CPT: Pharmacometrics & Systems Pharmacology最新文献_第2页

Population Pharmacokinetic Modeling and Pediatric Exposure of Dexamethasone Sodium Phosphate Encapsulated in Erythrocytes (eDSP) Administered Monthly for Treatment of Neurological Symptoms of Patients With Ataxia Telangiectasia. 红细胞包封地塞米松磷酸钠（eDSP）治疗共济失调毛细血管扩张患者神经系统症状的人群药代动力学模型和儿童暴露

IF 3 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-09-22 DOI: 10.1002/psp4.70103

Deniz Ozdin, Leila Kheibarshekan, Giovanni Mambrini, Pierre-Olivier Tremblay

{"title":"Population Pharmacokinetic Modeling and Pediatric Exposure of Dexamethasone Sodium Phosphate Encapsulated in Erythrocytes (eDSP) Administered Monthly for Treatment of Neurological Symptoms of Patients With Ataxia Telangiectasia.","authors":"Deniz Ozdin, Leila Kheibarshekan, Giovanni Mambrini, Pierre-Olivier Tremblay","doi":"10.1002/psp4.70103","DOIUrl":"https://doi.org/10.1002/psp4.70103","url":null,"abstract":"The EryDex System (EDS) is a drug/device combination, which has been tested in clinical trials for ataxia telangiectasia (AT). EDS encapsulates dexamethasone sodium phosphate (DSP) solution in autologous erythrocytes at the point of care, and encapsulated DSP (eDSP) is infused back into the patient. Low doses of dexamethasone are released from erythrocytes over a 30-day period. This study aimed to (1) characterize the pharmacokinetics (PK) of dexamethasone released from intravenously infused eDSP based on data collected in clinical trials of healthy adults and pediatric AT patients, and to (2) simulate and extrapolate exposure measures of dexamethasone following intravenous infusion of eDSP administered once per month over 6 months in a pediatric population. The population PK model was developed using dense PK data from a phase 1 study in healthy adults and sparse PK data from a phase 3 study in pediatric AT patients. Three dose levels were studied, and the overall PK population included 24 healthy adults and 109 AT patients. The PK of dexamethasone released from eDSP was described using a simplified two-compartment model, adequate for estimating systemic exposure despite not fully capturing RBC release kinetics indicative of a triphasic pattern. The model showed a good fit, and future refinement will include mechanistic release modeling as more in vitro and in vivo data become available. Monte Carlo simulations of eDSP showed a rapid peak at 0.67 h, followed by sustained dexamethasone release; faster in the first 24 h, then slower over 20-30 days. No accumulation occurred with once-monthly dosing.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124299","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 Dose-Aware Model for Revealing Dose-Risk Relationship of Drug-Drug Interaction. 揭示药物-药物相互作用剂量-风险关系的剂量感知模型。

IF 3 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-09-18 DOI: 10.1002/psp4.70114

Yi Shi, Anna Sun, Yuedi Yang, Hongmei Nan, Jing Xu, Mu Shan, Michael T Eadon, Jing Su, Pengyue Zhang

引用次数: 0

Nipocalimab Dose Selection in Generalized Myasthenia Gravis. 尼波卡利单抗治疗广泛性重症肌无力的剂量选择。

IF 3 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-09-17 DOI: 10.1002/psp4.70109

Belén Valenzuela, Martine Neyens, Yaowei Zhu, Sindhu Ramchandren, Anne-Gaëlle Dosne, Jocelyn H Leu, Ruben Faelens, Leona E Ling, Juan-José Pérez-Ruixo

{"title":"Nipocalimab Dose Selection in Generalized Myasthenia Gravis.","authors":"Belén Valenzuela, Martine Neyens, Yaowei Zhu, Sindhu Ramchandren, Anne-Gaëlle Dosne, Jocelyn H Leu, Ruben Faelens, Leona E Ling, Juan-José Pérez-Ruixo","doi":"10.1002/psp4.70109","DOIUrl":"https://doi.org/10.1002/psp4.70109","url":null,"abstract":"Nipocalimab is a fully human immunoglobulin G (IgG)1 monoclonal antibody (mAb) designed to selectively block the IgG binding site of neonatal fragment crystallizable receptor (FcRn) to inhibit IgG recycling and decrease circulating IgG, including pathogenic IgG autoantibodies (such as antiacetylcholine receptor, anti-muscle-specific kinase, and anti-low-density lipoprotein-related protein 4 antibodies in generalized myasthenia gravis [gMG]). A mechanistic model, integrating serum nipocalimab concentrations, FcRn occupancy, and total serum IgG data from five phase 1 studies in healthy adult participants and one phase 2 (Vivacity-MG) study in adult participants with gMG, was developed. The relationship between total serum IgG reduction and placebo-corrected MG-Activities of Daily Living score change from baseline in participants with gMG was also characterized. Nipocalimab exhibited nonlinear target (FcRn)-mediated disposition, causing rapid, reversible, and concentration-dependent FcRn occupancy and IgG reduction (up to 85%) in healthy participants and participants with gMG. The PK of nipocalimab after a single intravenous (IV) administration is consistent with that after repeated IV administrations, with no accumulation following every 2 weeks (Q2W) dosing. The PK of nipocalimab and its effect on IgG reduction were similar between healthy participants and participants with gMG. Model-based simulations indicated that the IV dose of 15 mg/kg Q2W, starting 2 weeks after a 30 mg/kg IV loading dose, was the lowest Q2W maintenance dose predicted to achieve the target of 70% median of the average change in IgG reduction in participants with gMG and was the recommended dose for the pivotal phase 3 Vivacity-MG3 study in a gMG population.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074631","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

QPRapp: A Web-Based Platform for PK/PD Simulations and Early Feasibility Analysis. QPRapp：基于web的PK/PD模拟与早期可行性分析平台。

IF 3 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-09-15 DOI: 10.1002/psp4.70107

Saroj Dhakal, Yorgos M Psarellis, Nikhil Pillai, Panteleimon D Mavroudis

{"title":"QPRapp: A Web-Based Platform for PK/PD Simulations and Early Feasibility Analysis.","authors":"Saroj Dhakal, Yorgos M Psarellis, Nikhil Pillai, Panteleimon D Mavroudis","doi":"10.1002/psp4.70107","DOIUrl":"https://doi.org/10.1002/psp4.70107","url":null,"abstract":"Quantitative pharmacology research application (QPRapp) is a web-based, interactive, and easy to use Shiny for Python interface, which facilitates evaluation of dose-exposure relationships, pharmacokinetic/pharmacodynamic (PK/PD) assessment of small and large molecules, and calculation of target occupancy for mono-, bi-, and tri-specific molecules. The dashboard sidebar offers a streamlined approach that incorporates multiple inputs, with various drop-down options to conduct respective simulations. The user can specify the type of molecule (small or large), number of model's compartments (one or two), and for large molecules, the number of drug's targets (one, two, or three). Additionally, the user can choose among the four indirect response PD models and execute the corresponding PK/PD simulations for small molecules. The platform application allows users to easily export simulated scenarios as CSV files for further analysis. Boasting features such as target-mediated drug disposition (TMDD) and early feasibility analysis (EFA) for multi-specific molecules, this application can assist project teams with limited computational expertise in applying model-informed drug development (MIDD) during the early stages of drug discovery and development.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069242","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

Modeling and Simulation Identifies Endocytosis Uptake Rate and Fraction Unbound as Important Predictors of Oligonucleotide Pharmacokinetics. 模型和模拟确定内吞摄取速率和未结合分数是寡核苷酸药代动力学的重要预测因子。

IF 3 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-09-10 DOI: 10.1002/psp4.70108

Felix Stader, Abdallah Derbalah, Adriana Zyla, Cong Liu, Iain Gardner, Armin Sepp

{"title":"Modeling and Simulation Identifies Endocytosis Uptake Rate and Fraction Unbound as Important Predictors of Oligonucleotide Pharmacokinetics.","authors":"Felix Stader, Abdallah Derbalah, Adriana Zyla, Cong Liu, Iain Gardner, Armin Sepp","doi":"10.1002/psp4.70108","DOIUrl":"https://doi.org/10.1002/psp4.70108","url":null,"abstract":"Therapeutic oligonucleotides (TOs) represent an emerging modality, which offers a promising alternative treatment option, particularly for intracellular targets. The two types of TOs, antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs), distribute highly into tissues, especially into the liver and the kidneys. However, molecular processes at the cellular level such as the uptake into the cell, endosomal escape, binding to the target mRNA, and redistribution back to the systemic circulation are not well characterized because experimental data and assays are lacking. We developed a whole-body PBPK model for TOs and verified the predictive performance against clinically observed data for three ASOs and five siRNAs. The predicted concentration-time profiles were in accordance with the clinically observed data for all investigated TOs, and all pharmacokinetic parameters were predicted within twofold. Sensitivity analysis with the evaluated PBPK model revealed that the endocytosis uptake rate and the fraction unbound in plasma impact the peak concentration (Cmax), time to Cmax (tmax), and the area under the curve (AUC) of a subcutaneously administered ASO, whereas the redistribution rate and the nuclease clearance had minor to no impact. The mathematical model can guide the development of required in vitro assays for key parameters to better understand the pharmacokinetics of TOs. PBPK models, parameterized with reliable in vitro data, could be used in the future to predict the pharmacokinetics in special populations with limited clinical data to ensure a safe and effective therapy.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029204","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

Response to "Enhance Multistate Models With Clinically Meaningful Graphs". 对“用临床有意义的图形增强多状态模型”的回应。

IF 3 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-09-05 DOI: 10.1002/psp4.70111

Moustafa M A Ibrahim, Maria C Kjellsson, Mats O Karlsson

引用次数: 0

Enhance Multistate Models With Clinically Meaningful Graphs. 用临床有意义的图形增强多状态模型。

IF 3 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-09-05 DOI: 10.1002/psp4.70110

Joachim Grevel

引用次数: 0

Rosuvastatin PBPK Modeling: Incorporating Liver Concentrations and Effects of Ethnicity, Genetic Polymorphisms, Lactone Formation, DDI and Pregnancy. 瑞舒伐他汀PBPK模型：结合肝脏浓度和种族、遗传多态性、内酯形成、DDI和妊娠的影响。

IF 3 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-08-25 DOI: 10.1002/psp4.70097

Ankit Balhara, Robert H Weber, Jashvant D Unadkat

{"title":"Rosuvastatin PBPK Modeling: Incorporating Liver Concentrations and Effects of Ethnicity, Genetic Polymorphisms, Lactone Formation, DDI and Pregnancy.","authors":"Ankit Balhara, Robert H Weber, Jashvant D Unadkat","doi":"10.1002/psp4.70097","DOIUrl":"https://doi.org/10.1002/psp4.70097","url":null,"abstract":"Rosuvastatin (RSV), a potent HMG-CoA reductase inhibitor, is widely used for the management of hyperlipidemia and prevention of cardiovascular disease. Its absorption and disposition are primarily transporter-mediated, involving intestinal absorption by OATP2B1 and efflux by BCRP; hepatic uptake by OATP1B1, OATP1B3, OATP2B1, and NTCP; and biliary excretion by BCRP and MRP2. Given its minimal metabolism, RSV serves as a model substrate for transporter-based drug absorption, disposition, and DDI studies. We developed and verified a PBPK model of RSV using a middle-out approach, incorporating extensive in vitro and in vivo data. The model was verified with > 75 datasets, including plasma and hepatic RSV concentrations from PET imaging studies. The model successfully captured RSV PK profiles in the Caucasian, Chinese, Malay, Japanese, and Korean populations. It also accurately captured the interconversion of RSV and RSV-lactone, changes in RSV PK due to OATP1B1 and BCRP polymorphisms, and DDI with rifampin or cyclosporine. Sensitivity analyses revealed that reduced hepatic OATP1B1 activity and/or intestinal BCRP efflux are likely determinants of altered RSV PK in the third trimester. Compared to previous models, our model extensively incorporates genetic polymorphisms, ethnic variability, reversible metabolism to the lactone, DDI, and pregnancy, allowing its use in the future to facilitate RSV dose optimization in multiple populations, including pregnant individuals.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945921","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

Model-Informed Drug Development for Ligelizumab in Patients With Chronic Spontaneous Urticaria. 慢性自发性荨麻疹患者利利珠单抗的模型知情药物开发。

IF 3 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-08-23 DOI: 10.1002/psp4.70098

Andrzej Bienczak, Aurelie Gautier, Eva Hua, Yan Ji, Emil Scosyrev, Serge Smeets, Thomas Severin, Anton Drollmann, Manmath Patekar, Marina Savelieva

{"title":"Model-Informed Drug Development for Ligelizumab in Patients With Chronic Spontaneous Urticaria.","authors":"Andrzej Bienczak, Aurelie Gautier, Eva Hua, Yan Ji, Emil Scosyrev, Serge Smeets, Thomas Severin, Anton Drollmann, Manmath Patekar, Marina Savelieva","doi":"10.1002/psp4.70098","DOIUrl":"https://doi.org/10.1002/psp4.70098","url":null,"abstract":"Model-informed drug development (MIDD) has been increasingly applied to guide decision-making, ameliorate efficiency, and enhance the likelihood of successful trials. The development of ligelizumab, a humanized anti-IgE monoclonal antibody, in chronic spontaneous urticaria (CSU) illustrated how MIDD can be applied to support central aspects of drug development, such as dose selection and trial design, pediatric drug development and extrapolation, generation of evidence to support potential labeling, optimizing treatment outcomes, and enhancing patient access. In this manuscript, we provide an overview of the key modeling and simulation analyses that were part of the MIDD approach for the development of ligelizumab in CSU and how they were staggered around the availability of interim and final data from the Phase 2 and Phase 3 studies. Furthermore, we present details of the non-linear mixed-effects models characterizing the population pharmacokinetics and exposure-response relationship of ligelizumab for efficacy in adolescent and adult patients with CSU.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945893","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

Population Pharmacokinetic Model of Pegbing in Healthy Subjects and Chronic Hepatitis B Patients. Pegbing在健康人群和慢性乙型肝炎患者中的人群药代动力学模型。

IF 3 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-08-21 DOI: 10.1002/psp4.70104

Weizhe Jian, Yalin Yin, Rong Chen, Pingyao Luo, Tianyu Wang, Jianbo Gu, Zhengfang Du, Lei Cai, Tianyu Bao, Junsheng Xue, Ruoyi He, Tianyan Zhou

{"title":"Population Pharmacokinetic Model of Pegbing in Healthy Subjects and Chronic Hepatitis B Patients.","authors":"Weizhe Jian, Yalin Yin, Rong Chen, Pingyao Luo, Tianyu Wang, Jianbo Gu, Zhengfang Du, Lei Cai, Tianyu Bao, Junsheng Xue, Ruoyi He, Tianyan Zhou","doi":"10.1002/psp4.70104","DOIUrl":"https://doi.org/10.1002/psp4.70104","url":null,"abstract":"Pegbing (peginterferon alpha-2b) is a polyethylene glycol-modified interferon α-2b injection that has demonstrated favorable efficacy and safety profiles in the treatment of chronic hepatitis B (CHB). This study aimed to develop a population pharmacokinetic (PopPK) model of Pegbing in both healthy subjects and CHB patients and to investigate the influence of covariates on its pharmacokinetic behavior. Pharmacokinetic data were obtained from a Phase I trial in healthy volunteers and a Phase II trial in CHB patients. A one-compartment model with a target-mediated drug disposition (TMDD) component incorporating IFN receptor downregulation was established to describe the pooled data from 28 healthy subjects and 39 CHB patients. Physiologically reasonable parameters were estimated, providing a good description and prediction of the model. Furthermore, the final PopPK model was externally validated using an independent dataset of 115 CHB patients. In the covariate analysis, health status (healthy v.s. CHB) was a significant covariate, affecting the Pegbing absorption rate, creatinine clearance was associated with clearance, and body weight affected the volume of distribution. Compared with healthy subjects, CHB patients exhibited a consistent area under the curve (AUC) but a higher Cmax. A PopPK model of Pegbing in both healthy volunteers and CHB patients was successfully established. Based on the model simulation, covariate-based dose adjustment is unnecessary for CHB patients with normal renal function.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945937","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