step chemical imidization. For comparison, poly(pyromellitic dianhydride-co-4,4'-oxydianiline) (PMDA-ODA PI) was also synthesized via thermal imidization. The resulting 6-FDA-DPEDBA PI film was not only soluble in common polar solvents with high boiling points, such as N,N-dimethylacetamide (DMAc) and N,N-dimethylformamide (DMF), but also soluble in common low-boiling-point polar solvents, such as chloroform (CHCl3) and dichloromethane (CH2Cl2), at room temperature. The resulting novel PI showed a 5% weight loss temperature (T5d) at 360 °C under a nitrogen atmosphere. The resulting PI film was colorless and transparent with a transmittance of 87.1% in the visible light region ranging from 400 to 760 nm. The water absorption of the novel PI film was of 1.78%. The PI film also possessed a good moisture barrier and hydrophobicity. Furthermore, the resulting PI film displayed a low dielectric constant of 2.17 at 106 Hz at room temperature. In conclusion, the novel PI film exhibited much better optical transparency, lower moisture absorption, and a lower dielectric constant as well as better solubility than the PMDA-ODA PI film, which is insoluble in any solvent, although its thermal stability is not better than that of PMDA-ODA PI.

Population Pharmacokinetics of Orally Administered Clindamycin to Treat Prosthetic Joint Infections: A Prospective Study.

A population PK model of clindamycin orally administered to patients with prosthetic joint infections (PJIs) was developed using NONMEM 7.5. Monte-Carlo simulations were run to determine the probability of obtaining bone clindamycin concentrations equal to at least the MIC or four times the MIC for several MIC values and dosing regimens. One hundred and forty plasma concentrations prospectively obtained from 20 patients with PJIs were used. A one-compartment model with first-order absorption and elimination appropriately described the data. Mean PK-parameter estimates (F being the bioavailability) were: apparent clearance, CL/F = 23 L/h, apparent distribution volume, V/F = 103 l and absorption rate constant, Ka = 3.53/h, with respective interindividual variabilities (coefficients of variation) of 14.4%, 8.2% and 59.6%. Neither goodness-of-fit curves nor visual predictive checks indicated bias. The currently recommended 600 mg q8h regimen provided a high probability of obtaining concentrations equal to at least the MIC, except for MIC ≥ the clinical breakpoint for Staphylococcus spp. (0.25 mg/L). For such MIC values, higher daily doses and q6h regimens could be considered.

Population pharmacokinetics of mycophenolate mofetil in pediatric patients early after liver transplantation.

Objective: To investigate the factors influencing the pharmacokinetics of mycophenolate mofetil (MMF) in pediatric patients after liver transplantation, and to establish a population pharmacokinetics model, which can provide a reference for clinical dosage adjustment. Methods: A prospective study in a single center was performed on pediatric patients who were administrated with mycophenolate mofetil dispersible tablets (MMFdt) for at least 4 days after liver transplantation continuously. Blood samples were collected in ethylene diamine tetraacetic acid anticoagulant tubes before dosing and 0.5, 1, 2, 4, 8, and 12 h after the morning intake of MMFdt. The concentrations of mycophenolic acid (MPA) in plasma were assayed with a validated reverse-phase high-performance liquid chromatography method. UGT1A8 518C > G, UGT1A9 -275T > A, UGT1A9 -2152C > T, UGT2B7 211G > T, SLC O 1B1 521T > C polymorphism were determined by Sanger sequencing. Nonlinear mixed effects modeling was used to establish the population pharmacokinetics (PPK) model. The predictability and stability of the model were internally evaluated by the goodness of fit plots, visual prediction check, normalized prediction errors, and bootstraps. Results: A two-compartment model with first-order absorption and first-order elimination was established with 115 MPA concentrations from 20 pediatric patients. The final model were: CL/F (L/h) = 14.8×(WT/7.5)0.75×(DOSE/11.16)0.452×е0.06, Ka (h−1) = 2.02×(WT/7.5)−0.25, Vc/F (L) = 6.01×(WT/7.5), Vp/F (L) = 269 (fixed), Q/F (L/h) = 15.4×(WT/7.5)0.75×е1.39. Where CL/F was the apparent clearance rate, Ka was the absorption rate constant, Vc/F was the apparent distribution volume of the central compartment, Vp/F was the apparent distribution volume of the peripheral compartment, Q/F was the atrioventricular clearance rate, WT was the body weight of the subject, and DOSE was the MMFdt administered dose. The model indicated there was large inter-individual variability in CL/F and Q/F after multiple dosing of MMFdt. Internal evaluation results showed that the final model had good stability and prediction performance. Conclusion: A stable and predictive population pharmacokinetic model of MMFdt in pediatric patients after the early stage of liver transplantation was established. The pediatric patient’s weight and the dose of MMFdt can be a reference to adjust the MMFdt dose.

Improving intestinal absorption and antibacterial effect of florfenicol via nanocrystallisation technology

To study the effects of nanocrystallisation technology on the intestinal absorption properties and antibacterial activity of florfenicol (FF). The florfenicol nanocrystals (FF-NC) were prepared by wet grinding and spray drying. Additionally, changes in particle size, charge, morphology, and dissolution of FF-NC in the long-term stability were monitored by laser particle sizer, TEM, SEM, paddle method, and the structure of FF-NC powder was characterised by nuclear magnetic resonance (NMR) test. The antibacterial activity, intestinal absorption and intestinal histocompatibility of FF-NC were investigated by the stiletto, mini broth dilution susceptibility test, in situ single-pass intestinal perfusion (SPIP) and haematoxylin–eosin (H–E) staining. After 12 months of storage, the particle size and zeta potential of FF-NC were 280.43 ± 8.21 nm and −19.64 ± 3.45 mV, and the electron microscopy results showed that FF-NC were nearly circular with no adhesion between particles. In addition, the drug loading, encapsulation efficiency, and dissolution of FF-NC did not change significantly during storage. The inhibition zone of FF-NC against Escherichia coli and Staphylococcus aureus was 21.37 ± 1.70 mm and 25.17 ± 2.47 mm, respectively. Compared with the FF, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of FF-NC are reduced, and the absorption rate constant (K a) and efficient permeability coefficient (P eff) of FF-NC in the three intestinal segments were increased by 1.28, 0.25, and 9.10 times and 0.59, 0.17, and 6.0 times, respectively. The results of tissue sections showed that FF-NC had little damage to the small intestinal. Nanocrystallisation technology is an effective method to increase the intestinal absorption and antibacterial activity of FF.

A numerical simulation approach of energy-absorbing anchor bolts for rock engineering

Energy-absorbing anchor bolts are widely used in geotechnical engineering , but there is no effective numerical simulation approach for evaluating them at the engineering application level. According to typical laboratory test results, the energy absorption criterion ( F ≥ F y ) and breakage criterion ( δ ≥ δ f ) are defined. The constant resistance energy absorption mechanical model and the increasing resistance energy absorption mechanical model are built. Based on the above two basic models, five mechanical models of energy-absorbing bolts, namely, constant resistance and large-deformation anchor bolts (CRLD), increasing resistance and large-deformation anchor bolts (IRLD), Y-bolts, cold drawn constant resistance and large-deformation anchor bolts (CCLD) and D-bolts, are developed. Based on the modification of cable elements in FLAC 3D (Fast Lagrangian Analysis of Continua in 3 Dimensions), the numerical models of the above five kinds of energy-absorbing bolts are established, and the implementation process and specific capabilities of these models are introduced in detail. Numerical tensile tests are carried out, and the results show that the program is effective in executing the above mechanical models. Numerical simulations of deep coal mine roadways supported with different energy-absorbing bolts and absorbing parameters were carried out. The results show that the effectiveness and sensitivity of the mechanical model of energy-absorbing bolts and conventional bolts are realized by this method. The breaking effect of conventional bolt support and the yield support effect of energy-absorbing bolts in the roadway can also be better simulated.

Population pharmacokinetics of voriconazole and initial dosage optimization in patients with talaromycosis.

The high variability and unpredictability of the plasma concentration of voriconazole (VRC) pose a major challenge for clinical administration. The aim of this study was to develop a population pharmacokinetics (PPK) model of VRC and identify the factors influencing VRC PPK in patients with talaromycosis. Medical records and VRC medication history of patients with talaromycosis who were treated with VRC as initial therapy were collected. A total of 233 blood samples from 69 patients were included in the study. A PPK model was developed using the nonlinear mixed-effects models (NONMEM). Monte Carlo simulation was applied to optimize the initial dosage regimens with a therapeutic range of 1.0–5.5 mg/L as the target plasma trough concentration. A one-compartment model with first-order absorption and elimination adequately described the data. The typical voriconazole clearance was 4.34 L/h, the volume of distribution was 97.4 L, the absorption rate constant was set at 1.1 h-1, and the bioavailability was 95.1%. Clearance was found to be significantly associated with C-reactive protein (CRP). CYP2C19 polymorphisms had no effect on voriconazole pharmacokinetic parameters. ‏Monte Carlo simulation based on CRP levels showed that a loading dose of 250 mg/12 h and a maintenance dose of 100 mg/12 h are recommended for patients with CRP ≤ 96 mg/L, whereas a loading dose of 200 mg/12 h and a maintenance dose of 75 mg/12 h are recommended for patients with CRP > 96 mg/L. The average probability of target attainment of the optimal dosage regimen in CRP ≤ 96 mg/L and CRP > 96 mg/L groups were 61.3% and 13.6% higher than with empirical medication, and the proportion of Cmin > 5.5 mg/L decreased by 28.9%. In conclusion, the VRC PPK model for talaromycosis patients shows good robustness and predictive performance, which can provide a reference for the clinical individualization of VRC. Adjusting initial dosage regimens based on CRP may promote the rational use of VRC.

The Radiation Temperature Characteristics of Sapphire under Shock Loading

A light gas gun was used to study the radiation temperature from the window material of sapphire. The luminescence characteristics were determined using a multi-wavelength pyrometer in the pressure range of 36–50 GPa. By improving the processing technology for the metal sample and assembly technology for the target, the eight-wavelength light radiation was measured from sapphire under shock pressure without phase transition. The experimental results showed that sapphire has luminous phenomenon from 36.5 GPa. The luminous intensity changes in a linear fashion, revealing the thickness of the radiating layer of shock-compressed sapphire with a constant absorption coefficient. The results indicated that the spectral distribution is a typical thermal radiation, which fits well with the grey-body spectrum. The radiation of sapphire under shock mostly came from the adiabatic shear banding, as determined by comparing the melting line of sapphire using a static high-pressure experiment and theoretical calculations with the radiation temperature. The study is an effective means to obtain the transparent material shock radiation temperature. Moreover, an effective approach is proposed to research the radiation mechanism of transparent material and the high pressure melting line.

Multiple catalytic polymerization of phthalonitrile resin bearing benzoxazine moiety: Greatly reduced curing temperature

Phthalonitrile resin is a high-performance thermosetting resin with excellent thermal stability, good mechanical properties, low water absorption and low dielectric constant, thus it shows great potential in aerospace, marine, and electronic packaging. However, the extremely high polymerization temperature and long curing cycle limit the practical application of phthalonitrile resin. It is revealed that the active species released by ring-opening of benzoxazine can promote the polymerization of phthalonitrile and the polymerization temperature of phthalonitrile resin containing benzoxazine (BAph) could be reduced to 240–280 ℃, but there is still difficultly in practical application. In this study, dicyandiamide (DCA), which contains reactive nitrile group and active amino groups, was selected as the curing agent to catalyze the curing reaction of BAph. The reaction activity, curing process and curing behavior of BAph-dca were investigated by differential scanning calorimetry (DSC), gelatin time (tgel) measurement and dynamic rheological analysis (DRA). The polymerization mechanism of BAph-dca was studied by Fourier transform infrared spectroscopy (FTIR) and DSC. It was shown that with 10 wt% of DCA, the initial exothermic temperature decreased from 222.9 ℃ (neat BAph) to 159.4 ℃, the peak temperature of ring-opening polymerization of benzoxazine (Tp1) decreased from 255.9 ℃ to 203.2 ℃, and the peak temperature of nitrile polymerization (Tp2) decreased from 288.5 ℃ to 271.6 ℃. Importantly, polymer films can be obtained at 200 ℃, which is substantially lower than the curing temperature of typical phthalonitrile resin. Moreover, the polymer films cured at 200 ℃ showed good thermal stability. The polymer film with 3 wt% of DCA showed initial decomposition temperature (Td5) of the 412 ℃ and the char yield (Yc) of 72.09 % at 800 ℃. This study is of great significance in reducing the polymerization temperature of phthalonitrile resin and promote its practical application.

A first principle comparison of arsenic-based double halide perovskite materials for photovoltaic and optoelectronic application

The comparison study of arsenic-based double halide perovskite materials concentrated on the physical properties is initiated based on first principle. The structure stability is confirmed by the tolerance factor, formation energy and elastic constant. The materials are ductile and ionic compounds through elastic properties. The range of band gap is from 0.882eV to 2.125eV, close to the recommended values for optoelectronic and photovoltaic application. The halogen atoms have great effects on electronic band structures while alkali metal does rarely. All small effective masses for the studied materials indicate high mobilities, favorable for carrier transport. The excellent light absorption properties corresponding to ultraviolet–visible–infrared region reveal great applicable potential for solar energy utilization. Among these materials, K2AgAsBr6 is the most suitable for use as a solar cell material and photocatalytic material because it has an ideal band gap value, high dielectric constant and good optical absorption properties.

Numerical Investigation of a Gear-Shaped Triple-Band Perfect Terahertz Metamaterial Absorber as Biochemical Sensor

In this work, a triple-band perfect metamaterial absorber (MA) in the terahertz (THz) regime is demonstrated for different biochemical sensing applications. The metasurface’s unit cell is made up of a distinct metallic gear-shaped core with eight identical teeth and two concentric circular rings (CCRs) on the top layer. Finite-difference time-domain (FDTD) method-based software is utilized for modeling and numerical analysis, and a genetic algorithm (GA) is employed to optimize some geometric parameters of the absorber. The proposed MA shows almost 100% absorption in the frequency range from 0.5 to 4.5 THz. The MA becomes almost insensitive to polarization angle when the number of gear tooth has been increased. Resonance frequencies can be tweaked by adjusting the top layer’s geometric parameters while maintaining the absorption constant. The influence of different metals and forms in the top layer, such as solid and hollow circular metallic cores, on absorption spectra is also illustrated in this article. The modeled MA can detect glucose, ethanol, oils, and cancer cells (BCCs) by changing the resonance frequency and peak absorption of the spectra due to the variation in refractive index (RI) of the sample. When detecting ethanol, the absorber achieves a maximum sensitivity and figure of merit (FOM) of 56.67 THz/RIU and 358.7 RIU <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">−1</sup> , respectively. In addition, the effects of incident angle of light and bending of MA on absorption are analyzed in this study. With this unique feasible design, structural tunability, and high sensitivity, the proposed absorber exhibits good promise in detecting biochemicals in the THz region.

Optical properties of low background PEN structural components for the Legend-200 experiment

Polyethylene Naphthalate (PEN) plastic scintillator has been identified as potential self-vetoing structural material in low-background physics experiments. Radio-pure scintillating components have been produced from PEN using injection compression molding technology. These low-background PEN components will be used as optically active holders to mount the Germanium detectors in the Legend-200 neutrinoless double beta decay experiment. In this paper, we present the measurement of the optical properties of these PEN components. The scintillation light emission spectrum, time constant, attenuation and bulk absorption length as well as light output and light yield are reported. In addition, the surface of these PEN components has been characterized and an estimation of the surface roughness is presented. The light output of the final Legend-200 detector holders has been measured and is reported. These measurements were used to estimate the self-vetoing efficiency of these holders.

Population Pharmacokinetics of Oral Brepocitinib in Healthy Volunteers and Patients.

Brepocitinib is a tyrosine kinase 2 and Janus kinase 1 inhibitor in development for treatment of inflammatory autoimmune diseases. This analysis aimed to add to the pharmacokinetic knowledge of the medication, through development of a population pharmacokinetic model and identification of factors that affect drug disposition. Plasma samples from 5 clinical trials were collated, composed of healthy volunteers, patients with psoriasis and patients with alopecia areata taking oral brepocitinib. NONMEM was used to develop a population pharmacokinetic model, and patient demographics were tested as covariates. The final model was a 1-compartment model with first-order absorption. The typical values for apparent clearance and apparent volume of distribution were 18.7 L/h (78% coefficient of variation [CV]) and 136 L (60.5% CV), respectively. Absorption was rapid with an absorption constant of 3.46 h, with an absorption lag of 0.24 hours observed with the oral tablet formulation. The proportional residual error was found to be 52.7% CV in healthy volunteers and 87.5% CV in patients. High-fat meals were associated with a reduction in both the rate (69.9% lower) and extent (28.3% lower) of absorption, while Asian populations had reduced clearance (24.3% lower). Nonlinear pharmacokinetics were observed at doses of 175 mg and above, with a 35.1% higher relative bioavailability at these doses. There were insufficient data to describe this nonlinearity as a continuous relationship. This initial description of the population pharmacokinetics will act as a foundation for the model-informed drug development of brepocitinib and will facilitate future modeling of this medicine. ClinicalTrials.gov numbers NCT02310750 NCT03236493 NCT03656952 NCT02969018 NCT02974868.