Clinical Pharmacokinetics最新文献

{"title":"Spatial Pharmacokinetic and Pharmacodynamic Modeling in Airway Mucus.","authors":"Yuchen Guo, Jinqiu Yin, Sirin Yonucu, Catherijne A J Knibbe, Tingjie Guo, J G Coen van Hasselt","doi":"10.1007/s40262-025-01575-4","DOIUrl":"https://doi.org/10.1007/s40262-025-01575-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>Diseases such as cystic fibrosis (CF) and non-CF bronchiectasis can cause extensive mucus formation in the lung, which may affect drug distribution and effects. As such, quantitative understanding of drug distribution in mucus may guide treatment optimization. Here, we aimed to develop a modeling framework to evaluate spatial distribution of drugs in mucus with CF as a proof of concept. In a case study, we demonstrated how spatial PK models can be used to predict spatial antimicrobial pharmacodynamics (PD).</p><p><strong>Methods: </strong>A spatial pharmacokinetic (PK) model in mucus was developed using discretized partial differential equations. Hypothetical drugs with realistic ranges for molecule/particle size (radius, r), mucin binding affinity, and half-lives were used to evaluate the impact of drug-specific factors on spatial distribution in mucus. Mucin concentration and muco-ciliary clearance were evaluated as biological system-specific factors. We then demonstrated how the spatial PK model can be used to predict antimicrobial drug effects of imipenem against the pathogen Pseudomonas aeruginosa in mucus.</p><p><strong>Results: </strong>Under intravenous PK profiles, molecular/particle size (r) was found to play a dominant role in mucus drug diffusion, while drug-mucin interactions and muco-ciliary clearance showed a minor impact. Small molecule drugs (r <1 nm) could readily penetrate mucus, whereas large molecules or particles (r >20 nm) showed differential spatial drug distribution. Our case study demonstrates that baseline spatial bacterial organization can impact the treatment outcome of imipenem against mucus-associated infections.</p><p><strong>Conclusion: </strong>The developed spatial PK modeling framework enabled quantitative description of the spatial distribution of drugs in airway mucus and can be of relevance to guide optimization of treatment strategies.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-Drug Interactions Between Direct Oral Anticoagulants and Other Medications in Patients with Pulmonary Embolism: Results from the Lungenembolie Augsburg (LEA).","authors":"Klaus Peter Schmelzer, Dennis Freuer, Simone Fischer, Thomas M Berghaus, Jakob Linseisen, Christa Meisinger","doi":"10.1007/s40262-025-01556-7","DOIUrl":"10.1007/s40262-025-01556-7","url":null,"abstract":"<p><strong>Background and aim: </strong>Direct oral anticoagulants (DOACs) are now a well-established class of medication for blood clot prevention and treatment. So far, literature evaluating real-world data on the drug-drug interactions (DDIs) between DOACs and other medications in patients with pulmonary embolism (PE) is limited. This study aims to investigate these interactions in patients with PE to address this and improve patient care.</p><p><strong>Materials and methods: </strong>In a retrospective study, patients' medications were recorded upon hospital discharge and reviewed again 3 months later. A clinical decision support system (AiDKlinik^® Release 3.5) was initially used to screen for DDIs and drug-related problems. Subsequently, medications were entered into Lexicomp^®, a comprehensive drug interaction database, to gain detailed scientific explanations and references for the identified interactions and their mechanisms. Binary logistic random intercept models were used to identify potential risk factors of drug-anticoagulation interactions.</p><p><strong>Results: </strong>The 477 included PE patients had a median intake of five drugs. Drug-anticoagulation interactions depended strongly on the number of medications taken (P value < 0.001). However, the association was non-linear, resulting in a saturation effect for a higher number of drugs. The odds ratio for having at least one drug-anticoagulation interaction was 0.40 (95% confidence interval 0.17-0.96; P value = 0.040) in patients with hypertension.</p><p><strong>Conclusions: </strong>The potential for DDIs with DOACs represents a significant concern. By being aware of the most common interactions, risk factors and avoidance strategies, the safety and efficacy of therapy can be optimized.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1575-1585"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenging Traditional ADME Assumptions for Physiologically Based Pharmacokinetic Models for Intravenous Administration of Iron-Carbohydrate Nanomedicines: Potential Utility of Gold Nanoparticle Models as a Roadmap.","authors":"Amy Barton Alston, Zhoumeng Lin, Heather Herd Gustafson, Beat Flühmann, Reinaldo Digigow, Vanesa Ayala-Nunez, Stephan Schmidt","doi":"10.1007/s40262-025-01561-w","DOIUrl":"10.1007/s40262-025-01561-w","url":null,"abstract":"<p><p>Intravenous iron-carbohydrate complexes are a class of nanomedicines that are widely used globally to treat iron deficiency and iron deficiency anemia associated with a wide spectrum of disease states. Despite being widely used in clinical practice for more than seven decades, the understanding of their in vivo disposition including tissue biodistribution and kinetics of the nanoparticle degradation at the cellular level is not well-understood. Moreover, the critical quality attributes that influence in vivo pharmacokinetics have not been fully defined. In particular, the carbohydrate moiety plays an influential role in how the nanoparticulate iron-carbohydrate complex interacts with the biological system. Developing a physiologically based pharmacokinetic (PBPK) model would facilitate a deeper understating of the key nanomedicine attributes that predict in vivo performance. Because endogenous iron metabolism complicates pharmacokinetic modeling for this complex class of drugs, models of gold nanoparticles may provide a substantive roadmap to begin to build a viable PBPK model for iron-carbohydrate nanomedicines. In the future, PBPK models that integrate recent mechanistic data regarding tissue biodistribution and intracellular iron kinetics for parameterization have the potential to improve manufacturing quality and clinical use of these complex drugs.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1477-1494"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pharmacology Profile of the Claudin 18.2 Antibody Zolbetuximab.","authors":"Jianning Yang, Akihiro Yamada, Kohei Shitara, Rui-Hua Xu, David Ilson, Sara Lonardi, Samuel J Klempner, Yoko Ueno, Masato Takeuchi, Janet Pavese, Tomasz Wojtkowski, Maria Matsangou, Srinivasu Poondru","doi":"10.1007/s40262-025-01552-x","DOIUrl":"10.1007/s40262-025-01552-x","url":null,"abstract":"<p><p>Zolbetuximab is a first-in-class chimeric (mouse/human) monoclonal antibody targeted to the tight junction protein claudin 18.2 (CLDN18.2), an emerging biomarker in gastric/gastroesophageal junction (G/GEJ) cancer. This review summarizes the clinical pharmacology of zolbetuximab on the basis of available clinical trial data. Population pharmacokinetics (PK) were evaluated using data from eight clinical studies (n = 714). Zolbetuximab PK following intravenous administration was described by a two-compartment model with linear and time-dependent clearance components. On the basis of simulations using the 800/600 mg/m² every 3 weeks (Q3W) dosing regimen from phase 3 trials, gastrectomy (versus no gastrectomy) was predicted to increase zolbetuximab C_trough by ≥ 50%, but without apparent effects on the benefit-risk profile of zolbetuximab. No dose adjustments are necessary for individuals with mild/moderate renal impairment or mild hepatic impairment. Zolbetuximab PK was not different among the ethnicities evaluated (White, Asian, Chinese, Japanese, Korean). There were no apparent safety or PK ramifications of zolbetuximab coadministration with oxaliplatin or 5-fluorouracil. The incidence of antidrug antibodies to zolbetuximab was low, with no apparent clinical consequence. Exposure-response analysis suggested that higher zolbetuximab exposures may prolong survival outcomes but may also increase the probability of experiencing gastrointestinal events and infusion-related reactions. A proposed alternative 800/400 mg/m² every 2 weeks (Q2W) regimen for use in combination with Q2W chemotherapy was shown to have comparable safety and efficacy to the 800/600 mg/m² Q3W regimen. Zolbetuximab, the first and only approved therapy targeted to CLDN18.2, is a valuable new treatment option for patients with CLDN18.2-positive, locally advanced unresectable or metastatic G/GEJ cancer.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1465-1476"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TDM-Based Tailored Dosing of Durvalumab in Lung Cancer Patients: A Comprehensive Population Pharmacokinetic-Pharmacoeconomic Evaluation.","authors":"Fenna de Vries, Eric J F Franssen, Arthur A J Smit, Dirk Jan A R Moes, Anthonie J van der Wekken, Thijs Oude Munnink, Jeroen J M A Hendrikx, Daphne W Dumoulin, Stijn L W Koolen, Wietske Kievit, Michel M van den Heuvel, Rob Ter Heine","doi":"10.1007/s40262-025-01555-8","DOIUrl":"10.1007/s40262-025-01555-8","url":null,"abstract":"<p><strong>Background: </strong>The increasing use of immune checkpoint inhibitors, such as durvalumab, places a significant financial burden on healthcare systems, strains hospital capacities, and contributes to environmental concerns.</p><p><strong>Objective: </strong>We aimed to develop alternative dosing strategies to optimize durvalumab administration, reduce unnecessary drug use, and ensure sustainable cancer care without sacrificing efficacy.</p><p><strong>Methods: </strong>Using the population pharmacokinetic model developed by the licensing holder, we designed two alternative dosing strategies for non-small cell lung cancer based on therapeutic drug monitoring. Adjustments were made to the dose or administration interval, following regulatory standards for in silico dose optimization. A pharmacoeconomic evaluation was conducted to estimate potential cost savings from a medical perspective.</p><p><strong>Results: </strong>Both alternative strategies achieved high exposure levels, with 98.1-99.0% of patients exceeding a predefined efficacy target, surpassing the 95.4% predicted by the license holder for the approved 10 mg/kg 2-weekly regimen. They also reduced overall drug exposure by 7-24% and eliminated drug wastage, resulting in an average annual cost reduction of €25,163 (22.9%) per patient.</p><p><strong>Conclusion: </strong>Therapeutic drug monitoring-guided adjustments for durvalumab offer a potentially cost-saving way to optimize drug use, reduce healthcare burdens, and lessen environmental impact while ensuring adequate patient exposure. Our proposal's evidence provides a solid basis for a non-inferiority study.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1507-1515"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Modeling of Factor IX Activity Following Administration of Fidanacogene Elaparvovec Gene Therapy in Participants with Hemophilia B.","authors":"Jessica Wojciechowski, Puneet Gaitonde, Jim H Hughes, Patanjali Ravva","doi":"10.1007/s40262-025-01535-y","DOIUrl":"10.1007/s40262-025-01535-y","url":null,"abstract":"<p><strong>Background and objective: </strong>Fidanacogene elaparvovec (BEQVEZ™), an adeno-associated virus-based gene therapy approved for the treatment of hemophilia B, enables endogenous production of factor IX (FIX), preventing bleeding and reducing the need for FIX replacement. Nonlinear mixed-effects models are routinely used for population pharmacokinetic analyses of FIX replacement therapies but have not previously been applied to FIX activity observations from gene therapy trials. A nonlinear mixed-effects modeling approach was used to characterize FIX activity following fidanacogene elaparvovec and/or FIX replacement, identify covariates affecting FIX activity, and estimate the longer-term durability of FIX activity after a single dose of fidanacogene elaparvovec.</p><p><strong>Methods: </strong>Population modeling using NONMEM^® was performed with FIX activity data pooled from 11 clinical trials in participants with hemophilia B (three fidanacogene elaparvovec studies [n = 63]; eight nonacog alfa studies [n = 274]). FIX activity was assessed by one-stage clotting assays.</p><p><strong>Results: </strong>FIX activity was described by a compartmental model for gene and protein expression and a three-compartment model for FIX disposition. Covariates included age and body weight on gene-therapy-related parameters. Following fidanacogene elaparvovec administration, model-predicted FIX activity reached a median (90% prediction interval) peak of 13.5 (3.12-41.3) IU/dL and remained within 50% of the peak for a median of 8.67 (0.411-15.0) years. At 15 years post-infusion, median predicted FIX activity was 4.11 (1.15-17.6) IU/dL.</p><p><strong>Conclusions: </strong>Model-based estimates showed that a single dose of fidanacogene elaparvovec elicited long-lasting elevations in FIX activity, suggesting most individuals would not require prophylactic FIX replacement for at least 15 years post-infusion.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT00364182, NCT01335061, NCT00037557, NCT00093171, NCT00093210, NCT03861273, NCT03307980, NCT02484092.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1531-1548"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Influence of Patient Factors on the Population Pharmacokinetics of Colchicine: Implications for Safe and Effective Dosing.","authors":"Daniel F B Wright, Hailemichael Z Hishe, Nicola Dalbeth, Anne Horne, Jill Drake, Janine Haslett, Lisa K Stamp","doi":"10.1007/s40262-025-01551-y","DOIUrl":"10.1007/s40262-025-01551-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>The factors that predict colchicine plasma concentrations and the impact on safety and efficacy are under-researched. We aimed to determine the probability of achieving steady-state plasma concentrations within the nominal therapeutic range of 0.5-3 ng/mL.</p><p><strong>Methods: </strong>Colchicine plasma concentrations from 78 people with gout were analysed using non-linear mixed effects. Body size, kidney function, concomitant drugs, ethnicity, sex, age and adherence were tested as covariates in the model. Simulations were conducted to determine the probability of achieving steady-state minimum, maximum and average concentrations within the therapeutic range of 0.5-3 ng/mL under different doses and for different patient characteristics. We considered colchicine doses that produced > 80% of steady-state average concentrations < 3 ng/mL and > 0.5 ng/mL to have a reasonable probability of safety and efficacy.</p><p><strong>Results: </strong>A two-compartment pharmacokinetic model with zero-order absorption was the best fit. Body weight, sex and statin use were significant predictors of colchicine pharmacokinetics, reducing the between-subject variance on clearance by about 40%. The model predicted that colchicine dosages of ≤ 1.5 mg daily carry a low risk of toxicity based on the criteria defined here. Efficacious concentrations were achieved for all dosages tested except 0.5 mg daily, where concentrations below the proposed therapeutic range may occur in those with a body weight > 80 kg. Higher colchicine dosages of > 1.5 mg daily may exceed the proposed upper limit of safety in many individuals, particularly those with low body weight who are taking statins.</p><p><strong>Conclusion: </strong>A model for the pharmacokinetics of colchicine was developed and evaluated. Low-dose regimes (≤ 1.5 mg daily) are not predicted to achieve concentrations above the proposed safety threshold of 3 ng/mL in most people, although concentrations below the lower limit of the therapeutic range may occur in those taking 0.5-mg doses who are > 80 kg in body weight. Higher colchicine dosages of > 1.5 mg daily may exceed the proposed upper limit of safety in individuals with low body weight who are taking statins.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1517-1529"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Double Peaking Phenomena in Pharmacokinetic Disposition Revisited.","authors":"Malaz Yousef, Dion R Brocks, Raimar Löbenberg, Neal M Davies","doi":"10.1007/s40262-025-01559-4","DOIUrl":"10.1007/s40262-025-01559-4","url":null,"abstract":"<p><p>Multiple peaking in pharmacokinetics refers to the occurrence of two or more peaks of drug plasma concentrations following a single dose administration. It complicates interpretation of pharmacokinetics parameters and influences clinical decision-making regarding drug efficacy and bioequivalence. This review re-examines and extends an earlier seminal review on the physicochemical and formulation-related causes and physiological mechanisms of multiple peaking. In addition to the previously discussed mechanisms, factors such as lymphatic drug uptake, enterogastric recycling, hepatoenteric recycling, dual absorption pathways, overdose scenarios, and pharmacobezoar formation have also been identified as contributors to the multiple peaking phenomenon. Furthermore, the role of specialized formulations, particularly pulsatile drug delivery systems (PDDS), has been explored in relation to their impact on this complex pharmacokinetics behavior. Moreover, this review highlights advanced modeling tools, namely physiologically based pharmacokinetic modeling (PBPK), illustrating how they can be applied to decipher complex absorption profiles, and highlights bioequivalence considerations for products exhibiting multiple peaks, such as partial area under the curve (pAUC). Improved identification and modeling of this phenomenon is critical to optimizing drug development, therapeutic monitoring, precision dosing, and regulatory decision-making.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1435-1463"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, Pharmacodynamics, and Urinary Recovery of Oral Mescaline Hydrochloride in Healthy Participants.","authors":"Lorenz Mueller, Aaron Klaiber, Laura Ley, Anna M Becker, Jan Thomann, Dino Luethi, Yasmin Schmid, Matthias E Liechti","doi":"10.1007/s40262-025-01544-x","DOIUrl":"10.1007/s40262-025-01544-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Mescaline is a classic serotonergic psychedelic with a long history of human use. The present study analyzed the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship, and urinary recovery of oral mescaline hydrochloride.</p><p><strong>Methods: </strong>Data from 105 single-dose administrations (100-800 mg) in 49 participants from two phase I trials were analyzed with compartmental pharmacokinetics and pharmacokinetic-pharmacodynamic modeling. A one-compartment model with first-order absorption, elimination, and a lag time was used to describe mescaline plasma concentrations. Acute subjective effects, assessed by visual analog scales (range 0-100%), were modeled using a sigmoid E_max model linked to plasma concentrations via a first-order rate constant (k_e0).</p><p><strong>Results: </strong>Mescaline showed dose-proportional increases in total exposure and maximal concentrations, with a peak concentration reached within 2.0 h (geometric mean) and a half-life of 3.5 h across all doses. Mean model-predicted onset of \"any drug effect\" occurred around 1 hour post-dose. Maximum predicted effect intensity and duration increased with dose, from 13% and 2.8 h at 100 mg to 89% and 15 h at 800 mg. Over all conditions, 53% of the dose was excreted into urine unchanged, and 31% was excreted as the main metabolite 3,4,5-trimethoxyphenylacetic acid over 24-30 h.</p><p><strong>Conclusions: </strong>These findings provide the first detailed pharmacokinetic-pharmacodynamic characterization of mescaline in humans and indicate an oral bioavailability of at least 53%, limited by first-pass metabolism to 3,4,5-trimethoxyphenylacetic acid, followed by predominant renal elimination of both analytes.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov identifier: NCT04227756 and NCT04849013.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1495-1506"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Antidrug Antibodies in Oncolytic Viral Therapy: A Dynamic Modelling Approach in Cancer Patients Treated with V937 Alone or in Combination.","authors":"Zinnia P Parra-Guillen, Iñaki F Trocóniz, Tomoko Freshwater","doi":"10.1007/s40262-025-01546-9","DOIUrl":"10.1007/s40262-025-01546-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Oncolytic viruses (OVs) are a growing immuno-oncology therapeutic class that rely on their capability to activate the dormant endogenous anti-tumor immune response in order to control or eradicate tumor cells. Given their intrinsic mechanisms of action and their biological nature, development of antidrug antibodies (ADA) represents an important aspect to consider during clinical evaluation. ADAs can potentially affect viral kinetics and/or dynamics, ultimately resulting in reductions or even loss of drug efficacy. Here, we present a semi-mechanistic pharmacokinetic/pharmacodynamic model characterizing the interplay between V937 and neutralizing ADA in cancer patients receiving the V937 oncolytic virus.</p><p><strong>Methods: </strong>The quantitative framework has been developed integrating viral load and ADA titers from 208 cancer patients who received V937 following intratumoral or intravascular administration, in monotherapy or in combination with pembrolizumab.</p><p><strong>Results: </strong>The model successfully captured both V937 time course and the dynamics of ADAs under the different settings, showing no meaningful impact of ADAs on viral kinetics. Moreover, tumor response was neither affected by the preexistence or development of ADAs, which can be explained by the primary role of the immune system in the response.</p><p><strong>Conclusions: </strong>This quantitative and (semi-) mechanistic framework can be expanded to other oncolytic viruses and used to explore under which scenarios a relevant impact could be observed, thus supporting the development of novel oncolytic viral therapies.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1549-1559"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}