Clinical Pharmacokinetics最新文献

{"title":"Clinical Pharmacokinetics of Polmacoxib (CG100649): A Tissue-Selective Dual COX-2 and Carbonic Anhydrase I/II Inhibitor.","authors":"Marlon C Mallillin, Md Harunur Rashid, Yasmin Abouelbaqa, Kamal Dua, Raimar Löbenberg, Neal M Davies","doi":"10.1007/s40262-026-01715-4","DOIUrl":"https://doi.org/10.1007/s40262-026-01715-4","url":null,"abstract":"<p><p>Polmacoxib (CG100649; Acelex) is a first-in-class non-steroidal anti-inflammatory drug that combines selective cyclooxygenase-2 (COX-2) inhibition with high-affinity binding to carbonic anhydrase I/II (CA-I/II). Approved for osteoarthritis in South Korea (2015) and India (2023), it exhibits pharmacokinetic (PK) properties distinct from other coxibs. The objective of this review is to review the clinical PK and pharmacokinetic-pharmacodynamic (PK-PD) profile of polmacoxib, compare it with other coxibs, and identify key evidence gaps. PubMed, Embase, Scopus, Web of Science, Google Scholar, and ClinicalTrials.gov were searched through June 2026, supplemented by reference lists and regulatory, patent, and Protein Data Bank records. The clinical PK profile of polmacoxib is dominated by erythrocyte sequestration via high-affinity binding to CA-I/II. After oral dosing, whole-blood concentrations exceed plasma concentrations by approximately 50-78 on average, with individual values approaching 120-fold, and terminal half-lives are approximately 121-203 h in blood and 100-167 h in plasma. A 2-compartment whole-blood model with mixed zero- and first-order absorption best describes the data, with serum iron, white-cell count, and age identified as covariates of clearance. The 2-mg once-daily dose substantially inhibits thromboxane B2 and ex vivo PGE2, with only modest, dose-dependent inhibition of urinary prostacyclin metabolite (PGI-M) that is of comparable magnitude, although less sustained, to celecoxib 200 mg after single dosing; the 2-mg dose is noninferior to celecoxib 200 mg on WOMAC pain endpoints in osteoarthritis. Ketoconazole produces only modest changes in plasma exposure, and PK data in hepatic impairment, renal impairment, older people, and non-Korean populations remain limited. Polmacoxib has a unique PK profile among coxibs, driven by erythrocyte carbonic anhydrase binding, which supports its proposed tissue-selective pharmacology. Further studies in special populations, drug-drug interactions, and post-marketing settings are needed to support broader global use.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191784","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":"Efsubaglutide Alfa: A Comprehensive Pharmacological Review.","authors":"Haolin Zheng, Run Yan, Fan Jiang, Yi Li, Gerald J Prud'homme, Qinghua Wang","doi":"10.1007/s40262-026-01713-6","DOIUrl":"https://doi.org/10.1007/s40262-026-01713-6","url":null,"abstract":"<p><p>Efsubaglutide alfa (also known as supaglutide) is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA) engineered as a GLP-1 analogue fused to a human immunoglobulin G2 (IgG2) fragment crystallisable (Fc) domain. This narrative review summarises published and publicly available evidence on efsubaglutide alfa pharmacology, pharmacokinetics/pharmacodynamics, dose-exposure-response relationships, drug-drug interaction potential, and clinical efficacy and safety in type 2 diabetes (T2D) and overweight/obesity. Efsubaglutide alfa has prolonged exposure (terminal half-life approximately 182-215 h) and low steady-state fluctuation, but dosing-interval selection should not be inferred from half-life alone. Available population pharmacokinetic and exposure-response analyses indicate that steady-state trough concentration is most informative for glycaemic response, whereas average and peak concentrations contribute to interpretation of weight response and gastrointestinal tolerability. Across available studies, predominantly conducted in Chinese populations, efsubaglutide alfa shows class-consistent improvements in glycaemic control and body weight, with gastrointestinal adverse events as the main tolerability limitation. Exploratory every 2-week dosing and post-discontinuation glycaemic durability findings remain hypothesis-generating. No head-to-head comparative trials dedicated cardiovascular or renal outcome trials, or large globally diverse datasets are yet available; therefore, the current evidence should be interpreted as a clinical pharmacology synthesis rather than a comparative positioning claim.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179645","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":"Physiologically Based Pharmacokinetic Modeling of Elexacaftor-Tezacaftor-Ivacaftor in Adults and Pediatric People with Cystic Fibrosis: Exploring Brain Exposure and Neuropsychiatric Adverse Events.","authors":"Clotilde Vellat, Laurent Bourguignon, Sabine Cohen, Philippe Reix, Romain Garreau","doi":"10.1007/s40262-026-01712-7","DOIUrl":"https://doi.org/10.1007/s40262-026-01712-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Elexacaftor-Tezacaftor-Ivacaftor (ETI) has dramatically improved clinical outcomes in cystic fibrosis. However, neuropsychiatric adverse events (NAEs) have been increasingly reported, particularly in pediatric patients. It remains unknown whether these NAEs could be driven by ETI brain exposure. This study aimed to develop a physiologically based pharmacokinetic model of ETI to explore the variability in systemic and central nervous system exposure across age.</p><p><strong>Methods: </strong>We included all pediatric patients treated between 2022 and 2024, and for whom at least one ETI plasma concentration was available. Demographic, pharmacokinetic, biological, genetic, and NAE data were collected. The physiologically based pharmacokinetic model was developed based on published pharmacokinetic data for both adult and pediatric populations and validated in our population using standard goodness-of-fit diagnostics. The validated model was used to simulate age-related differences in systemic and central nervous system exposure and to compare predicted exposure between children with and without reported NAEs in our cohort.</p><p><strong>Results: </strong>Fifty children were included with a mean age of 6.6 ± 4.4 years, contributing 279 plasma concentrations. Dose-normalized area under the concentration-time curves were two times higher in younger children for all three drugs. Neuropsychiatric adverse events were documented in 38% of patients and were more frequent in children aged under 6 years. The physiologically based pharmacokinetic model adequately described both adult and pediatric populations, with over 95% of predicted area under the concentration-time curves and maximum concentration being within 1.3-fold of their observed values. Simulations revealed that ETI plasma exposure was two-fold to four-fold higher in those aged 2-6 years when compared with adults. Although central nervous system penetration was substantial for ivacaftor and elexacaftor, but minimal for tezacaftor, simulated central nervous system exposure did not differ between children with and without reported NAEs.</p><p><strong>Conclusions: </strong>Younger children have higher dose-normalized exposure. While younger children experience more NAEs in our cohort, plasma and central nervous system exposures appeared similar between groups, suggesting that exposure may not be the only factor driving the NAEs. Further investigations are necessary.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147572","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":"Application of Pharmacometric Modelling Towards Precise Dosing in Neonates, Infants and Toddlers: A Scoping Review.","authors":"Ana S Rodríguez-Báez, Nina Kreuzberger, Claire Iannizzi, Kamran Irfan, Frederike Lentz, Anna Krueger, Norbert Benda, Ulrich Jaehde","doi":"10.1007/s40262-026-01670-0","DOIUrl":"https://doi.org/10.1007/s40262-026-01670-0","url":null,"abstract":"<p><strong>Background: </strong>One of the biggest challenges in the youngest paediatric population (≤ 2 years) is defining a safe and effective dose. Thus, growth and maturation are crucial aspects to consider when pharmacometric (PMX) approaches are applied to estimate key pharmacokinetic parameters that guide dose selection. Derived from this, diverse methodologies and mathematical functions have been proposed. However, there is currently no clear consensus on the use of pharmacometric approaches to guide model-based precision dosing in newborns, infants and toddlers.</p><p><strong>Aim: </strong>This scoping review aimed to provide a comprehensive overview of the current research status on the use of pharmacometric models for precise dosing in neonates, infants and toddlers.</p><p><strong>Methods: </strong>This scoping review was conducted in accordance with the Joanna Briggs Institute guidelines. MEDLINE and Embase were systematically searched from 1 January 2014 to 14 May 2025. Eligible were studies that applied PMX approaches in the youngest population. Data were extracted to identify scaling and maturation functions applied to guide paediatric dosing. Results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Review checklist.</p><p><strong>Results: </strong>From 57 studies included, the most commonly applied PMX approaches were population pharmacokinetics (75%) followed by physiologically based pharmacokinetic modelling (25%). Main application areas included antimicrobial therapy (30%), antiepileptic therapy (12%) and antineoplastic therapy (10%). The most commonly used allometric approaches were the fixed allometric scaling exponent based on a power function (37%), diverse exponents  on body weight (34%), anatomical and physiological scaling (19%), others (8%) and not reported (2%), with normalisation primarily to standard adult body weight (36%) or the median value (27%) and applied to total clearance, intercompartmental clearance and volume of distribution. Maturation functions were typically incorporated using sigmoidal (49%), power (8%), exponential (7%) or linear functions (4%), depending on post-menstrual or post-natal age.</p><p><strong>Conclusion: </strong>This review provides an overview of commonly applied PMX approaches in paediatrics, emphasising the importance of including allometry and maturation functions, and shows the variety of methodological strategies used to guide paediatric dose selection in the youngest population.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126957","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":"Assessing the Influence of CYP3A4 Inhibitors on Voriconazole Exposure across CYP2C19 Genotypes: A Physiologically Based Pharmacokinetic Model Analysis.","authors":"Sahithi Thotakura, Anil R Maharaj","doi":"10.1007/s40262-026-01703-8","DOIUrl":"https://doi.org/10.1007/s40262-026-01703-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Voriconazole (VCZ) is a triazole antifungal agent used to treat invasive infections. It has narrow therapeutic index and exhibits high interindividual variability due to cytochrome P450 (CYP) 3A4 autoinhibition and CYP2C19 polymorphism. As VCZ is a CYP3A4 substrate, it is susceptible to drug-drug interactions (DDIs) with CYP3A4 inhibitors, resulting in increased VCZ exposure. However, due to the differences in CYP2C19 activity, the fraction of VCZ metabolized by CYP3A4 varies across CYP2C19 genotypes. As a result, coadministration of CYP3A4 inhibitors could result in genotype-dependent increases in VCZ exposure, leading to a disproportionate risk for toxicity across genotypes. Despite this, the clinical impact of CYP3A4 inhibition on VCZ exposure across different CYP2C19 genotypes remains poorly characterized.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;The purpose of this study was to develop a genotype-specific VCZ physiologically based pharmacokinetic (PBPK) model to assess the impact of CYP3A4 inhibition and CYP2C19 polymorphism on VCZ exposure.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A genotype-specific VCZ PBPK model was developed and evaluated in PK-Sim&lt;sup&gt;®&lt;/sup&gt; using observed VCZ pharmacokinetic and DDI data. VCZ-CYP3A4 inhibitor DDI potential was assessed by comparing model predicted VCZ exposure with or without CYP3A4 inhibitors across CYP2C19 genotypes. Due to VCZ's CYP3A4 autoinhibition, DDI potential was assessed following single doses of VCZ and at steady state. Furthermore, the risk of toxicity was determined by estimating the percentage of virtual individuals with VCZ trough concentrations (C&lt;sub&gt;trough&lt;/sub&gt;) exceeding 5.5 mg/L, a toxic threshold associated with serious adverse events such as neurotoxicity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Model simulations with a strong CYP3A4 inhibitor (clarithromycin) across CYP2C19 genotypes demonstrated greater relative increases in VCZ exposure after a single dose compared with steady state. Following clarithromycin coadministration, a genotype-dependent increase in single-dose VCZ exposure (relative to VCZ alone) was found, with geometric mean fold increases of 1.57, 1.78, 2.31, and 3.24 in extensive, normal, intermediate, and poor metabolizers, respectively. However, steady-state increases in VCZ exposure with clarithromycin were minimal and similar across CYP2C19 genotypes: 1.40-fold in extensive, 1.60-fold in normal, 1.41-fold in intermediate, and 1.26-fold in poor metabolizers. In the absence or presence of clarithromycin, model-predicted single-dose C&lt;sub&gt;trough&lt;/sub&gt; levels did not exceed the toxic threshold in any genotype. In contrast, compared with VCZ alone, clarithromycin coadministration increased the percentage of virtual individuals with steady-state C&lt;sub&gt;trough&lt;/sub&gt; levels beyond the toxic threshold. This increased from 2 to 11% in normal, 24 to 50% in intermediate, and 63 to 87% in poor metabolizers, while no meaningful change was exhibited in extensive me","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127028","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 of Efavirenz in Pregnancy and Postpartum with and Without First-line Tuberculosis Drugs: Results from IMPAACT P1026s.","authors":"Marije Van Schalkwyk, Jiajia Wang, Adrie Bekker, Eric Decloedt, Gerhard B Theron, Mark F Cotton, Tim R Cressey, Deo Wabwire, Chelsea Stotz, Kevin Knowles, Kathleen George, Renee Browning, Kittipong Rungruengthanakit, Lubbe Wiesner, Edmund V Capparelli, Alice M Stek, Mark Mirochnick, David E Shapiro, Brookie M Best, Ahizechukwu C Eke","doi":"10.1007/s40262-026-01690-w","DOIUrl":"https://doi.org/10.1007/s40262-026-01690-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Efavirenz (EFV) pharmacokinetics (PK) may be influenced by both pregnancy-related physiological changes and concurrent treatment for drug-sensitive tuberculosis (DS-TB), and intensive 24-h EFV PK data during rifampin (RIF)/ isoniazid (INH) treatment in pregnant women living with HIV (PWLHIV) and TB disease are lacking. We evaluated EFV PK in a prospective cohort of PWLHIV receiving WHO-recommended oral daily EFV alongside RIF and INH (with or without ethambutol [EMB] and pyrazinamide [PZA]).</p><p><strong>Methods: </strong>Participants enrolled between 20 and 37⁺⁶ weeks gestation and underwent steady-state intensive 24-h PK sampling during second trimester (2T), third trimester (3T), and 2-8 weeks postpartum (PP) when eligible. PK parameters (AUC_0-24, C_max, C_min and CL/F) were characterized using noncompartmental analysis, and paired comparisons across pregnancy stages were made using geometric mean ratios (GMR) with 90% confidence intervals (CI); α = 0.10. PK outcomes were compared with a previously published cohort of PWLHIV without TB and evaluated against protocol-defined therapeutic targets.</p><p><strong>Results: </strong>Of 22 participants, PK data were available for 12, 21 and 13 participants in 2T, 3T and PP, respectively. In 3T (3T↔PP: n = 13), EFV exposure was lower than PP: AUC_0-24 was 19% lower (GMR 0.81 [0.69-0.95]; p = 0.008), C_max 16% lower (GMR 0.84 [0.76-0.94]; p = 0.033), C_min 25% lower (GMR 0.75 [0.63-0.90]; p = 0.003), and apparent oral clearance (CL/F) 24% higher (GMR 1.24 [1.06-1.46]; p = 0.057). 2T GMRs were directionally similar to 3T but were underpowered (2T↔PP: n = 4). Although median EFV concentrations exceeded therapeutic thresholds, 38% of participants did not meet target AUC_0-24 or C_min. In contrast, in the non-TB group, the EFV AUC_0-24 and C_max were similar in pregnancy and postpartum (3T AUC_0-24 GMR 0.94 [0.86-1.02]; p = 0.373 and C_max GMR 1.07 [0.95-1. 02]; p = 0.167). No infants acquired HIV during follow-up.</p><p><strong>Conclusions: </strong>Late pregnancy combined with DS-TB treatment is associated with lower EFV exposure. Further investigation is needed to determine the clinical significance of these findings, but frequent viral load monitoring is advised in PWLHIV with TB disease receiving EFV-based antiretroviral treatment.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT00042289.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105112","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":"Pharmacokinetic-Pharmacodynamic Modelling of Repeated Ocrelizumab Dosing in Relapsing-Remitting Multiple Sclerosis.","authors":"Trond Trætteberg Serkland, Anna-Kristina Fredheim Oma, Erik I Hallin, Mathias H Øverås, Gro Owren Nygaard, Kjell-Morten Myhr, Øivind Torkildsen, Susanna Röblitz, Silje Skrede","doi":"10.1007/s40262-026-01692-8","DOIUrl":"10.1007/s40262-026-01692-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Although the standard regimen consists of fixed 6-monthly infusions, therapeutic duration may vary between patients, highlighting the need for individualized dosing strategies. The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model able to predict patient-specific treatment responses, as a step towards a clinically applicable tool for optimizing OCR dosing precision in RRMS.</p><p><strong>Methods: </strong>Serum OCR concentrations and CD19⁺ lymphocyte counts from 11 treatment-naïve patients with newly diagnosed RRMS were analyzed. Samples were collected over 24 weeks following the first and second OCR infusions. Data were analyzed using a nonlinear mixed-effects population modelling approach in Monolix Suite 2023R1, with parameter estimation performed via the stochastic approximation expectation-maximization algorithm. Several structural models were evaluated, and model performance was assessed by fit statistics and visual predictive checks.</p><p><strong>Results: </strong>The resultant two-compartment PKPD model successfully described OCR disposition and CD19⁺ lymphocyte depletion/repopulation. The final model included clearance of OCR without target-mediated elimination and described the effect of OCR on the dynamics of CD19⁺ lymphocyte counts. Simulations demonstrated the ability of the model to estimate the time to CD19⁺ lymphocyte repopulation and to explore optimal time for follow-up measurements.</p><p><strong>Conclusion: </strong>A novel PKPD model for OCR in RRMS that integrates drug exposure and CD19⁺ lymphocyte kinetics is presented. Although a small number of patients is included in the current study, this framework represents an important step toward clinically applicable, model-informed dosing strategies, with the potential to enhance treatment precision and support personalized therapy in RRMS.</p><p><strong>Clinical trials registration number: </strong>OVERLORD-MS: NCT04578639, ROS-MS: NCT06663111.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1541-1552"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849896","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 Pharmacokinetics and Pharmacodynamics of Marstacimab, an Anti-tissue Factor Pathway Inhibitor Monoclonal Antibody, in Adolescent and Adult Participants with Hemophilia.","authors":"Satyaprakash Nayak, Akiyuki Suzuki, Patanjali Ravva, Sangeeta Raje","doi":"10.1007/s40262-026-01695-5","DOIUrl":"10.1007/s40262-026-01695-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Marstacimab, a monoclonal antibody that targets tissue factor pathway inhibitor (TFPI), was developed for prophylactic treatment of hemophilia, with or without inhibitors. A nonlinear mixed-effects modeling approach was used to characterize plasma marstacimab and TFPI concentrations and identify covariates impacting marstacimab concentration.</p><p><strong>Methods: </strong>Population modeling using nonlinear mixed-effects modeling (NONMEM) 7.5.0 software was performed with marstacimab and total TFPI concentration data pooled from 213 participants across 6 clinical trials including healthy volunteers (n = 63) and participants with hemophilia (n = 150). Participants received subcutaneous marstacimab at doses ranging from 30 mg to 450 mg. Plasma samples to determine marstacimab and total TFPI were analyzed using validated assays. An E_max pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to link model-predicted free TFPI concentrations to peak thrombin.</p><p><strong>Results: </strong>Marstacimab and total TFPI concentrations were adequately described with a target mediated drug disposition (TMDD) model with nonlinear clearance. Body weight was the key structural covariate. After adjusting for body weight, no clinically relevant effect of age (adolescent vs adult), race (Asian vs non-Asian), participant status (healthy vs hemophilia) or mild hepatic impairment was seen. There was good agreement between observed and model-predicted peak thrombin levels in adults and adolescents, with no clinically relevant differences between the populations.</p><p><strong>Conclusions: </strong>A TMDD model with first-order absorption and quasi-steady-state approximation adequately characterized marstacimab PK and total TFPI concentrations. An E_max model adequately described the relationship between model-predicted free TFPI and peak thrombin. The PK/PD simulation indicated that no changes in dosing regimen based on age or body weight were warranted.</p><p><strong>Clinical trials registration: </strong>ClinicalTrials.gov: NCT02531815, NCT02974855, NCT03363321, NCT03938792, NCT04832139, NCT04878731.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1591-1612"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891020","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":"Pharmacokinetics and Target Attainment of Antimicrobial Drugs Throughout Pregnancy. Part II: Cephalosporins.","authors":"Femke A Elzinga, Kaylee R M Ferrier, Fabian Mulder, Eline H van der Veen, Jelmer R Prins, Lars C Nijdam, Marjolijn N Lub-de Hooge, Rik L J Winter, Jos G W Kosterink, Daan J Touw, Paola Mian","doi":"10.1007/s40262-026-01696-4","DOIUrl":"10.1007/s40262-026-01696-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>Understanding the pharmacokinetics (PK) of antibiotics in pregnant women is essential for safe and effective treatment. This review is part of a series that evaluates the PK, exposure, and target attainment of antibiotics during pregnancy. Part II focuses on cephalosporins and investigates if evidence-based dosing regimens are developed.</p><p><strong>Methods: </strong>A systematic literature search was conducted using PubMed on 24 July 2025. Articles containing PK data on pregnant women treated with any of the 35 selected cephalosporins were classified as relevant. Extracted PK and target attainment parameters included volume of distribution (Vd), clearance (CL), drug concentrations, area under the curve, elimination half-life (t_1/2), probability of target attainment, and proposed dosing regimens.</p><p><strong>Results: </strong>Of 219 articles identified, 44 met the inclusion criteria, covering 14 out of 35 cephalosporins. During second (T2) and third (T3) trimesters of pregnancy, Vd (9.2-18.4%) and CL (30.8-100%) were higher compared with nonpregnant, first trimester, or postpartum women. Consequently, reduced target attainment was reported in T2 and T3 pregnant women. Evidence-based dosing regimens were proposed for pregnant women receiving cefazolin, cefuroxime, cefoxitin, ceftazidime, cephradine, cefatrizine, and ceftizoxime.</p><p><strong>Conclusions: </strong>During pregnancy, an increase in Vd and CL was observed, indicating a potential need for higher or additional dosages, or shorter dosing intervals to achieve target attainment. However, evidence-based dosing adjustments were identified for only seven cephalosporins. These findings highlight significant gaps in knowledge and underscore the need for further research to characterize PK profiles and establish dosing recommendations for the remaining cephalosporins in pregnant women.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1463-1515"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148825588","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 Pharmacokinetics and Disposition of Imrecoxib.","authors":"Shengnan Zhao, Charlie Li, Marlon C Mallillin, Raimar Löbenberg, Neal M Davies","doi":"10.1007/s40262-026-01705-6","DOIUrl":"10.1007/s40262-026-01705-6","url":null,"abstract":"<p><p>Imrecoxib is a cyclooxygenase-2-preferential nonsteroidal anti-inflammatory drug approved in China for the symptomatic treatment of osteoarthritis and is currently marketed only in China. This narrative review evaluates its clinical pharmacokinetics, including disposition, special populations, drug-drug interactions, and evidence for dose adjustment. After oral administration, imrecoxib reaches peak plasma concentrations within 2-3 h, and food increases systemic exposure. It is highly protein bound and extensively metabolised sequentially from imrecoxib (M0) to 4'-hydroxymethylimrecoxib (M1), then to the aldehyde intermediate 4'-formylimrecoxib (M-CHO), and finally to 4'-carboxyimrecoxib (M2). Cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6) mediate M1 formation, while M2 formation also involves aldehyde oxidase. Both M1 and M2 are pharmacologically active, and M2 is the predominant circulating metabolite. Unchanged urinary excretion is negligible, whereas M1, M2, and their conjugates contribute to renal elimination. Severe renal impairment markedly increases M2 exposure (area under the plasma concentration-time curve from time zero to the last measurable concentration [AUC_0-t] approximately 3.7-fold that in subjects with normal renal function) and reduces its apparent clearance to approximately 37% of that in subjects with normal renal function, although the clinical exposure-response consequences and the proposed reduced-dose regimens remain unvalidated. Moderate hepatic impairment markedly increases imrecoxib and M1 exposure (area under the plasma concentration-time curve from time zero to infinity [AUC_0-∞] approximately 10.8-fold and 3.2-fold that in matched healthy subjects, respectively), while M2 AUC_0-∞ increases by approximately 35%. In a small single-dose study, exposure to imrecoxib, M1, and M2 was numerically higher in older subjects, but the differences were not statistically significant and pharmacokinetic equivalence was not demonstrated. Currently, no definitive dose-adjustment recommendations have been established, although dose reduction may be considered in severe renal impairment; routine age-based adjustment is not supported, and the optimal regimen in hepatic impairment remains undefined. Multiple-dose imrecoxib did not meaningfully alter warfarin pharmacokinetics or anticoagulant response, whereas fluconazole increased imrecoxib maximum plasma concentration (Cₘₐₓ) and AUC_0-t by approximately 88% and 72%, respectively, without comparable increases in M1 or M2 exposure. Current evidence is limited by small, mainly single-dose studies, predominantly Chinese populations, and the absence of validated exposure-response relationships integrating imrecoxib, M1, and M2. More robust studies are needed to define dose adjustment in organ impairment.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1429-1440"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988172","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}