CPT: Pharmacometrics & Systems Pharmacology最新文献

{"title":"Harnessing Open-Source Solutions: Insights From the First Open Systems Pharmacology (OSP) Community Conference.","authors":"André Dallmann, Denise Feick, Pavel Balazki, Salih Benamara, Rolf Burghaus, Marylore Chenel, Siak-Leng Choi, Henrik Cordes, Mariana Guimarães, Abdullah Hamadeh, Ibrahim Ince, Kathleen M Job, Tobias Kanacher, Andreas Kovar, Lars Kuepfer, Jörg Lippert, Julia Macente, Nina Nauwelaerts, Christoph Niederalt, Sheila Peters, Susana Proença, Masanobu Sato, Stephan Schaller, Jan Frederik Schlender, Annika Schneider, Erik Sjögren, Juri Solodenko, Alexander Staab, Paul Vrenken, Thomas Wendl, Wilhelmus E A de Witte, Donato Teutonico","doi":"10.1002/psp4.70028","DOIUrl":"https://doi.org/10.1002/psp4.70028","url":null,"abstract":"<p><p>In 2017, the free and open-source software Open Systems Pharmacology (OSP) was launched. Since then, OSP has evolved from a small community into a diverse network of stakeholders committed to advancing open-source solutions for model-informed drug development (MIDD). In this context, the first OSP Community Conference was hosted by Novartis in Basel, Switzerland, on October 7-8, 2024, which gathered over 100 attendees from more than 40 institutions. This perspective synthesizes key insights from the conference.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771723","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}

{"title":"Mechanistic Physiologically Based Pharmacokinetic Modeling of Dry Powder and Nebulized Formulations of Orally Inhaled TMEM16A Potentiator GDC-6988.","authors":"Rui Zhu, Ian Sorrell, Fang Ma, Miaoran Ning, Yoen-Ju Son, Gaohong She, Tom De Bruyn, Joshua Galanter, Nastya Kassir, Ryan Owen, Masoud Jamei, Iain Gardner, Yuan Chen","doi":"10.1002/psp4.70027","DOIUrl":"https://doi.org/10.1002/psp4.70027","url":null,"abstract":"<p><p>The orally inhaled route of administration for respiratory indications can maximize drug exposure to the site of action (lung) to increase efficacy while minimizing systemic exposure to achieve an improved safety profile. However, due to the difficulty of taking samples from different regions of the human lung, often only systemic pharmacokinetic (PK) samples are taken and assumed to be reflective of the lung PK of the compound, which may not always be the case. In this study, a mechanistic lung physiologically based pharmacokinetic (PBPK) model was built using a middle-out approach (i.e., combining elements of bottom-up prediction and using clinical data to inform some model parameters) to predict plasma and lung PK of an orally inhaled TMEM16A potentiator GDC-6988 in humans. The lung PBPK model accounted for lung deposition, lung and oral absorption, systemic clearance, and tissue distribution. The model was refined using data from a Phase 1b study with dry powder (DP) formulation and was also verified using data from a Phase 1 study with a nebulized (Neb) formulation. The refined model adequately captures the observed GDC-6988 plasma PK profiles in both the DP and Neb studies and allows prediction of the regional lung fluid and tissue concentrations. The sensitivity analyses showed that the systemic C_max depended on the ratio of airway to alveolar deposition, but this did not impact the AUC. This novel mechanistic lung PBPK modeling framework could be applied to predict plasma and regional lung exposure and inform the early clinical development of inhaled molecules (e.g., dose selection).</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763266","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}

{"title":"Middle-Out Physiologically Based Pharmacokinetic Modeling to Support Pediatric Dosing Recommendation for Alectinib.","authors":"Tamara van Donge, Elena Guerini, Amaury O'Jeanson, Neil Parrott, Clare Devlin, Cordula Stillhart, Nassim Djebli","doi":"10.1002/psp4.70020","DOIUrl":"https://doi.org/10.1002/psp4.70020","url":null,"abstract":"<p><p>Adult patients with anaplastic lymphoma kinase positive (ALK+) advanced non-small-cell lung cancer (NSCLC) are treated with 600 mg alectinib twice daily (BID) as first-line treatment. ALK positive solid and central nervous system (CNS) tumors are described in the pediatric population, with limited clinical data due to the rarity of the disease and challenges to determine the right dosing. This study aims to inform pediatric dose recommendations for alectinib by performing a middle-out physiologically based pharmacokinetic (PBPK) modeling approach, accounting for differences in absorption and enzyme maturation. The developed adult PBPK model is leveraging insights from two previously developed PBPK models (focusing on absorption and drug-drug interactions) and is complemented with newly generated data. The adult PBPK model is validated with pharmacokinetic data from two clinical studies in the adult population. The ratios between the predicted and observed steady-state AUC after 600 mg BID for 28 days are within the acceptable range in three different adult body weight categories (from 0.81 to 1.02). Initial pediatric dose recommendations are informed by population PK model predictions (assuming no maturation of enzymes) and aim to have similar exposure to the adult population. Intrinsic clearance values for all contributing CYP enzymes are included in the pediatric PBPK model to account for changes in enzyme maturation. The current PBPK model confirmed that the recommended alectinib doses by population PK predictions were accurate for the pediatric age range, with one exception: patients younger than 3.5 years are suggested to receive 100 mg BID, instead of 190 mg BID.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751474","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}

{"title":"Precision Medicine in Oncology: Imatinib Dosing in the Obese Cancer Population Using Virtual Clinical Trials.","authors":"Khairulanwar Burhanuddin, Afzal Mohammed, Nurul Afiqah Burhanuddin, Raj K S Badhan","doi":"10.1002/psp4.70018","DOIUrl":"https://doi.org/10.1002/psp4.70018","url":null,"abstract":"<p><p>This study investigates the impact of obesity on imatinib pharmacokinetics in cancer patients by utilizing physiologically based pharmacokinetic modeling (PBPK) and virtual clinical trial approaches and evaluates the effectiveness of therapeutic drug monitoring (TDM)-guided dose adjustment to recover the imatinib trough concentration (C_min) into the target concentration. PBPK models were validated against clinical data from lean, overweight, and obese cancer populations. Simulations revealed significant physiological differences across body-mass-index categories, including higher body surface area, liver weight, and cardiac output in obese individuals, coupled with lower CYP3A4 enzyme activity and hematocrit levels, which translated into pharmacokinetic differences. Obese patients exhibited significantly lower imatinib maximum concentration and area-under-the-curve values. C_min levels, a key determinant of therapeutic response, were consistently lower in the obese cohort, with a greater proportion of individuals falling below the subtherapeutic threshold (< 750 ng/mL); nevertheless, the differences are not statistically significant. TDM-guided dose adjustments improved C_min levels across BMI groups. For patients with C_min between 450 and 750 ng/mL, dose increases of 1.5-2.0 times effectively restored levels to the target range (750-1500 ng/mL). However, individuals with C_min < 450 ng/mL often failed to achieve therapeutic levels, suggesting limited benefit from further dose escalation and a need for alternative therapies. This study underscores the importance of PBPK modeling and TDM in tailoring imatinib therapy for obese cancer patients by addressing physiological differences and optimizing dosing strategies for better outcomes.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728837","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}

{"title":"Correction to \"Comparing Scientific Machine Learning With Population Pharmacokinetic and Classical Machine Learning Approaches for Prediction of Drug Concentrations\".","authors":"","doi":"10.1002/psp4.70024","DOIUrl":"https://doi.org/10.1002/psp4.70024","url":null,"abstract":"","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708957","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}

{"title":"Pharmacokinetic Model-Informed Precision Dosing of Natalizumab in Multiple Sclerosis.","authors":"Stefan P H van den Berg, Alyssa A Toorop, Femke Hooijberg, Gertjan Wolbink, Nivea M F Voelkner, Liza M Y Gelissen, Joep Killestein, Zoé L E van Kempen, Thomas P C Dorlo, Theo Rispens","doi":"10.1002/psp4.70014","DOIUrl":"https://doi.org/10.1002/psp4.70014","url":null,"abstract":"<p><p>Intravenous natalizumab is an effective treatment for relapsing-remitting multiple sclerosis. However, the standard treatment interval of 4 weeks may be excessive for many patients. Personalized interval extension using therapeutic drug monitoring (TDM) can result in adequate drug exposure while reducing hospital visits and healthcare costs. Here, we investigate to which extent TDM-guided personalized dosing can benefit from model-informed precision dosing (MIPD). Individual posterior PK estimates were derived using patient weight and two trough concentrations at the standard dose interval by Bayesian estimation using a newly developed population PK model. MIPD was compared to a previously deployed TDM-guided stratified personalized dosing protocol (SPD) using a decision tree to personalize dosing intervals. Accuracy (mean prediction error) of the predicted dosing intervals was 4.8% versus 24% for model-informed estimates versus decision tree, respectively, when aiming for a 10 μg/mL trough concentration, and 4.8% versus 86% when aiming for 5 μg/mL. Corresponding precision (root mean square error) was 2.3 versus 4.0, and 1.5 versus 5 μg/mL. Finally, we evaluated the feasibility of a MIPD approach to attain a therapeutic trough of 2 μg/mL. Simulating MIPD showed a reduction in the average infusions versus the standard interval by 40%, with an average dose interval of 7 weeks, while maintaining adequate drug exposure. MIPD was concluded to be superior to the conventional TDM-guided personalized dosing approach in terms of enhanced precision in individual dose interval selection, enabling more efficient interval extensions. Simulations supported the clinical deployment of natalizumab MIPD.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662980","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}

{"title":"A Model-Based Approach to Evaluate Anti-Drug Antibody Impact on Drug Exposure With Biologics: A Case Example With the CD3 T-Cell Bispecific Cibisatamab.","authors":"Javier Sanchez, Philippe B Pierrillas, Nicolas Frey, Gregor P Lotz, Siv Jönsson, Lena E Friberg, Nicolas Frances","doi":"10.1002/psp4.70019","DOIUrl":"https://doi.org/10.1002/psp4.70019","url":null,"abstract":"<p><p>The administration of biologics can lead to immunogenic responses that trigger anti-drug antibody (ADA) formation. ADAs can decrease drug exposure. A population pharmacokinetic (popPK) model was developed to describe clinical PK data with and without ADA-driven exposure loss with CEA-directed T-cell bispecific antibody cibisatamab. The PK of cibisatamab was evaluated in two clinical studies (as a single agent and in combination with the checkpoint inhibitor atezolizumab) in patients. The popPK model was developed on cibisatamab clinical PK data using the Stochastic Approximation -Expectation Maximization (SAEM) algorithm implemented in Monolix. Cibisatamab's PK followed a two-compartment model with linear clearance decreasing over time and ADA-associated exposure loss. ADA-driven exposure loss was implemented in the model by accounting for ADA formation, reversible binding to cibisatamab, and elimination of both free ADA and the ADA-cibisatamab complex from the central compartment. The impact of ADAs on PK exposure was time-dependent in the model, with the ADA formation described as a function of time (increasing from zero, reaching its estimated maximum value, and possibly decreasing down to 94% of this maximum value in some patients). The final model included a mixture component differentiating patients with and without exposure loss due to ADA formation (75% and 25% of patients, respectively). The investigated patient demographics, dose or dosing schedule, or atezolizumab coadministration were not identified as factors influencing exposure loss due to ADAs. The developed model can be used to differentiate patients with and without ADA-driven exposure loss, as well as for a precise PK characterization in patients even with ADA formation.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662960","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}

{"title":"Less Is More: Design Considerations for Interactive Pharmacometrics Tools-A Case Study Using the Model Visualization Platform (MVP) App.","authors":"Steve Choy, Jin Gyu Kim, Julia Korell","doi":"10.1002/psp4.70023","DOIUrl":"https://doi.org/10.1002/psp4.70023","url":null,"abstract":"<p><p>The shiny R package has enabled pharmacometrics (PMX) scientists to create and share interactive R-based tools, or \"shiny apps\". Initially, shiny apps are developed ad hoc (i.e. project specific) to provide simulations, and their complexity have evolved to be more general-purpose and \"platform-like\" in recent years. Despite their complexity and increased amount of features, an unexplored aspect is the design considerations for user interface and user experience (UI/UX) to optimize end-user interactivity and enjoyment.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662979","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}

{"title":"Population Pharmacokinetics and Exposure-Response Modeling for Evinacumab in Children, Adolescents, and Adults With Homozygous Familial Hypercholesterolemia.","authors":"Sébastien Bihorel, Robert Dingman, Jeanne Mendell, Yuhuan Wang, Poulabi Banerjee, Robert Pordy, John D Davis, A Thomas DiCioccio, Lutz Harnisch","doi":"10.1002/psp4.70016","DOIUrl":"https://doi.org/10.1002/psp4.70016","url":null,"abstract":"<p><p>Evinacumab, an angiopoietin-like 3 (ANGPTL3) inhibitor, significantly reduces low-density lipoprotein cholesterol (LDL-C), independent of low-density lipoprotein receptor, in patients with homozygous familial hypercholesterolemia (HoFH). A population pharmacokinetic (PK)/pharmacodynamic (PD) model was previously developed to characterize evinacumab exposure and LDL-C response in adolescents and adults. In this analysis, the PK/PD model was refined to include children aged 5 to < 12 years and to characterize the lipoprotein apheresis effect on LDL-C reduction. The PK of evinacumab was characterized by a two-compartment model with parallel linear and non-linear elimination. Linear disposition parameters were allometrically scaled by body weight. Baseline ANGPTL3 concentrations and disease status (non-HoFH vs. HoFH) influenced the maximum target-mediated rate of elimination but had a minimal effect on evinacumab exposures at 15 mg/kg intravenous doses every 4 weeks across weight/age groups. In patients with HoFH, the LDL-C reduction was adequately described by an indirect response model in which evinacumab inhibits the formation of LDL-C and that includes a secondary elimination process quantifying the lipoprotein apheresis effect. Older age was associated with a decrease in baseline LDL-C. An increase in body weight was associated with a reduction in the maximum inhibitory effect of evinacumab. Model-based simulations showed that while evinacumab exposure is reduced with decreasing age/body weight, younger patients are predicted to have a comparable or greater magnitude of LDL-C reduction than older patients at a dose of 15 mg/kg. Overall, the model adequately predicted the evinacumab exposure and LDL-C reduction in children, adolescents, and adults with HoFH, aligning with clinically relevant observations.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647549","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}

{"title":"Comparison of Model-Predicted and Observed Evinacumab Pharmacokinetics and Efficacy in Children Aged < 5 Years With Homozygous Familial Hypercholesterolemia.","authors":"Sébastien Bihorel, Robert Dingman, Jeanne Mendell, Katy C Norman, Richard T George, Xue-Qiao Zhao, Robert Pordy, Daniel Garcia, Wendy S Putnam, Geetha Raghuveer, Brian W McCrindle, Elena Fornari, Ivo Baric, Shubha Srinivasan, Melissa Diamond, Eliot A Brinton, John D Davis, A Thomas DiCioccio, Lutz Harnisch","doi":"10.1002/psp4.70017","DOIUrl":"https://doi.org/10.1002/psp4.70017","url":null,"abstract":"<p><p>Evinacumab, an angiopoietin-like 3 inhibitor, significantly reduces low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). Herein, we report pharmacokinetic and efficacy analyses of evinacumab in < 5-year-old patients with HoFH. Population pharmacometric models characterizing evinacumab exposure and LDL-C response accounting for lipoprotein apheresis effect in ≥ 5-year-old patients were adapted for growth and maturation to predict and compare evinacumab and LDL-C concentrations across age/weight groups in virtual ≥ 6-month-old patients receiving 15 mg/kg evinacumab intravenous (iv) infusions every 4 weeks (q4w). As expected from allometric theory, weight-based dosing resulted in decreasing evinacumab exposures with declining body weight. Consistent with trends observed in > 5-year-old patients, the predicted percent change from LDL-C baseline (%∆LDL-C) was generally comparable or even higher in < 5-year-old patients (63.0%-68.5%) than in 5- to < 18-year-old patients (61.3%-67.8%) or adults (51.7%), with the predicted percentages of patients achieving %∆LDL-C > 50% also higher in < 5-year-old patients (82.0%-86.9%) versus 5- to < 18-year-old patients (72.0%-84.5%) and adults (54.8%). Through a managed access program, six 1- to < 5-year-old patients received between 5 and 23 iv infusions of 15 mg/kg evinacumab q4w. Rapid and clinically meaningful LDL-C reductions were observed, with %∆LDL-C at the last reported dose ranging from 41.3% to 77.3%. Based on the actual patient dosing and plasmapheresis history, model-predicted evinacumab and LDL-C concentrations were comparable to the observed data collected in the managed access program. Overall, this analysis provides evidence for the use of evinacumab 15 mg/kg iv q4w dosing regimen in 6-month-old to 5-year-old patients.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647548","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}