CPT: Pharmacometrics & Systems Pharmacology最新文献_第3页

A Quantitative Systems Pharmacology Model That Describes Neurofilament Light Dynamics During Alzheimer's Disease Progression. 描述阿尔茨海默病进展过程中神经丝光动力学的定量系统药理学模型。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-17 DOI: 10.1002/psp4.70062

Polina Maliukova, Tatiana Karelina

{"title":"A Quantitative Systems Pharmacology Model That Describes Neurofilament Light Dynamics During Alzheimer's Disease Progression.","authors":"Polina Maliukova, Tatiana Karelina","doi":"10.1002/psp4.70062","DOIUrl":"https://doi.org/10.1002/psp4.70062","url":null,"abstract":"Neurofilament proteins are important constituents of neuronal cytoskeleton, along with microtubules. An increased concentration of neurofilament light (NfL) protein in cerebrospinal fluid (CSF) and plasma is considered a potential biomarker of axonal degeneration, which occurs in various neurodegenerative diseases including Alzheimer's disease (AD). The goal of this study was to develop a QSP model describing the change in the concentration of NfL in the brain, CSF, and plasma during the progression of AD for populations of AD patients manifesting different combinations of biomarkers (amyloid, tau, brain atrophy), to estimate the contributions of different mechanisms to neurodegeneration. The model correctly describes the dynamics of neurofilament proteins during neurodegeneration processes, which depend on cytoskeletal degradation and the release of neurofilament proteins from degenerated axons into cerebrospinal fluid and plasma. These processes are driven by disruptions of neuron homeostasis in AD, such as changes in protein degradation, axonal transport deficits, and the accumulation of pathological amyloid and hyperphosphorylated tau. The model was validated against clinical data and demonstrated correct predictions for anti-tau therapy while showing a tendency to overestimate efficacy of anti-amyloid therapy (lecanemab). This supports the idea that amyloid therapy contribution to neurodegeneration is limited, and that treatment should focus on other mechanisms.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of Four Semi-Mechanistic Models for Predicting Glycemic Control With a Glucagon Receptor Antagonist in People With Type 2 Diabetes. 预测2型糖尿病患者胰高血糖素受体拮抗剂血糖控制的四种半机制模型的评价

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-17 DOI: 10.1002/psp4.70058

Austin Yue Feng Tan, Karen Schneck, Parag Garhyan, Eric Chun Yong Chan, Lai San Tham

{"title":"Evaluation of Four Semi-Mechanistic Models for Predicting Glycemic Control With a Glucagon Receptor Antagonist in People With Type 2 Diabetes.","authors":"Austin Yue Feng Tan, Karen Schneck, Parag Garhyan, Eric Chun Yong Chan, Lai San Tham","doi":"10.1002/psp4.70058","DOIUrl":"https://doi.org/10.1002/psp4.70058","url":null,"abstract":"Glycated hemoglobin (HbA1c) is the gold standard for measuring long-term glycemic efficacy over at least 3 months in Type 2 diabetes (T2D). Being able to predict HbA1c using glucose response from studies of less than 3 months would be useful. Four semi-mechanistic HbA1c models (ADOPT, FFH, FHH, and IGRH) were evaluated for their predictive performance of longer-term HbA1c at 24 weeks of treatment using glucose and HbA1c data up to 4 weeks of treatment. A novel glucagon receptor antagonist (LY2409021) was evaluated in T2D patients for glycemic control. The models were built using LY2409021 pharmacokinetics, glucose, and HbA1c data from a 4-week Phase 1b study. Predictive performance of the models was assessed based on comparing model-estimated and observed HbA1c values from a 24-week Phase 2b study. Metrics for predictive performance included: (a) mean change from baseline HbA1c (ΔHbA1c) at Week 24 between observed and simulated values; (b) mean prediction error (MPE) for bias; and (c) root mean squared error (RMSE) for precision. Overall, the FHH and IGRH models closely predicted the mean ΔHbA1c at Week 24 within 0.1% difference from the observed values in the Phase 2b study. Both models also had reasonable bias (absolute MPE < 0.1%) and precision (RMSE < 0.3%) estimates. Conversely, the ADOPT and FFH models over-predicted the mean reduction in HbA1c by 0.288% and 0.153%, respectively. The FHH and IGRH models featured transit compartments for modeling long delays between glucose and HbA1c. Thus, these models better represented the physiology and provided superior predictive performance.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tutorial for Modeling Delays in Biological Systems in the NONMEM Software 在NONMEM软件中建模生物系统中的延迟教程。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-16 DOI: 10.1002/psp4.70046

Robert J. Bauer, Wojciech Krzyzanski

{"title":"Tutorial for Modeling Delays in Biological Systems in the NONMEM Software","authors":"Robert J. Bauer, Wojciech Krzyzanski","doi":"10.1002/psp4.70046","DOIUrl":"10.1002/psp4.70046","url":null,"abstract":"Delays in biological systems are a common phenomenon. The models for delays require specialized mathematical and numerical techniques such as transit compartments, delay differential equations (DDEs), and distributed DDEs (DDDEs). Because of mathematical complexity, DDEs and particularly DDDEs are infrequently used for modeling. DDEs are supported by most pharmacometric programs. Recently, DDDEs have been implemented in NONMEM that greatly improve the applicability of this technique in pharmacokinetic and pharmacodynamic (PKPD) modeling. The objective of this tutorial is to provide examples of PKPD models with delays and demonstrate how to implement them in NONMEM. All examples provide a brief description of the biology and pharmacology underlying model equations, explain how they are coded in the NONMEM control stream, and discuss results of data analysis models were used for. NONMEM codes for all models are presented in supporting information (Data S1). The tutorial concludes with a discussion of the pros and cons of presented delay modeling techniques with guidelines for which one might be preferred given the nature of the delay, available data, and the task to be performed.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"14 7","pages":"1133-1155"},"PeriodicalIF":3.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Viral Dynamic Models During COVID-19: Are We Ready for the Next Pandemic? COVID-19期间的病毒动态模型：我们为下一次大流行做好准备了吗？

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-02 DOI: 10.1002/psp4.70055

Aurelien Marc, Joshua T Schiffer, France Mentré, Alan S Perelson, Jérémie Guedj

引用次数: 0

Population Pharmacokinetics and Exposure-Response Relationship of Hemoporfin in Pediatric Patients With Port-Wine Stain. 儿童波特酒染色患者血红蛋白的人群药动学及暴露-反应关系。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-05-30 DOI: 10.1002/psp4.70050

Rong Chen, Bin Zhang, Jining Tao, Qingyu Yao, Tianyan Zhou, Lin Ma, Zigang Xu

{"title":"Population Pharmacokinetics and Exposure-Response Relationship of Hemoporfin in Pediatric Patients With Port-Wine Stain.","authors":"Rong Chen, Bin Zhang, Jining Tao, Qingyu Yao, Tianyan Zhou, Lin Ma, Zigang Xu","doi":"10.1002/psp4.70050","DOIUrl":"https://doi.org/10.1002/psp4.70050","url":null,"abstract":"Hemoporfin, a porphyrin derivative photosensitizer, has been approved for the treatment of port-wine stain (PWS) in adults. However, its optimal dose for the pediatric population remains unclear. This study aimed to explore appropriate dosing for pediatric patients with PWS through population pharmacokinetics (PopPK) and exposure-response (ER) analysis. Data from a prospective pilot study of hemoporfin photodynamic therapy in pediatric PWS patients, as well as a phase I study in healthy adult volunteers, were utilized for the analysis. The pharmacokinetics of hemoporfin in the pediatric population can be described by a three-compartment model with linear elimination following allometric scaling rules. Simulations indicated that simply scaling down the approved adult dose of 5 mg/kg based on weight for the pediatric population, which is a common practice among clinicians, may lead to reduced drug exposure in pediatric patients. Mean Cmax and AUC0-30min in pediatric patients were 18.7% and 30.5% lower than those in adults, respectively. A positive relationship was identified between AUC0-30min and the probability of investigators or patients giving high ratings for efficacy, suggesting that improved efficacy may be achieved with higher hemoporfin exposure. A series of dosing regimens were explored to match exposure in the pediatric population to that of the adult population. These findings may accelerate the development of pediatric indications for hemoporfin and help address the unmet medical needs of pediatric patients with PWS.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Examining the Reliability of Model-Based Meta-Analysis (MBMA) Outcomes: A Simulation Study. 基于模型的meta分析（MBMA）结果的可靠性检验：一项模拟研究。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-05-29 DOI: 10.1002/psp4.70053

Jiesen Yu, Ting Li, Jieren Luo, Qingshan Zheng, Lujin Li

{"title":"Examining the Reliability of Model-Based Meta-Analysis (MBMA) Outcomes: A Simulation Study.","authors":"Jiesen Yu, Ting Li, Jieren Luo, Qingshan Zheng, Lujin Li","doi":"10.1002/psp4.70053","DOIUrl":"https://doi.org/10.1002/psp4.70053","url":null,"abstract":"Model-based meta-analysis (MBMA) can be utilized to synthesize literature data and predict drug efficacy, particularly suitable for constructing external comparator arms for non-randomized controlled trials (NRCTs). This study evaluated the reliability of MBMA by comparing covariate models generated through MBMA to individual patient data. A pharmacodynamic covariate model, commonly employed in MBMA, was used to set true parameter values and simulate data across various scenarios. The reliability of MBMA models was assessed by comparing estimated to true parameter values and identifying optimal conditions for MBMA use. Linear and nonlinear covariate models were evaluated in 24 scenarios, focusing on the relative deviations of parameter estimates from their true values. Evaluation metrics included minimization successful rate, covariate introduction rate, and the accuracy of parameters such as Emax, ET50, and covariate influences. Both model types showed similar reliability in most scenarios. Notably, model performance significantly improved when the number of included trials was 10 or more, the distribution of covariates exceeded 66.6% of its median, and the covariate impact coefficient was greater than 0.15. The study identified critical factors and thresholds that influence the accuracy of MBMA modeling. Enhanced accuracy in synthetic control analysis using MBMA was achieved under specified conditions, highlighting the effectiveness of MBMA in NRCT applications.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Multiple Imputation Workflow for Handling Missing Covariate Data in Pharmacometrics Modeling 在药物计量学建模中处理缺失协变量数据的多重输入工作流。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-05-29 DOI: 10.1002/psp4.70039

My-Luong Vuong, Geert Verbeke, Erwin Dreesen

{"title":"A Multiple Imputation Workflow for Handling Missing Covariate Data in Pharmacometrics Modeling","authors":"My-Luong Vuong, Geert Verbeke, Erwin Dreesen","doi":"10.1002/psp4.70039","DOIUrl":"10.1002/psp4.70039","url":null,"abstract":"Covariate missingness is a prevalent issue in pharmacometrics modeling. Incorrect handling of missing covariates can lead to biased parameter estimates, adversely affecting clinical practice and drug development dosing decisions. Single imputation is usually favored by pharmacometricians for its simplicity, but it ignores the uncertainty about imputed values, potentially leading to biased estimates and standard errors. Multiple imputation, in contrast, generates multiple plausible values from a predictive distribution, addressing this uncertainty and thus is a preferable approach over single imputation to handle covariate missingness. Yet, its application in pharmacometrics remains limited due to perceived complexity. To address this, we developed a multiple imputation workflow specifically tailored for pharmacometricians, encouraging wider adoption of this more reliable method in pharmacometrics modeling. We compared single imputation and multiple imputation in estimating covariate effects using a publicly available dataset on warfarin pharmacokinetics in healthy volunteers. A one-compartment population pharmacokinetic model with baseline body weight as the only covariate was used to describe the warfarin pharmacokinetics. We simulated five scenarios in which 6.25%, 12.5%, 25%, 50%, and 75% of the subjects had their body weight missing under a missing at random mechanism conditioned on age and sex. We confirm that multiple imputation better reflects uncertainty estimates than single imputation, regardless of the degree of missingness. This confirms multiple imputation as a superior alternative to single imputation for handling missing covariate data in pharmacometrics.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"14 6","pages":"991-1005"},"PeriodicalIF":3.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Target-Mediated Drug Disposition (TMDD) Revisited: High Versus Low-Affinity Approximations of the TMDD Model 靶介导药物处置（TMDD）再访：TMDD模型的高亲和力与低亲和力近似。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-05-27 DOI: 10.1002/psp4.70048

Ronny Straube

引用次数: 0

A Multiscale Quantitative Systems Pharmacology Model for the Development and Optimization of mRNA Vaccines mRNA疫苗开发与优化的多尺度定量系统药理学模型

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-05-26 DOI: 10.1002/psp4.70041

Lorenzo Dasti, Stefano Giampiccolo, Elisa Pettinà, Giada Fiandaca, Natascia Zangani, Lorena Leonardelli, Fabio De Lima Hedayioglu, Elio Campanile, Luca Marchetti

{"title":"A Multiscale Quantitative Systems Pharmacology Model for the Development and Optimization of mRNA Vaccines","authors":"Lorenzo Dasti, Stefano Giampiccolo, Elisa Pettinà, Giada Fiandaca, Natascia Zangani, Lorena Leonardelli, Fabio De Lima Hedayioglu, Elio Campanile, Luca Marchetti","doi":"10.1002/psp4.70041","DOIUrl":"10.1002/psp4.70041","url":null,"abstract":"The unprecedented effort to cope with the COVID-19 pandemic has unlocked the potential of mRNA vaccines as a powerful technology, set to become increasingly pervasive in the years to come. As in other areas of drug development, mathematical modeling is a pivotal tool to support and expedite the mRNA vaccine development process. This study introduces a Quantitative Systems Pharmacology (QSP) model that captures key immune responses following mRNA vaccine administration, encompassing both tissue-level and molecular-level events. The model mechanistically describes the biological processes from the uptake of mRNA by antigen-presenting cells at the injection site to the subsequent release of antibodies into the bloodstream. This two-layer model represents a first attempt to link the molecular mechanisms leading to antigen expression with the immune response, paving the way for the future integration of specific vaccine attributes, such as mRNA sequence features and nanotechnology-based delivery systems. Calibrated specifically for the BNT162b2 SARS-CoV-2 vaccine, the model has undergone successful validation across various dosing regimens and administration schedules. The results underscore the model's effectiveness in optimizing dosing strategies and highlighting critical differences in immune responses, particularly among low-responder groups such as the elderly. Furthermore, the model's adaptability has been demonstrated through its calibration for other mRNA vaccines, such as the Moderna mRNA-1273 vaccine, emphasizing its versatility and broad applicability in mRNA vaccine research and development.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"14 7","pages":"1213-1224"},"PeriodicalIF":3.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Establishing the Exposure-QT Relationship During Bedaquiline Treatment Using a Time-Varying Tuberculosis-Specific Correction Factor (QTcTBT) 利用时变结核特异性校正因子（QTcTBT）建立贝达喹啉治疗期间的暴露- qt关系。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-05-14 DOI: 10.1002/psp4.70047

Thanakorn Vongjarudech, Anne-Gaëlle Dosne, Bart Remmerie, Mats O. Karlsson, Elin M. Svensson

{"title":"Establishing the Exposure-QT Relationship During Bedaquiline Treatment Using a Time-Varying Tuberculosis-Specific Correction Factor (QTcTBT)","authors":"Thanakorn Vongjarudech, Anne-Gaëlle Dosne, Bart Remmerie, Mats O. Karlsson, Elin M. Svensson","doi":"10.1002/psp4.70047","DOIUrl":"10.1002/psp4.70047","url":null,"abstract":"Evaluating QT prolongation induced by anti-tuberculosis (TB) drugs in patients with active TB, who often experience tachycardia, is challenging due to the limitations of Fridericia's correction factor (QTcF) in decorrelating QTc from heart rate (HR). Previous exposure-QTcF analyses in patients with active TB were able to alleviate the limitation of QTcF but required advanced model-based methodologies, incorporating a non-drug-related, “secular” trend in the model to dissociate drug and non-drug-related effects on QT. Recently, we developed and validated a time-varying QT correction method (QTcTBT) that more accurately accounts for the HR changes during TB treatment. In the present work, using data from 429 patients with multidrug-resistant TB across two Phase IIb trials, we re-evaluated the exposure-QTc relationship for bedaquiline by applying QTcTBT instead of QTcF. Our analysis showed that when HR changes were accounted for using QTcTBT, a typical maximum M2 (bedaquiline metabolite) concentration (326 ng/mL, mean maximal concentration (Cmax) at the end of 2-week loading phase) was associated with a 7 ms QTc interval prolongation (90% CI: 5.9–8.2). This estimate closely aligns with the previously reported M2 effect of 7.9 ms (90% CI: 6.8–9.3), derived from the exposure-QTcF model. The consistency between the two methodologies further supports the use of QTcTBT for estimating the QTc prolongation effects of anti-TB drugs.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"14 7","pages":"1252-1261"},"PeriodicalIF":3.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0