bluuebunny/crossref_metadata_2025 huggingface dataset:
Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analysis of Danicamtiv in Heart Failure with Reduced Ejection Fraction
Authors: Jarugula Praneeth , Basu Sanchita , Chao Longfei , Maruyama Sonomi , Murthy Bindu , Merali Samira
Published: February 2025

Objectives: Danicamtiv is an investigational drug that works as a cardiac myosin activator and could be a potential treatment option for heart failure with reduced ejection fraction (HFrEF). Successful development in this potential indication is contingent on a favorable benefit-risk profile, favorable pharmacokinetic profile and identifying an exposure-response relationship using key echocardiograph (ECHO) parameters indicative of improving systolic function. Population pharmacokinetic (PK) and PK/pharmacodynamic (PK/PD) modeling were performed to better understand the potential of danicamtiv.Methods: Data from 29 patients in the phase 2a HFrEF PoC study1 was used to perform population PK and PK/PD modeling in NONMEM 7.4. ECHO parameters such as systolic ejection time (SET) and stroke volume were evaluated as PD endpoints using a linear or Emax model. Model performance was evaluated using goodness of fit plots. Final parameter estimates from the population PK-PD model were used to perform simulations using mrgsolve in R to assess dosing. 1000 simulation runs were performed at each evaluated dose. Results: A one compartment model with zero-order absorption described the concentration data well. The inter-individual variability on apparent clearance and apparent volume of distribution was 23.6% and 18.1%. Among ECHO parameters evaluated, SET demonstrated the strongest relationship to danicamtiv exposure, which was described by an Emax model. Heart rate (HR) was a significant, physiologically relevant covariate on baseline SET. Subjects with lower HR had higher SET. Exposure-response relationship with stroke volume data was characterized indirectly through the linear relationship between SET and stroke volume previously described in literature2.Conclusion: Population PK analysis demonstrated relatively low variability and minimal complexities in the PK of danicamtiv. The exposure-response analysis suggests 25-100 mg BID is the optimal clinical dose range to be further evaluated in future studies without the need of therapeutic drug monitoring. Danicamtiv exposure has an indirect relationship with stroke volume through its relationship with SET, which supports the hypothesis that danicamtiv increases contractility. Overall, danicamtiv appears to have favorable properties within the context of other agents with similar mechanism of action in the literature.Citations: 1 Voors AA, et al. Eur J Heart Fail. 2020; 22(9):1649-1658.2Weissler AM, et al. Am Heart J. 1961; 62(3):367-378.
Development of a Population Pharmacokinetic Model for Ganciclovir to Assess the Renal Impairment Impact in Chinese Patients
Authors: tian zhiteng , Tian Zhiteng , Yang Zhenzhen , Liu Dongyang , Supervisor Ph.D. , Researcher Senior
Published: February 2025

Objectives: The ganciclovir (GCV) by intravenous administration is the gold standard treatment of cytomegalovirus infection or prevention in solid organ transplantation, which dose should be adjusted according to the renal function[1]. There are high interindividual pharmacokinetic variability in ganciclovir, mainly due to wide variability in renal function and body weight[2]. This study aimed to develop and verify a population pharmacokinetic model for GCV in Chinese patients, to explain the high variability between individuals and quantitatively explore the impact of renal impairment (RI) on the pharmacokinetics (PK) of GCV. Methods: Clinical data and serum GCV levels were collected from Chinese patients that received intravenous GCV therapy. Ganciclovir concentration-time data were analyzed using nonlinear mixed-effect modeling (NONMEM v.21.11.1). The preferred estimation algorithm was the first-order conditional estimation with interaction (FOCE-I). PK modeling and covariate analyses were performed. Bootstrap and visual predictive checks were used to determine model adequacy. Results:In total, 131 GCV serum concentration measurements were obtained from routine therapeutic drug monitoring in 73 patients after intravenous administration. The PK profile of GCV was conformed to an one-compartment model with first-order elimination. After multivariate analyses, only the categorical covariate RI (renal impairment degrees including normal, mild, moderate and severe were classified based on eGFR) (P < 0.001) were included as covariates on clearance (CL). In the final model, the estimated CL and volume of distribution (V) were 22.3 L/h and 178 L, respectively. The inclusion of RI contributed to a decrease of interindividual variability (IIV) of CL by 47.6%. The final model demonstrated that CL was 0.451, 0.156, 0.096 times of the normal population for mild, moderate, and severe renal impairment population, respectively. The covariate RI revealed that the deterioration of renal impairment was closely associated with the reduction in CL. Conclusions: A large interindividual variability was quantitatively explored from the PK profile of GCV among Chinese patients, and RI could partially explain the interindividual variability. The developed model results could lead to refine recommendation for dose adjustment according to the various degrees of renal impairment.Citations: Citations:[1] Humar A, Snydman D; AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009, 9 Suppl 4: S78-86. [2] Franck B, Woillard JB, Théorêt Y, Bittencourt H, Demers E, Briand A, Marquet P, Lapeyraque AL, Ovetchkine P, Autmizguine J. Population pharmacokinetics of ganciclovir and valganciclovir in paediatric solid organ and stem cell transplant recipients. Br J Clin Pharmacol. 2021, 87(8): 3105-3114.
Simulations to Inform Dose Selection for a Phase 2b Trial Investigating TOUR006, a Fully Human Anti-IL6 Antibody, for Treatment of Thyroid Eye Disease
Authors: Debroy Swati , Erickson Kristine , Comisar Craig , Seiff Stuart , Chyung Yung , Iarrobino Ryan , DeGoma Emil , Martin Paul
Published: February 2025

Objectives: Thyroid eye disease (TED) is an autoimmune disease in which the eye muscles and fatty tissue behind the eye become inflamed leading to bulging of eyes. Due to the key role of Interleukin 6 (IL-6) in the pathogenesis of TED, IL-6 inhibition has been used off label as a treatment. TOUR006 (previously known as PF-04236921) is a selective fully human IgG2 mAb that binds IL-6 with high affinity. It has been dosed in >400 subjects to date. We predicted effective dosing regimens of TOUR006 for TED, using a population PK/PD model of C-reactive protein (CRP), a marker of IL-6 pathway activity.Methods: A PK and PK/PD (CRP) model for TOUR006 was developed by Li et. al, based on 5 clinical studies conducted with PF-04236921 in healthy volunteers and patients with autoimmune conditions other than TED [1]. Serum CRP, widely used as a surrogate for IL-6 pathway activity was selected as a biomarker. Several combinations of dosing frequencies (q4w or q8w) and dose levels (10 to 50 mg) were evaluated. Simulations were used to identify optimal subcutaneous (SC) dosing scenarios targeting ≥90% CRP suppression from baseline or < 2 mg/L for the virtual TED population assuming modeled inflammatory behavior similar to rheumatoid arthritis. Any simulated subject with a CRP level less than 2 mg/L was set to 90% CRP reduction for analysis purposes. The simulations were performed by sampling the participants from a subpopulation with baseline serum CRP of >2 mg/L to 10 mg/L, comparable to most TED patients. Sensitivity analysis was performed to estimate response for population with higher bodyweight.Results: Simulations predict that a dosing schedule of 20 mg SC q8w and 50 mg SC q8w will result in ≥90% CRP suppression (or < 2 mg/L) in most virtual participants with TED. Further, the 20 mg q8w regimen may achieve the targeted efficacy in participants with moderate levels of IL-6 pathway activation (baseline CRP of 2 to 10 mg/L), while the 50 mg q8w regimen may be needed if IL-6 pathway activation is greater in TED or there are participants with relatively higher levels of IL-6-driven inflammation. Additionally, fixed subcutaneous dosing for TOUR006 without weight-based adjustment was found to be appropriate.Conclusion: The simulations for 20 mg and 50 mg q8w of SC TOUR006 predict that these doses/regimens are likely to target ≥90% CRP suppression from baseline in most TED subjects, thus producing a robust therapeutic effect.Citations: [1] Li C, et al. Pharmacokinetics and C-reactive protein modelling of anti-interleukin-6 antibody (PF-04236921) in healthy volunteers and patients with autoimmune disease. Br J Clin Pharmacol (2018) 84;2059–2074.
PKPD modeling and simulation of an inhaled antibiotic targeting Gram-negative bacteria, using a bacteriophage-derived endolysin.
Authors: Kang Jueun , Han Sungpil
Published: February 2025

Patients with pneumonia frequently experience a high prevalence of respiratory tract infections. The increasing global prevalence of multidrug-resistant Gram-negative bacteria urgently necessitates the development of new antimicrobial agents for the treatment of infections caused by Gram-negative bacteria. Bacteriophage endolysins, bacteriophage-encoded enzymes, are potentially significant for the treatment of multidrug-resistant bacterial infections. Its mechanism involves the targeted hydrolysis of the bacterial cell wall, leading to rapid eradication of Gram-negative bacteria.In non-clinical experiments, we have demonstrated that bacteriophage endolysins exhibit promising antimicrobial efficacy against pneumococcus, the causative agent of pneumonia in humans. We examined the in vitro antibacterial efficacy of endolysin and observed its highly effective reduction of colony-forming units (CFU) across a range of Gram-negative bacteria. Additionally, we validated its antibacterial activity against the colistin-resistant E. coli mcr-1-positive FORC81 strain, confirming that LNT103 is also active against colistin-resistant bacteria.In a mouse model of pneumonia caused by Acinetobacter baumannii and treated with endolysin, resulted in 100% mortality in the control group by day 1. In contrast, approximately 50% of the mice treated with LNT103 survived until day 7, indicating a significant increase in survival compared with the control group. Additionally, improved survival rates were observed in the antibiotic-treated groups.To predict human pharmacokinetic (PK) parameters, we have calculated in three species (mouse, rat, and dog). In mice, intravenous (IV) administration of a 30 mg/kg dose resulted in a mean bioavailability in plasma of 15.5%, with a PK profile characterized by area under the curve (AUC) 33,184.78 ng·hr/mL, half-life (t1/2) 1.99 hr, clearance (CL) 901.25 mL/hr/kg, and steady-state volume of distribution (Vdss) 129.18 mL/kg.In rats, IV administration of a 25 mg/kg dose resulted in PK parameters of AUC 35,413.45 ng·hr/mL, t1/2 0.28 hr, CL 705.67 mL/hr/kg, and Vdss 71.56 mL/kg.In dogs, IV administration of a 25 mg/kg dose resulted in PK parameters of AUC 90,968.04 ng·hr/mL, t1/2 0.3 hr, CL 282.69 mL/hr/kg, and Vdss 86.75 mL/kg.Based on these studies, we aim to conduct PK/PD modeling and simulation of inhaled endolysin using non-clinical data to predict its pharmacokinetics in humans, thereby identifying the optimal exposure or dose.Citations: [1]Secher et al., Correlation and clinical relevance of animal models for inhaled pharmaceuticals and biopharmaceuticals, Adv. Drug Delivery Rev (2020)[2]Borghardt et al.,Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs, AAPS J 17(4):853-70. (2015)
NMsim: Simulate Nonmem models seamlessly in R without any model reimplementation
Authors: Delff Philip
Published: February 2025

Objectives: While Nonmem is widely used for its strengths and flexibility in estimation of pharmacometricsmodels, post-processing including simulation is often preferably handled in R. The new R packageNMsim (available on CRAN) fills this gap by allowing simulation of Nonmem models directlyfrom R. In contrast to other powerful simulation packages, NMsim relies on Nonmem to performthe simulation, hence eliminates the need for translating to other software.NMsim aims at providing a seamless and close to model-independent R interface to simulation ofNonmem models only dependent on estimation control stream and a simulation data set.NMsim works on both ADVAN subroutines and $PRED models and can currently perform the followingtypes of simulations:• New subjects (default)• Typical subject (ETAs equal 0)• Subjects already estimated in Nonmem model (EBE’s)• Simulation with parameter uncertaintyMoreover, NMsim provides an interface to modify control streams. This can among other things beused to modify parameter values.Methods: NMsim does not simulate, translate or otherwise interpret a Nonmem model. Instead, it automatesthe Nonmem simulation workflow (including execution of Nonmem). In the example given above,NMsim will do the following:• Save the simulation input data in a csv file for Nonmem• Create a simulation input control stream based on file.mod matching the saved simulationdata set• Update and fix initial values based on estimate (from file.ext)• Run Nonmem on the generated simulation control stream• Collect output data tables, combine them, and merge with the simulation input data• Return the collected data in RNMsim is written in R and data.table leveraging functionality from the NMdata R package.Results: NMsim provides a simulation interface that does not require reimplementation of a Nonmemmodel. This reduces amount of work and risk of errors. It allows for simulation of all intermediatemodel steps simplifying simulation-based model qualification, and for automation of a wide rangeof simulation based analyses.In this poster presentation, we showcase the capabilities of NMsim through examples of differenttypes of simulations of a popPK model. From the information provided on the poster and the freelyavailable R package, the audience will be able to perform simulations on their own models withoutany further model coding.Conclusions: By bridging the gap between Nonmem’s powerful modeling capabilities and the readily availabilityof a simulation interface in R, NMsim expedites model development and evaluation. We believethat our package will facilitate collaboration and innovation in the pharmacometrics community,ultimately advancing drug development efforts.Citations: [1] 2024. NMdata: Preparation, Checking and Post-Processing Data for PK/PD Modeling. https://cran.rproject.org/package=NMdata[2] 2024. NMsim: Simulate Nonmem models from R. https://philipdelff.github.io/NMsim[3] 2024. NMsim: Seamless ‘Nonmem’ Simulation Platform. https://cran.r-project.org/web/packages/NMsim
Model-Based Meta Analysis for the IPSOS Trial in Platinum Ineligible NSCLC Patients
Authors: Chen Joseph , Wada Russell , Zhang Nancy , Graupner Vilma , Morris Stefanie , Hu Youyou , Zhang Wei , Kassir Nastya , Wu Benjamin , Chan Phyllis
Published: February 2025

Introduction/Objectives: IPSOS (NCT03191786) is a Phase III trial that compared atezolizumab (atezo) monotherapy (mono) vs. single-agent chemotherapy (chemo) (gemcitabine or vinorelbine) in patients with treatment-naïve locally advanced or metastatic NSCLC deemed unsuitable for platinum-doublet chemo. The study demonstrated significant OS improvement in the atezo arm compared to single-agent chemo (gemcitabine or vinorelbine); stratified HR of 0.78 (95% CI: 0.63, 0.97; p-value of 0.028) [1]. The IPSOS control arm only allowed gemcitabine or vinorelbine, while other single agent chemo could have been used. Thus, this model-based meta-analysis (MBMA) extracted OS from published literature in patients similar to the IPSOS trial, adjusting for heterogeneity across trials, to estimate OS HR between the IPSOS active and control arms vs. historical control arms in which other single agent chemo were used. The aim was to demonstrate the non-inferiority of the IPSOS control arm vs. historical control, and assess atezo treatment benefits. Methods: A literature search was based on the following criteria of the clinical trial participants: chemo-naïve; advanced or metastatic NSCLC; platinum-ineligible; elderly (≥ 70 years of age); ECOG ≥ 2; taking paclitaxel, docetaxel, gemcitabine, pemetrexed, or vinorelbine mono. Summary-level OS data were extracted by digitizing Kaplan-Meier curves and only trials with ≥ 50 participants were included in the MBMA database. A list of potential covariates were pre-specified, and the database was augmented by imputing missing covariate values. A nonparametric approach, modeling the conditional probability of OS data [2] was implemented. Results: The assembled database consisted of summary-level data from 26 trials with 41 arms and 3637 participants. ECOG was the only significant covariate identified. After adjusting for ECOG, the model-predicted HR for the IPSOS control arm relative to historical trials was 0.543 (95% CI: 0.435,0.677). In addition, the HR for the IPSOS atezo mono arm relative to historical trials was 0.418 (95%CI: 0.335,0.522). Conclusions: Overall, the results of the MBMA support the clinical benefit seen in the IPSOS trial. Citations: Lee SM, Schulz C, Prabhash K, et al. First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study [published correction appears in Lancet. 2023 Aug 5;402(10400):450]. Lancet. 2023;402(10400):451-463.Turner DC, Wada R, Zhou H, et al. Model-based meta-analysis of non-small cell lung cancer with standard of care PD-1 inhibitors and chemotherapy for development decision making. CPT Pharmacometrics Syst Pharmacol. 2023;12(11):1751-1763.
An innovative paradigm for non-small cell lung cancer clinical trial simulations through the Integration of a quantitative systemic pharmacology model and pharmacodynamic model of gemcitabine
Authors: GREUGNY Elea THIBAULT , Ratto Nicolas , Etheve Loïc , Boissel Jean-Pierre , Holford Nicholas , L'Hostis Adèle , Monteiro Claudio
Published: February 2025

Objectives: We propose an approach that combines a quantitative systemic pharmacology (QSP) disease model of non-small cell lung cancer (NSCLC) [1] with an existing drug pharmacodynamics (KPD) model of gemcitabine [2]. Through a minimal calibration step and limited data, this integrative framework seeks to bridge the gap between understanding disease progression mechanisms and drug actions, paving the way for a new paradigm in simulating and optimizing clinical trials. Methods: The combined model is constructed by integrating the NSCLC disease model, which accounts for tumor growth and other relevant phenomena, with the segment of the gemcitabine KPD model representing treatment time-course and magnitude. The logical connection between both models is established based on gemcitabine's inhibition of tumor growth, as outlined in the KPD model. Due to a significant difference in modeling hypotheses—specifically, the assumption of tumor steady state in the KPD model, which differs from the dynamic nature of the disease progression model—two additional parameters are introduced in the combined model. These parameters are calibrated to reproduce the median patient behavior observed in the clinical data used to build the KPD model. Results: A virtual population is created based on the patient characteristics and the estimated variability of PD parameters provided by Tham et al. [2]. The clinical results provided in the previous publication are successfully reproduced through simulations of gemcitabine treatment on this virtual population. Conclusions: The combination of disease and treatment models, coupled with minimal calibration, offers significant enhancements to both models' capabilities. This approach holds promise for the future of QSP modeling.Citations: [1] L'Hostis, A. et al. Knowledge-based mechanistic modeling accurately predicts disease progression with gefitinib in EGFR-mutant lung adenocarcinoma. npj Systems Biology and Applications vol. 9 (2023).[2] Tham, L.-S. et al. A Pharmacodynamic Model for the Time Course of Tumor Shrinkage by Gemcitabine + Carboplatin in Non–Small Cell Lung Cancer Patients. Clinical Cancer Research vol. 14 4213–4218 (2008).
Meta-Analysis of Levamisole Pharmacokinetics Across Diverse Species
Authors: Cheng ChunFu , Jeong Yoo-seong , Jusko William
Published: February 2025

Objectives: The study aims to (1) perform a literature search and meta-analysis to recover pharmacokinetic (PK) parameters of levamisole (LVM) across various species, (2) evaluate potential relationships among these PK parameters using allometric two-compartment model (a2CM), and (3) employ a minimal physiological-based pharmacokinetic (mPBPK) model to analyze the plasma concentration time-course of LVM across eight species.Methods: Data were collected from PubMed and Google Scholar, spanning publications from 1930 to 2024. PK parameters were gathered for 19 species, with eight species selected for detailed analysis. PK parameters were assessed using non-compartmental analysis (NCA) and allometric scaling. A two-compartment model (2CM) was used for initial PK profiling. An mPBPK model was developed to fit the plasma concentration-time data, incorporating physiological parameters like blood volume, cardiac output, and body weight across species. Both models were fitted to IV and oral (PO) data using maximum likelihood methods.Results: The study found that the clearance (CL) of LVM across species showed a low power coefficient (b=0.26) when scaled allometrically, indicating unique PK properties. The volume of distribution (Vss) demonstrated a strong correlation with body weight (b=0.89). The absorption rate constant (ka) had a poor allometric relationship (b=0.25), while bioavailability (F) was consistent across species (b=0.08). Joint fitting of the a2CM and mPBPK models provided similar results, with the mPBPK model showing better fit and lower coefficients of variation (CV%). The mPBPK model with a unified tissue partition coefficient (Kp) and pig-specific Kp parameter provided the most accurate fits. The study highlighted the consistency in bioavailability (50-100%) across species, with exceptions such as the goat.Conclusion: Levamisole exhibits consistent allometric properties across multiple species, characterized by a low clearance power coefficient and proportional volume of distribution to body weight. The mPBPK model demonstrated better overall fitting compared to the a2CM model, capturing species-specific PK profiles effectively. This study underscores the value of allometric scaling and mPBPK modeling in cross-species PK assessments, providing insights into levamisole's disposition in diverse biological systems.Citations: [1] Song, D., & Jusko, W. J. (2021). Across-species meta-analysis of dexamethasone pharmacokinetics utilizing allometric and scaling modeling approaches. Biopharmaceutics & drug disposition, 42(5), 191–203.[2] Jeong, Y. S., & Jusko, W. J. (2021). Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species. Pharmaceuticals (Basel, Switzerland), 14(6), 545.
Population Pharmacokinetic Modeling of IMP7068 in Patients with Advanced Solid Tumors
Authors: He Yanna , Li Yiheng , Hsieh Chih-Yi , Xu Cong , Cai Suixiong , Tian Ye , Xia Huan , Li Baoyue , Zhang Congcong , Mei Chongzi , Wang Jian , Xie Simin , Wang Bing
Published: February 2025

Objectives: IMP7068 is a potent and selective inhibitor of WEE1 kinase. Following oral administration IMP7068 is predominantly metabolized by CYP3A4 in the liver. The major metabolite, IMP7253, is also pharmacologically active. Population pharmacokinetic (PK) modeling was conducted to characterize the concentration-time profiles of IMP7068 and IMP7253 in patients with advanced solid tumors.Methods: The population PK analysis was based on data from the Phase 1 dose-escalation study (IMP7068-101). The dataset contains 1006 and 1028 quantifiable PK observations of IMP7068 and IMP7253, respectively, from 48 cancer patients at 10 dose cohorts who received orally administered IMP7068. The pooled IMP7068 and IMP7253 PK data were simultaneously modeled using NONMEM (Version 7.4.3). The predictive performances of the final PK model were assessed by goodness-of-fit diagnostics.Results: A parent-metabolite model was developed to describe the time-dependent PK of IMP7068 and IMP7253 in cancer patients. The PK of IMP7068 was adequately described by a two-compartment model with delayed first-order absorption (mean absorption transit time = 1.42 h) for orally administered IMP7068, and parallel first-order and nonlinear elimination pathways from the central compartment. A one-compartment model was developed for IMP7253, with input assuming the result of IMP7068 metabolism (i.e., the nonlinear elimination pathway of IMP7068). Time-dependent CYP3A4 inhibition was incorporated in the oral bioavailability of IMP7068 and nonlinear clearance of IMP7068 and IMP7253. For the parent drug IMP7068, the estimated apparent clearance of the first-order elimination pathway (CL/F) and steady-state volume of distribution were 125 L/h and 6860 L, respectively. No covariates were added to the combined PK model.Conclusions: The pooled PK data of IMP7068 and IMP7253 from Study IMP7068-101 was adequately described by a parent-metabolite model with time-dependent oral bioavailability (IMP7068) and nonlinear clearance (IMP7068 and IMP7253). No covariates were added in the final PK model.Citations: NA
Model-Informed Dose Justifications and Clinical Pharmacology Strategy of Posaconazole in Japanese Patients for Prophylaxis and Treatment Against Fungal Infection
Authors: Hasegawa Chihiro , Iwasa Takashi , Yoshitsugu Hiroyuki , Wrishko Rebecca
Published: February 2025

Objectives: Posaconazole is a globally approved broad-spectrum triazole antifungal compound. In Japanese patients, posaconazole has identical dosing regimens as those approved globally for both tablet and intravenous formulations. We report a model-informed approach for dose justification of posaconazole in the Japanese population as either high-risk patients with fungal infections (prophylaxis patients) or patients with fungal infections (treatment patients), as well as a newly added/updated perspective from [1], i.e., a clinical pharmacology strategy of posaconazole focused on both ethnicity (Japanese vs. non-Japanese populations) and disease status (healthy participants vs. patients) which were potentially confounding. Methods: A simultaneous population pharmacokinetic (PK) model for tablet and intravenous formulation was developed on the basis of a data set including Japanese data from healthy participants and treatment patients [1]. The PK profiles and exposure distributions in Japanese patients were predicted and compared against non-Japanese patients. Relationships between the post hoc posaconazole exposures and frequently observed clinical adverse events were evaluated. Although clinical trials for Japanese prophylaxis patients were not conducted, PK profiles in Japanese prophylaxis patients were predicted using the population PK model and demographic covariate information obtained from the published literature. Results: Based upon the globally approved dosing regimen, posaconazole exposure distribution was predicted to be the highest in Japanese treatment patients, and generally similar between Japanese and foreign prophylaxis patients. An inter-study comparison based on PK data in healthy participants indicated lack of effects of ethnicity on PK of posaconazole, suggesting that the disease status and demographic factors including body weight and age, rather than ethnicity, are important covariates on posaconazole PK. Exposures in Japanese patients exceeded the efficacy target level (500 ng/mL). Safety profiles in Japanese treatment patients with the highest exposures were clinically acceptable without specific concerns to Japanese patients and appeared to have no relationship with posaconazole exposures. Conclusions: From PK, safety, and efficacy perspectives, the use of the same dosing regimen as in foreign patients was justified in Japanese prophylaxis and treatment patients.Citations: [1] Iwasa T, et al. J Clin Pharmacol. 2023; 63: 421-434.
Predictive Pharmacokinetic Analysis of Novel PLCG2 Inhibitors Using GastroPlus and ADMET Predictor
Authors: Hajjawi Malek , Clayton Brent , Silva Lais Da , Quinney Sara , Richardson Timothy
Published: February 2025

Objectives: : Over the last twenty years, there has been a growing utilization of different in vitro models within the pharmaceutical sector to examine absorption, distribution, metabolism, and excretion (ADME) processes. This surge can be attributed to the significant role that poor ADME properties play, accounting for 40% of drug candidate setbacks during the clinical phase of drug development]In the quest to develop effective treatments for Alzheimer's Disease (AD), a series of novel compounds targeting PLCG2 were evaluated using in silico physiologically based pharmacokinetic (PBPK) modelingMethods: Utilizing GastroPlus and ADMET Predictor, we simulated the pharmacokinetic profiles of eight compounds. The aim was to predict oral bioavailability, plasma and brain exposure, and other critical pharmacokinetic parameters following a 0.25 mg dose administered as an immediate-release (IR) solution. Results :The compounds exhibited high absorption, with the fraction absorbed (Fa) and the fraction of dose permeated (FDp) nearing 100% for all compounds. The fraction of the dose that reaches systemic circulation (F) ranged from 60.649% to 79.631%. Peak plasma concentrations (Cmax) varied between 7.5914 µM and 20.887 µM, with time to reach peak plasma concentration (Tmax) occurring at 0.16 to 0.24 hours. The highest brain concentrations (Cmax Brain) were observed with TAD-0411074 and TAD-0411110, at 54.598 µM and 75.465 µM, respectively. Area under the curve (AUC) from zero to infinity (AUC0-inf) and to the last measured time point (AUC0-t) highlighted the systemic exposure, with TAD-0411110 achieving the highest AUC0-inf at 50.365 µg·h/mL. Liver exposure (Cmax Liver) and unbound plasma (CmaxU plasma) and brain (CmaxU Brain) concentrations provided insights into the distribution and potential efficacy within target tissues. The compounds demonstrated varied half-lives, ranging from 1.12 hours for TAD-0411797 to 8.71 hours for TAD-0410462. Conclusions: These findings underscore the potential of these PLCG2 inhibitors as promising candidates for AD treatment, meriting further in vivo investigation and optimization.Citations: 1. Cai, H., et al., Evaluation of an integrated in vitro–in silico PBPK (physiologically based pharmacokinetic) model to provide estimates of human bioavailability. International journal of pharmaceutics, 2006. 308(1-2): p. 133-139.
Clinical Trial Simulation to Assess Sample Size and Power For Detecting Differences in Pharmacokinetic Exposure Metrics
Authors: Huang Hannah , Liao Ken , Zhao Molly , Agoram Balaji , Chaturvedula Ayyappa
Published: February 2025

OBJECTIVES: The objective of this analysis is to demonstrate a general simulation-based methodology to assess sample size and power for clinical studies with exposure metric based end points. _x000D_ _x000D_ METHODS: A two-compartment model following intravenous administration with moderate between subject variability on pharmacokinetic parameters was used for pharmacokinetic (PK) simulations. An example drug development scenario of infusion time change from 1-hour to 0.5-hour was used. PK profiles of reference and test populations were simulated following single dose and steady-state using 1-hour and 0.5-hour infusion times, respectively. Non-compartmental analysis was conducted to derive test and reference population-based exposure metrics, including maximum concentration [Cmax] and average concentration [Cavg] from individual predictions (IPRED). Random sampling was conducted from the test and reference populations to represent a parallel design PK evaluation trial with various sample sizes (n=6, 12, 20, 30, 40 or 50). The geometric mean ratios (GMR) of test to reference Cmax and Cavg were calculated for each trial. The process was repeated 1000 times to generate virtual clinical trials for each sample size scenario. Power to detect a nominal 20% difference between test and reference population was calculated as percentage of trials with GMR within 0.8-1.2. In addition, the entire power calculation process was repeated to evaluate scenarios with an assumed true difference of 25% lower exposure in test compared to reference population._x000D_ _x000D_ RESULTS: Sample size of ≥6 can achieve >80% probability of correctly concluding that Cmax and Cavg for 0.5-h co-admin are within ±20% of those for 1-h infusion when no true differences between test and reference populations are assumed. Sample size of ≥40 patients would provide >80% probability of correctly concluding that Cmax and Cavg for 0.5-h co-admin are outside ±20% of those for 1-h infusion when the true difference is 25% between test and reference population._x000D_ _x000D_ CONCLUSIONS: Clinical trial simulation using population PK models can provide an assessment of sample size and power for studies with PK exposure metric driven endpoints. It is more advantageous than traditional power calculation as it is more intuitive, adaptable to different study designs, and incorporates known PK variability related to intrinsic and extrinsic factors as well as differences in dosing. The framework presented can be generally applied in various scenarios in drug development with drug specific models of varying complexities with simple simulation workflows.Citations: N/A
Nipocalimab pharmacokinetic/pharmacodynamic and exposure-response modeling in pregnancies at risk for early-onset severe (EOS) HDFN
Authors: Zhou Jessie , Leu Jocelyn , Xiong Yuan , Lam Edwin , Ling Leona , Amin Umair , Sirah Waheeda , Saeed-Khawaja Shumyla , Mirza Arpana , Komatsu Yosuke , Williams Jannine , Kordy Kattayoun , cella Ricardo Rojo , Vermeulen An , Samtani Mahesh
Published: February 2025

Objectives: Hemolytic disease of the fetus and newborn (HDFN) is a rare, immune-mediated red blood cell (RBC) disorder, where maternal IgG alloantibodies attack fetal RBCs. Nipocalimab is a fully human monoclonal antibody designed to selectively block the IgG binding site on neonatal Fc receptors (FcRn). Modeling approaches were used to characterize the pharmacokinetic/pharmacodynamic (PK/PD) and exposure-response (E-R) relationships of nipocalimab in the Phase 2 UNITY study in pregnancies at risk for EOS-HDFN.Methods: UNITY is a multicenter, open-label, single-arm study evaluating the safety, efficacy, and PK/PD of nipocalimab in pregnant individuals at risk for EOS-HDFN. Data from three Phase 1 studies in healthy volunteers and the UNITY study were combined and utilized for the PK/PD and E-R modeling. Nipocalimab PK and FcRn occupancy (RO) were characterized by a 2-compartment target-mediated-drug-disposition (TMDD) model following intravenous (IV) doses. A PK/PD model was established to describe the observed longitudinal IgG data following IV doses. E-R relationships were explored to correlate nipocalimab PK or total IgG with efficacy and safety endpoints.Results: Nipocalimab PK exhibited nonlinear behavior. The developed TMDD PK model characterized the time courses of nipocalimab PK and FcRn RO. The PK/PD model indicated high potency of nipocalimab to reduce the maternal total IgG levels. Similar to total IgG, maternal alloantibodies decreased and showed a correlation with maternal total IgG. At the studied dose levels in UNITY, nipocalimab fully saturated FcRn, leading to decreased maternal alloantibodies and inhibition of their placental transfer. E-R modeling for primary efficacy and selected safety (ie, infection) endpoints showed that optimal responses have been achieved in EOS-HDFN participants.Conclusions: This study demonstrates the correlation of nipocalimab PK and FcRn RO with reduction in total IgG and alloantibodies, as well as with clinical efficacy and safety endpoints. These relationships inform the appropriate dose regimen for evaluation in the pivotal Phase 3 study in EOS-HDFN.Disclosures: JZ, JHL, YX, EL, LEL, UA, WS, SSK, AM, YK, JW, KK, RRC, AV are employees of Janssen and may hold stock/stock options from Johnson & Johnson.Encore Information: the results in this abstract have been previously presented in part at [Society for Maternal Fetal Medicine (SMFM) Pregnancy Meeting; National Harbor, Maryland; February 10-14, 2024] and published in the conference proceedings as abstract [232], as well as on American Journal of Obstetrics Gynecology volume 230, issue 1, supplement, S138, January, 2024, DOI:https://doi.org/10.1016/j.ajog.2023.11.254Citations: n/a
BIOMASSANI QAYTA ISHLASH ORQALI ENERGETIK JIHATDAN QIMMATLI MAHSULOTLARGA AYLANTIRISH TEXNOLOGIYALARI
Authors: Xoliqov Komil Nurmahmatovich
Published: February 2025

The density of briquetted biomass is nearly 6 times higher than the original bulk density of the biomass. The available methods for processing products include thermo-chemical, physico-chemical, and biological methods. The "cold" briquetting process of raw biomass often requires the addition of a binder. The pyrolysis method is effectively used to improve the consumer properties of the finished solid briquetted or granulated fuel obtained from biomass. High temperatures up to 2000°C are applied in gasification in the flow. Due to the simplicity of the equipment and relatively low energy consumption, the main share (about 75%) is used for producing solid biomass fuels. The main types of biomass used in pyrolysis processes are wood chips and organic waste. After grinding the obtained wood charcoal, pyrolyzed pellets are produced from it. Another advantage of using plant biomass for pyrolysis is that it contains lignin.
Word formation processes in English translation of Surah Ar-Rahman by Abdullah Yusuf Ali
Authors: Nazir Adnan , Masood Muhammad Hamzah , Arshad Rubab
Published: February 2025

The aim of this study is to identify the different types of word formation from the English translated version of the Surah Ar-Rahman by Abdullah Yusuf Ali. By using O'Grady and Archibald (2016) theory and adopting a mixed-method approach, Surah Ar-Rahman was analyzed qualitatively and quantitatively. A total of five types of word formation processes were found. The researchers found 58 inflections, 14 derivations, 8 loan words, 5 compound words, and 3 instances of suppletion. Apart from that, no other word formation process was found. This indicates, the translator, while translating, used different languages to convey the actual essence of the Arabic words. This implies that the translator employed various techniques in order to accurately present the message of the source text into the intended language. In translation, the translator employed suppletion by using other words or other forms of words entirely in place of those which did not have direct counterparts in the target language. This paper will be highly beneficial to specialists and researchers whose focus is on religious texts translation as well as language specialists interested in morphology of translation.
Import of counterfeited products versus enforcement of intellectual property rights in Pakistan
Authors: Saleem Mughal Shehla , Liaqat Baig Zaheer
Published: February 2025

Protection of intellectual property rights is a great concern in the modern economies and its scope has increased from national to global level. Pakistan Customs service has transformed itself to protect national frontiers against the violations of Intellectual property rights at the import and export stage of the goods to play its dynamic role in socioeconomic development of the country. Previously conducted research on the intellectual property rights did not address the role of Pakistan Custom Service adequately. This article tried to fill in the gaps by highlighting the role of Pakistan Customs Service in countering the violations of the Intellectual property rights. This study is conducted by employing qualitative research method. Officials of Pakistan customs service perform their duties under certain prevalent laws for the enforcement of intellectual property rights. But like all other public organization Pakistan customs also face some challenges and limitation in the performance of their duties. However these challenges can be addressed through effective awareness campaigns and amending the existing legislature to cater the changing needs of the intellectual property rights violations.
Intelligent Inventory Management System: Innovation and Implementation of Restaurant Food Management
Authors: Li Donghui
Published: February 2025

This paper aims to design and implement an advanced intelligent inventory management system for restaurants, optimizing the ingredient management process to ensure food safety and provide healthier dining options for customers. In the context of frequent concerns about food safety, a system capable of precisely monitoring the quality and shelf life of ingredients is particularly important. By reducing the use of expired and contaminated ingredients, such a system not only helps prevent food-borne illnesses but also reduces food waste by optimizing storage and usage, thereby lowering operational costs and environmental impact. Additionally, intelligent inventory management can assist restaurants in offering dishes that meet health standards, enhancing consumer trust and improving the restaurant’s brand image. Implementing this system not only aids in improving the operational efficiency of restaurants but also underscores the critical role of technology in maintaining public health and promoting a culture of healthy eating.
New thiosemicarbazones possessing activity against SARS-CoV-2 and H1N1 influenza viruses
Authors: Zhupikova Olga A. , Yarovaya Olga Ivanovna , Marenina Mariya K. , Meshkova Yulia V. , Belenkaya Svetlana V. , Shcherbakov Dmitriy N. , Zaykovskaya Anna V. , Pyankov Oleg V. , Zarubaev Vladimir V. , Mikhalsky Mikhail G. , Fedorov Alexey Yu. , Arkhipov Sergey G. , Potkin Vladimir Ivanovich , Kolesnik Irina A. , Ivanov Andrey Viktorovich , Salakhutdinov Nariman Faridovich , Khvostov Mikhail V.
Published: February 2025

New thiosemicarbazones based on 5-arylisoxazole-3-carbaldehyde and substituted pyrrolecarbaldehydes have been obtained. The test for ability to inhibit the main viral protease 3Clpro of SARS-CoV-2 virus revealed a compound with activity against both corona- and influenza viruses.
Selective hydrogenation of nitrobenzene to aniline over LaNiO3
Authors: Tkachenko Olga P. , Shuvalova Elena Vladimirovna , Zemlianskii Petr Vital'evich , Davshan Nikolay A , Kustov Leonid Modestovich
Published: February 2025

Perovskite LaNiO3 prepared by the glycine-nitrate method was studied by XPS, XRD and SEM-EDS. This substance was tested as the catalyst in the hydrogenation of nitrobenzene to aniline in ethanol (150 °C, 1.5 MPa H2). The selectivity for aniline was 95.6
Significant impact of 3-positioned substituent on the fluorescent properties of 5-hydroxyisoquinolones
Authors: Belyy Alexander Yu , Sokolova Alena D , Salikov Rinat Faritovich , Trainov Konstantin P , Platonov Dmitry Nikolaevich , Tomilov Yury Vasil'evich
Published: February 2025

Fluorescent properties of 5-hydroxyisoquinolone-3,4,6,7,8- pentacarboxylates and their 4,6,7,8-tetracarboxylate analogs lacking a 3-positioned electron-withdrawing ester group differ substantially. The presence of an electron-withdrawing group at position 3 in the 5-hydroxyisoquinolone system was found crucial for their vibrational relaxation in the anionic forms, which highlights the importance of substitution pattern providing valuable insights for future research in this area.
Extraordinary sulfur/oxygen exchange between P=S and C=O bonds during the reaction of γ-amino ynones ketones with secondary phosphine sulfides
Authors: Volkov Pavel Anatol'evich , Verkhoturova Svetlana Il'yasovna , Arbuzova Svetlana Nikolaevna , Khrapova Kseniya O. , Bidusenko Ivan A. , Zinchenko Sergei V , Trofimov Boris Aleksandrovich
Published: February 2025

Unknown reactivity patterns of P=S and C=O bonds were observed when γ-amino α, β-ynones reacted with secondary phosphine sulfides affording, instead of the addition/ cyclization products, 1,2-dihydro-3H-pyrrole-3-thiones and the corresponding secondary phosphine oxides. The reaction mechanism involves the sulfur/oxygen exchange between the P=S and C=O functions. This is the first case of the successful competition between the P=S and P-H moieties as nucleophiles for electrophilic triple bond.
Synthesis, HPLC isolation and structural characterization of three new C60(CF3)18 isomers
Authors: Tamm Nadezhda Borisovna , Markov Vitaliy Yuryevich , Troyanov Sergey Igorevich
Published: February 2025

Three new C60(CF3)18 isomers have been synthesized by high-temperature trifluoromethylation of [60]fullerene with gaseous CF3I, isolated by HPLC, and structurally characterized by single crystal X-ray diffraction using synchrotron radiation.
Polyfluorinated Blatter radicals
Authors: Gulyaev Dmitry A. , Gadimov Nurlan V. , Gritsan Nina Pavlovna , Kadilenko Evgeny M. , Shangin Pavel G , Syroeshkin Mikhail Aleksandrovich , Sosunov Egor A , Tretyakov Eugene Viktorovich
Published: February 2025

The first benzotriazinyl radicals containing fluorine atoms in both aryl substituents were synthesized from polyfluorophenylhydrazines and 4-fluoro-N-phenylbenzimidoyl chloride. Their crystal structure and magnetic properties were studied thus revealing strong antiferromagnetic interactions (J/kB from -160 to -185 K).
The impact of the judgment in Case C-211/22 Super Bock on the assessment of vertical pricing agreements
Authors: Kanton Krzysztof
Published: February 2025

The article discusses the impact of the judgment of the Court of Justice of the European Union (CJEU) in the Super Bock case (C-211/22) on the assessment of vertical pricing agreements under EU competition law. The judgment underscores the need to apply an economic approach when assessing whether an agreement, which provides for the setting of fixed or minimum resale prices, constitutes a restriction of competition ‘by object’. In this judgment, the CJEU rejects the previous formalistic approach – present in the practice of the EC and NCAs – which automatically qualified RPMs as anti-competitive, without analyzing its economic and legal context. The article also analyzes the practical implications of the judgment for NCAs, including the President of UOKiK.