CPT: Pharmacometrics & Systems Pharmacology最新文献

{"title":"Target-Mediated Drug Disposition (TMDD) Revisited: High Versus Low-Affinity Approximations of the TMDD Model.","authors":"Ronny Straube","doi":"10.1002/psp4.70048","DOIUrl":"https://doi.org/10.1002/psp4.70048","url":null,"abstract":"<p><p>Target-mediated drug disposition (TMDD) is often associated with high-affinity binding to a target resulting in nonlinear pharmacokinetics. For large molecules, such as monoclonal antibodies, this can lead to increased clearance at sub-saturating concentrations. However, for small molecules, target binding can protect the drug from a fast systemic clearance. Here, we show that both types of behaviors can be described by simple expressions arising from a high-affinity approximation of the standard TMDD model. Interestingly, the celebrated Michaelis-Menten (MM) approximation arises in the opposite limit of low affinity and if the systemic drug clearance is sufficiently slow. Our derivation contains a previously missing factor in front of the MM constant that becomes important when target and drug-target complex elimination rates are different. As a measure of target suppression, we also derive simple expressions for the free target to baseline ratio and compare our approximations with data from large and small molecules.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149665","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 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":"https://doi.org/10.1002/psp4.70041","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"https://doi.org/10.1002/psp4.70047","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Systems Toxicology Modeling of Acetaminophen Pharmacokinetics and Hepatic Biomarkers After Overdoses of Extended-Release and Immediate-Release Formulations in Adults With Chronic Alcohol Use or Low Glutathione.","authors":"Kyunghee Yang, James J Beaudoin, Brett A Howell, James Mullin, Elham Amini, John C K Lai, Cathy K Gelotte, Sury Sista, Evren Atillasoy","doi":"10.1002/psp4.70045","DOIUrl":"https://doi.org/10.1002/psp4.70045","url":null,"abstract":"<p><p>Acetaminophen (APAP), an over-the-counter analgesic and antipyretic, can cause hepatotoxicity when ingested in large overdoses. APAP has multiple formulations including immediate-release (IR) and extended-release (ER) preparations. A recently published consensus statement on the management of APAP poisoning indicated that management of APAP-ER overdose is the same as that for APAP-IR overdose. Consistent with this consensus, it was previously reported that quantitative systems toxicology (QST) modeling using DILIsym predicted similar pharmacokinetic (PK) and hepatic biomarker profiles for the APAP-ER and APAP-IR formulations after overdose in healthy adults. Hepatic injury from APAP is caused by the reactive metabolite, N-acetyl-ρ-benzoquinone imine (NAPQI), which is formed predominantly by CYP2E1-mediated metabolism and eliminated by hepatic glutathione. As such, conditions that can increase NAPQI production (e.g., CYP2E1 induction by alcohol) or decrease hepatic glutathione stores (e.g., underling liver disease) may impact PK and susceptibility to hepatotoxicity after overdose of APAP-IR and APAP-ER. In the current study, APAP-IR and APAP-ER models in chronic alcohol users and individuals with low hepatic glutathione were developed and verified within DILIsym. Simulations using verified models predicted similar PK and hepatic biomarker profiles for the APAP-ER and APAP-IR formulations in moderate and excessive chronic alcohol users and adults with low hepatic glutathione levels after single acute overdoses up to ~100 g and repeat supratherapeutic ingestions (up to 7.8 g/day for 10 days). These results further support that approaches to manage APAP-IR overdoses can be applied to manage APAP-ER overdoses in adults with chronic alcohol consumption or lower hepatic glutathione levels.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982782","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":"An Integrative Mechanistic Model of Type 1 IFN-Mediated Inflammation in Systemic Lupus Erythematosus.","authors":"Alina Volkova, Victor Sokolov, Florencia Tettamanti, Meghna Verma, Yaroslav Ugolkov, Kirill Peskov, Weifeng Tang, Holly Kimko","doi":"10.1002/psp4.70043","DOIUrl":"https://doi.org/10.1002/psp4.70043","url":null,"abstract":"<p><p>Type I interferon (IFN1) pathway-targeting therapies represent a highly promising class of remedies for the treatment of systemic lupus erythematosus. However, the overall clinical benefit of these compounds is afflicted by marked variability. In this study, we developed a quantitative systems pharmacology model of type I IFN-mediated inflammation and applied it for an indirect comparison of anifrolumab, sifalimumab, daxdilimab, and litifilimab pharmacodynamic response, represented in the model by the change in IFN1 gene signature (IFNGS). The model consists of 20 ordinary differential equations and 68 parameters, among which four systemic parameters (including one random effect) were estimated using patient-level data from Phase IIb anifrolumab clinical trial. Within-target and within-pathway validation was performed using study-level pharmacokinetics, IFNα, and/or IFNGS data from five anifrolumab, four sifalimumab, one daxdilimab, and one litifilimab trials. The model successfully captured overall trends in IFNGS at clinically relevant doses of these compounds and discriminated IFNGS response between patients with low (< 2.75) and high (≥ 2.75) baseline IFNGS. Overprediction of treatment benefit was observed for the low range of anifrolumab doses (100-150 mg every 4 weeks). In contrast, IFNGS response under 150 mg of daxdilimab was underpredicted, despite the accurate description of plasmacytoid dendritic cells and IFNα biomarkers. Results of the global sensitivity analysis revealed baseline IFNGS, IFNα, and IFNα fraction as key factors affecting treatment benefit the most. In terms of maximum IFNGS reduction, anifrolumab showed superior potential compared to sifalimumab, daxdilimab, and litifilimab (ΔIFNGS~25%), which was further enhanced in patients with high baseline IFNGS or IFNα (ΔIFNGS~50%-60%).</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984969","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 Modeling of Selpercatinib to Support Posology in Pediatric Patients With RET-Altered Metastatic Thyroid Cancer or Solid Tumors.","authors":"Dan Liu, Jan-Stefan van der Walt","doi":"10.1002/psp4.70042","DOIUrl":"https://doi.org/10.1002/psp4.70042","url":null,"abstract":"<p><p>Selpercatinib is a first-in-class, highly selective, RET kinase inhibitor with CNS activity, approved for the treatment of RET-altered lung, thyroid, and other cancers. We report pharmacokinetic analyses to identify factors affecting selpercatinib steady-state exposure and support posology in pediatric patients. Population pharmacokinetic analyses using nonlinear mixed-effects modeling were performed on data from two ongoing, open-label, Phase 1/2 studies in adult and pediatric patients with advanced solid tumors. In LIBRETTO-001 (NCT03157128) patients (≥ 12 years) received oral selpercatinib from 20 mg once daily through 240 mg twice daily (BID) during phase 1 and 160 mg BID in phase 2. In LIBRETTO-121 (NCT03899792), patients (6 months-21 years) received doses based on body surface area (BSA), starting at a dose expected to match adult exposure of 160 mg BID. Overall, 8024 selpercatinib plasma concentration measurements from 830 patients were included in the pharmacokinetic analysis. The final model, a 2-compartment disposition model with sequential zero- and first-order absorption, was similar to a previously developed adult model, which identified weight, dose, and Asian race as covariates. Simulations performed using the final model suggested the following dose regimen as appropriate for patients aged 2-17 years: 40 mg three times a day for pediatric patients with a BSA of 0.33-0.65 m²; BSA-based dosing (92 mg/m² rounded for 40 and 80 mg capsules) for pediatric patients 2 to < 12 years, and BSA ≥ 0.66 m²; and weight-based dosing (120 mg BID < 50 kg and 160 mg BID ≥ 50 kg) for adolescent patients ≥ 12 years.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977962","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":"Effect of Cumulative Exposure on the Efficacy of Paroxetine: A Population Pharmacokinetic-Pharmacodynamic and Machine Learning Analyses","authors":"Keiichi Shigetome,&nbsp;Tomoko Egashira,&nbsp;Tetsu Tomita,&nbsp;Nagisa Higa,&nbsp;Kazuma Iwashita,&nbsp;Kazuya Morita,&nbsp;Miki Nishimura,&nbsp;Tetsuya Kaneko,&nbsp;Hitoshi Maeda,&nbsp;Kazunori D. Yamada,&nbsp;Ayami Kajiwara-Morita,&nbsp;Kentaro Oniki,&nbsp;Norio Yasui-Furukori,&nbsp;Junji Saruwatari","doi":"10.1002/psp4.70032","DOIUrl":"10.1002/psp4.70032","url":null,"abstract":"<p>Selective serotonin reuptake inhibitors (SSRIs) are widely used in depression treatment. However, the relationship between treatment efficacy and plasma concentrations remains unclear. We assessed whether the anti-depressive response can be predicted based on the pharmacokinetic (PK) data of paroxetine, a frequently used SSRI. During treatment, we measured the plasma paroxetine concentrations in 179 paroxetine-treated patients with major depressive disorder. Of these patients, 50 patients had received a pre-treatment personality assessment using the Temperament and Character Inventory at baseline, and their depression severity was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline and 1, 2, 4, and 6 weeks after treatment initiation. We conducted population PK modeling followed by a population PK-pharmacodynamic (popPK/PD) model to analyze the enhancement in depression severity until 6 weeks of paroxetine treatment using nonlinear mixed-effects modeling. Additionally, we developed machine learning models to predict the likelihood of remission after 6 weeks. The contribution of each feature to the prediction was explained using SHapley Additive exPlanations (SHAP) values. The area under the plasma paroxetine concentration-time curve during the first week (AUC_0–1week) and MADRS score after 1 week of treatment (MADRS_W1) were incorporated into the popPK/PD model. The SHAP values indicated that the AUC_0–1week and MADRS_W1 were the significant predictors of remission. Our results indicate that therapeutic responsiveness to paroxetine can be anticipated from its cumulative exposure, highlighting the clinical relevance of assessing SSRI blood concentrations.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"14 6","pages":"1119-1127"},"PeriodicalIF":3.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969210","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}

{"title":"Comprehensive Safety Exposure-Response Analysis to Support Ritlecitinib Dose Selection","authors":"Yeamin Huh,&nbsp;Ruolun Qiu,&nbsp;John Prybylski,&nbsp;Jessica Wojciechowski,&nbsp;Yuchen Wang,&nbsp;Vivek S. Purohit","doi":"10.1002/psp4.70030","DOIUrl":"10.1002/psp4.70030","url":null,"abstract":"<p>Ritlecitinib is a kinase inhibitor drug recently approved for the treatment of alopecia areata (AA) in both adults and adolescents based on a single, combined Phase 2b/3 study. Various QD doses with and without a loading dose have been evaluated in the pivotal Phase 2b/3 study. Therefore, characterization of the ritlecitinib safety profile becomes important to help inform the dose selection within the single Phase 2b/3 trial in conjunction with efficacy analysis. The purpose of this study is to characterize the safety profile of ritlecitinib with comprehensive exposure-response (ER) analyses. The concentration-QTc model was developed using a scientific white paper model, indicating no evidence of ritlecitinib-induced QTc prolongation. The semi-mechanistic PK/PD model well described the longitudinal profile of lymphocytes, indicating ritlecitinib-induced decrease in lymphocytes was marginal and the incidence of Grade 3/4 lymphopenia was predicted to be small across the investigated dose range except for a slight increase in the loading dose regimen. The ritlecitinib-dependent increase in the incidence of infections and rash was successfully described by a Poisson regression model using time-weighted average concentration as an exposure metric, indicating that the dose-dependent increase in the incidence of AEs is not dose-proportionally large in the investigated dose range. Covariate analysis within each model indicated that the safety ER relationship of ritlecitinib is similar across all the patient subgroups and no unique safety risks associated with ritlecitinib are anticipated in adolescent patients. Therefore, this comprehensive safety ER analysis supported the selection of the ritlecitinib 50 mg non-loading dose regimen for AA patients including both adults and adolescents.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"14 6","pages":"1108-1118"},"PeriodicalIF":3.1,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967396","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}

{"title":"Push Forward Clinical Management of Hematological Toxicity due to Lenalidomide Overexposure: Model-Informed Precision Dosing for Chinese Population With Renal Insufficiency.","authors":"Yi Ma, Zaiwei Song, Hao Bing, Huan He, Libo Zhao, Rongsheng Zhao","doi":"10.1002/psp4.70040","DOIUrl":"https://doi.org/10.1002/psp4.70040","url":null,"abstract":"<p><p>Dose-dependent hematological toxicity of lenalidomide has been reported previously, and thus, there is a clinical need for dose individualization to manage toxicities. The objectives of this study were to explore optimal individualized dosing regimens for Chinese B-cell malignancies patients with varying degrees of renal function, and to push forward clinical management of hematological toxicity due to lenalidomide overexposure. A total of 164 plasma concentrations of lenalidomide were obtained from 97 Chinese patients with multiple myeloma (MM) and B-cell non-Hodgkin lymphoma (NHL) from a multicenter prospective study. A population pharmacokinetic (PopPK) model for lenalidomide was developed by nonlinear mixed effect modeling. A Monte Carlo simulation was conducted to recommend model-informed precision dosing (MIPD) for patients with varying degrees of renal function. A one-compartment model with first-order elimination best described the pharmacokinetics of lenalidomide. The population typical values of lenalidomide were as follows: absorption rate constant (Ka) of 8.34 h^-1, apparent volume of distribution (V/F) of 37.4 L, and apparent clearance (CL/F) of 7.4 L/h. Creatinine clearance (CCr) was identified as a major covariate for CL/F, whereas other demographics or clinical characteristics had no significant effect on the model. When given the identical dose, Chinese patients exhibited a higher exposure than the predominantly non-Asian population at all dosage regimens, especially in patients with severe renal damage (CCr < 30 mL/min). For Chinese patients with CCr of 15-30 mL/min who do not require dialysis usually, compared to the dosing regimen of 15 mg every other day recommended by drug instructions, there exists a relatively lower risk of hematotoxicity when administered with 5 or 10 mg/day. For Chinese patients with CCr < 15 mL/min requiring dialysis, there was still a certain level of hematotoxicity risk associated with the dosing regimen of 5 mg/day recommended by drug instructions. The PopPK Model-based simulation suggests that Chinese patients may exhibit a higher exposure than the predominantly non-Asian population. For patients with severely impaired renal function, compared to dose adjustment in accordance with drug instructions, an individualized dosage strategy based on therapeutic drug monitoring (TDM) and MIPD would be preferable from a safety perspective.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972297","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":"Virtual Clinical Trial Reveals Significant Clinical Potential of Targeting Tumor-Associated Macrophages and Microglia to Treat Glioblastoma.","authors":"Blanche Mongeon, Morgan Craig","doi":"10.1002/psp4.70033","DOIUrl":"https://doi.org/10.1002/psp4.70033","url":null,"abstract":"<p><p>Glioblastoma is the most aggressive primary brain tumor, with a median survival of 15 months with treatment. Standard-of-care (SOC) consists of resection, radio- and chemotherapy. Clinical trials involving PD-1 inhibition with nivolumab combined with SOC failed to increase survival. A quantitative understanding of the interactions between the tumor and its immune environment that drive treatment outcomes is currently lacking. As such, we developed a mathematical model of tumor growth that considers CD8+ T cells, pro- and antitumoral tumor-associated macrophages and microglia (TAMs), SOC, and nivolumab. Using our model, we studied five TAM-targeting strategies currently under investigation for solid tumors. Our results show that PD-1 inhibition fails due to a lack of CD8+ T cell recruitment during treatment, explained by TAM-driven immunosuppressive mechanisms. Our model predicts that while reducing TAM numbers does not improve prognosis, altering their functions to counter their protumoral properties has the potential to considerably reduce post-treatment tumor burden. In particular, restoring antitumoral TAM phagocytic activity through anti-CD47 treatment in combination with SOC was predicted to nearly eradicate the tumor. By studying time-varying efficacy with the same half-life as the anti-CD47 antibody Hu5F9-G4, our model predicts that repeated dosing of anti-CD47 provides sustained control of tumor growth. We propose that targeting TAMs by enhancing their antitumoral properties is a highly promising avenue to treat glioblastoma and warrants future clinical development. Together, our results provide proof-of-concept that mechanistic mathematical modeling can uncover the mechanisms driving treatment outcomes and explore the potential of novel treatment strategies for hard-to-treat tumors like glioblastoma.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968731","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}