Clinical Pharmacokinetics最新文献

{"title":"Pharmacokinetics and Pharmacodynamics of Prusogliptin (DBPR108), a Once-Daily Dipeptidyl Peptidase-4 Inhibitor, in Patients with Type 2 Diabetes.","authors":"Wenfang Liu, Kexu Yang, Yang Lin, Chunyan Lu, Jingyi Liu, Huan Zhou, Juan Wang, Tianhao Zhang, Lingli Yao, Huanhuan Qi, Xiaofang Zhang, Rui Jia, Xiaoli Li, Shan Jing","doi":"10.1007/s40262-025-01501-8","DOIUrl":"10.1007/s40262-025-01501-8","url":null,"abstract":"<p><strong>Background and objective: </strong>DBPR108 (prusogliptin) is a novel, orally bioavailable dipeptidyl peptidase-4 (DPP-4) inhibitor. This study investigated the pharmacokinetics and pharmacodynamic characteristics of DBPR108 tablets in patients with type 2 diabetes.</p><p><strong>Methods: </strong>In this randomized, parallel-group, open-label, phase I study, Chinese adults with type 2 diabetes, glycated hemoglobin of 7.0-9.5%, and body mass index of 19-35 kg/m² were randomized 1:1:1 to once-daily DBPR108 50-, 100-, or 200-mg tablet groups. The primary endpoints included pharmacokinetic and pharmacodynamic characteristics after a single dose and multiple doses of DBPR108.</p><p><strong>Results: </strong>In total, 30 patients were randomized with 10 patients in each group. DBPR108 was quickly absorbed with median time to reach the maximum plasma concentration of 1.5-4 h at steady state. Exposure to DBPR108 at steady-state increased dose proportionally with mean maximum steady-state plasma DBPR108 concentration during dosage intervals of 119, 256, and 567 ng/mL in the 50-, 100-, and 200-mg groups, respectively. Accumulation ratio of DBPR108 ranged from 0.85 to 1.3, and steady state was reached after four continuous daily doses. After multiple doses of DBPR108, maximum inhibitory efficacy of DPP-4 increased with higher dose levels ranging from 62.1 to 89.4%. Active glucagon-like peptide-1 levels increased after DBPR108 administration. In addition, six patients experienced treatment-emergent adverse events without leading to treatment interruption or discontinuation.</p><p><strong>Conclusions: </strong>DBPR108 was well tolerated in Chinese patients with type 2 diabetes, and both the pharmacokinetic and pharmacodynamic profiles support once-daily dosage regimens of DBPR108 in future studies.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT05146869); registered 23 November 2021.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"703-713"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957082","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":"A Systematic Review of Pharmacokinetic Studies of Colistin and Polymyxin B in Adult Populations.","authors":"Puteri Juanita Zamri, Sazlyna Mohd Sazlly Lim, Fekade Bruck Sime, Jason A Roberts, Mohd Hafiz Abdul-Aziz","doi":"10.1007/s40262-025-01488-2","DOIUrl":"10.1007/s40262-025-01488-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;The pharmacokinetics of polymyxins are highly variable and conventional dosing regimens may likely lead to sub-optimal exposures and outcomes, particularly in critically ill patients with multi-drug-resistant infections. The aim of this systematic review is to describe the published pharmacokinetic data and to investigate variables that have been shown to affect the pharmacokinetics of colistimethate sodium, colistin, and polymyxin B in adult populations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Sixty studies were identified. A total of 27 and 33 studies described the pharmacokinetics of colistin and polymyxin B, respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The most common dosing regimen for colistimethate sodium was a loading dose of 9 MIU, followed by 9 MIU/day in two to three divided doses, while for polymyxin B, a loading dose of 100-200 mg, followed by 50-100 mg every 12 h was given. Studies that used colistin sulfate instead of colistimethate sodium reported lower inter-individual variability, which may be attributed to the formulation of colistin sulfate being an active drug. The volume of distribution for colistin is typically lower in healthy individuals than in critically ill patients, owing to variations in physiological and pathological conditions. The clearance of colistimethate sodium in critically ill patients not undergoing dialysis was higher, around 13 L/h, compared with those receiving continuous renal replacement therapy, where clearance ranged from 2.31 to 8.23 L/h. In patients receiving continuous renal replacement therapy, clearance of colistin was higher compared with colistimethate sodium (2.06-6.63 L/h and 1.57-3.85 L/h, respectively). Colistin protein binding in critically ill patients ranged from 51% to 79%. The volume of distribution of polymyxin B was similar between critically ill and acutely ill patients, with range of 6.3-33.1 L and 6.22-38.6 L, respectively. Clearance of polymyxin B was also almost similar between critically ill and acutely ill patients (range of 1.27-2.32 L/h). There were two studies that reported free drug concentrations instead of the total drug concentrations of polymyxin B. In critically ill patients, protein binding ranged from 48.8% to 92.4% for polymyxin B. Creatinine clearance was the most common patient characteristic associated with altered clearance of colistimethate sodium and/or colistin, and polymyxin B.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Critically ill patients exhibit complex pharmacokinetics for colistin and polymyxin B, influenced by renal function, body weight, and clinical factors such as acute kidney injury, augmented renal clearance, serum albumin, and liver function. These factors necessitate individualized dosing adjustments to avoid toxicity and achieve therapeutic efficacy. Model-informed precision dosing provides a promising approach to optimize their use by integrating population pharmacokinetic parameters, patient-specific varia","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"655-689"},"PeriodicalIF":4.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971767","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":"Impact of Hypothermic Temperature Control on Plasma and Soft Tissue Pharmacokinetics of Penicillin/Beta-Lactamase Inhibitor Combinations in Patients Resuscitated After Cardiac Arrest.","authors":"Alexandra-Maria Stommel, Peter Matzneller, Valentin Al Jalali, Beatrix Wulkersdorfer, Edith Lackner, Matthias Mueller, Christoph Dorn, Michael Holzer, Markus Zeitlinger","doi":"10.1007/s40262-025-01497-1","DOIUrl":"https://doi.org/10.1007/s40262-025-01497-1","url":null,"abstract":"<p><strong>Background and objectives: </strong>Penicillin/beta-lactamase inhibitors are often used to treat aspiration pneumonia in patients resuscitated after cardiac arrest (CA). The impact of hypothermic temperature control on the pharmacokinetics of amoxicillin/clavulanate (AMO/CLAV) and ampicillin/sulbactam (AMP/SULB) has not been studied. Our objective was to evaluate the effects of hypothermic temperature control on the plasma and soft tissue pharmacokinetics of AMO/CLAV and AMP/SULB, including pulmonary concentrations of AMP/SULB, in patients resuscitated after CA.</p><p><strong>Methods: </strong>This prospective clinical study involved ten adult patients after CA receiving either AMO/CLAV 2 g/0.2 g or AMP/SULB 2 g/1 g intravenously every 8 h. Patients underwent hypothermic temperature control (33 ± 1 °C) for 24 h, followed by normothermia. Plasma, urine, muscle, and subcutaneous pharmacokinetics were measured and plasma protein-binding assessed for each subject. Microdialysis determined unbound drug concentrations in soft tissues. The pulmonary concentration of AMP/SULB was analyzed in the epithelial lining fluid.</p><p><strong>Results: </strong>No significant differences in plasma pharmacokinetics or renal excretion of AMO/CLAV and AMP/SULB were observed between the two temperature conditions. Soft tissue concentrations showed no consistent trend. Pharmacokinetic/pharmacodynamic targets (time that the unbound plasma concentrations were above the minimal inhibitory concentration [MIC] for MIC up to 8 mg/L) were met but not for 16 mg/L. Pulmonary concentrations of AMP/SULB in the epithelial lining fluid showed no clear trend.</p><p><strong>Conclusion: </strong>This study indicates that hypothermic temperature control does not significantly affect plasma concentrations, soft tissue concentrations, or renal excretion of AMO/CLAV and AMP/SULB in patients resuscitated after CA. However, pulmonary concentrations of AMP/SULB exhibited interindividual variability.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"691-701"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970830","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":"Anti-infectives in Pediatric Patients with Cystic Fibrosis: A Comprehensive Review of Population Pharmacokinetic Analyses.","authors":"Aysenur Yaliniz, Mehdi El Hassani, Ana C Blanchard, Amélie Marsot","doi":"10.1007/s40262-025-01505-4","DOIUrl":"https://doi.org/10.1007/s40262-025-01505-4","url":null,"abstract":"<p><p>Pulmonary complications are the leading cause of morbidity and mortality in pediatric patients with cystic fibrosis. Altered pharmacokinetic parameters in this population, as well as high inter- and intra-individual variability, complicate the optimization of anti-infective treatments. In this review, we aim to summarize and describe all anti-infective population pharmacokinetic (popPK) models applied to pediatric populations with cystic fibrosis. Our objectives were to identify the most-reported structural models and retained covariates and to compare the dosing regimens used in clinical routine with those recommended in literature and guidelines. A literature search was done through the PubMed database from inception to August 2024. Studies were retained only if they complied with the inclusion and exclusion criteria. The review included 21 popPK models covering the pharmacokinetic profiles of eight different molecules. Among these, five are recommended antibiotics for treating pulmonary infections in patients with cystic fibrosis. All models incorporated body composition and/or renal function measures as covariates in their pharmacokinetic parameter equations. Standard dosing regimens in the studies were consistent with guidelines and literature recommendations. This is the first review summarizing and describing all anti-infective popPK models in pediatric patients with cystic fibrosis. Improved estimation of pharmacokinetic parameters and a clearer understanding of variability sources will enhance the optimization of antibiotic treatment in clinical practice. Finally, the impact of new targeted therapies on the management of this population will have to be closely monitored in the years ahead.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"631-653"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980335","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":"Pharmacometabolomics Detects Various Unreported Metoprolol Metabolites in Urine of (Potential) Living Kidney Donors and Kidney Transplant Recipients.","authors":"Wietske A Heddema, Marieke A J Hof, Piotr Sosnowski, Stephan J L Bakker, Gérard Hopfgartner, Frank Klont","doi":"10.1007/s40262-025-01502-7","DOIUrl":"10.1007/s40262-025-01502-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Metoprolol is primarily metabolized via the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme, which underlies interindividual variation in conversion rates and may benefit from pharmacogenetics-driven therapy personalization. However, the field relies heavily on knowledge of a drug's metabolism, often originating from early-phase clinical trials with single-dose administration in small samples of healthy volunteers. Pharmacogenetics could thus benefit from real-world drug metabolism studies.</p><p><strong>Methods: </strong>We conducted a real-world drug metabolism study for metoprolol in 18 (potential) living kidney donors and 374 kidney transplant recipients from the Transplant Lines Food and Nutrition Biobank and Cohort Study (NCT02811835) using existing liquid chromatography-high resolution mass spectrometry pharmacometabolomic data.</p><p><strong>Results: </strong>In both groups, we confirmed the presence of seven expected metabolites, including the high-abundance substances metoprolol acid and hydroxymetoprolol. We were unable to detect deisopropylmetoprolol and a metabolite known as \"H 119/68\". However, we did find putative further oxidized forms, namely the expected variant of deisopropylmetoprolol in which the primary amine is removed and the leftover methyl group is oxidized into a carboxylic acid (\"H 104/83\") and an unknown/unreported metoprolol metabolite that we refer to as \"metoprolol benzoic acid\". Moreover, we found nine other previously unknown/unreported metabolites, putatively reflecting N-glucuronidated metoprolol, four glucuronidated versions of hydroxymetoprolol, and a formylated, a glucuronidated, and two hydroxylated versions of metoprolol acid. Interestingly, the same metabolites were detected in potential living kidney donors and kidney transplant recipients, and metabolite profiles did not differ between both groups in principal component analysis.</p><p><strong>Conclusion: </strong>We found more metoprolol metabolites than previously reported, calling for replication studies and evaluation of pharmacogenetic testing approaches to realize safer, more effective metoprolol therapy.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"779-789"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970934","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 Pharmacokinetic Modelling of Remdesivir and Its Metabolite GS-441524 in Hospitalised Patients with COVID-19.","authors":"Darren M Roberts, Xin Liu, Suzanne L Parker, Andrew Burke, Jenny Peek, Jane E Carland, Bridin Murnion, Vincent Seah, Steven C Wallis, Chandra D Sumi, Saurabh Pandey, Hergen Buscher, Anthony Byrne, Indy Sandaradura, David Bowen, Simon Holz, Adam G Stewart, Krispin M Hajkowicz, Jason A Roberts","doi":"10.1007/s40262-025-01496-2","DOIUrl":"10.1007/s40262-025-01496-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>There are limited data testing whether the licensed dose of remdesivir and its active metabolite GS-441524 achieve target concentrations in hospitalised patients with confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of coronavirus disease-2019 (COVID-19). The objectives of this study were to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalised patients treated for COVID-19 and develop a model to inform dose optimisation in clinical use.</p><p><strong>Methods: </strong>This was a prospective, open-labelled, multi-centre, observational study in four Australian hospitals in adults with confirmed SARS-CoV-2 infection. Patients were administered the licensed remdesivir dose. Remdesivir and GS-441524 concentrations were quantified in multiple plasma samples at different times in the dosing interval by ultra-high-performance liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Patients were divided into two groups: pharmacokinetic model building and external validation. A population pharmacokinetic analysis was built using non-linear mixed-effects modelling. Monte Carlo simulations were performed to describe the impact of age, kidney function and dosing regimen on drug concentrations.</p><p><strong>Results: </strong>In total, 33 patients were enrolled (median age 70 years, estimated glomerular filtration rate (eGFR) 80 mL/min/1.73 m²). The pharmacokinetics for both compounds were adequately described by a two-compartment model (one compartment for each compound) with first-order elimination. Key covariates included in the final model were age and eGFR. GS-441524 plasma concentrations exceeded the lowest reported half-maximal effective concentration (EC₅₀) with the recommended dosage, and higher dosages exceeded the lowest reported 90%-effective concentration (EC₉₀).</p><p><strong>Conclusions: </strong>The licensed remdesivir dose may achieve target concentrations of GS-441524, but higher dosages may optimise outcomes. Dose adjustments are guided primarily by kidney function.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"743-756"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984152","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":"Model-Informed Dose Optimization of Pazopanib in Real-World Patients with Cancer.","authors":"Zhiyuan Tan, Swantje Völler, Anyue Yin, Amy Rieborn, Hans Gelderblom, Tom van der Hulle, Catherijne A J Knibbe, Dirk Jan A R Moes","doi":"10.1007/s40262-025-01504-5","DOIUrl":"https://doi.org/10.1007/s40262-025-01504-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Pazopanib is approved for metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma (STS) in a dose of 800 mg once daily (QD) taken under fasted conditions. In clinical practice, approximately 60% of patients require dose reductions due to toxicity, with severe liver toxicity necessitating treatment interruptions in over 10% of cases. While a trough concentration (C_min,ss) target of ≥ 20.5 mg/L has been established for mRCC efficacy, no specific threshold exists for liver toxicity. The objectives of this study were to develop a population pharmacokinetic (POPPK), an exposure-liver toxicity, and an exposure-tumor size dynamics model to optimize pazopanib initial dose in real-world patients.</p><p><strong>Methods: </strong>In total, 135 patients were included and treated with a median starting dose of 800 mg (interquartile range, IQR: 600-800 mg) QD pazopanib fasted with a median follow-up of 120 (IQR 63-372) days. A population pharmacokinetic model was developed using 460 concentration measurements from 135 patients. Exposure-liver toxicity was evaluated using time-to-event modeling, and exposure-tumor size dynamics was evaluated using tumor growth modelling.</p><p><strong>Results: </strong>The liver toxicity model, with 27 cases of grade ≥ 2 liver toxicity out of 135 patients (20%), identified a C_min,ss threshold of > 34 mg/L associated with a 3.35-fold increased toxicity risk (P < 0.01). Model simulations showed that an initial dose of 600 mg QD significantly reduced liver toxicity risk (P < 0.001) while maintaining C_min,ss ≥ 20.5 mg/L for 76% of the simulated individuals. Tumor size dynamics were analyzed using baseline and posttreatment tumor size measurements from 111 patients. The introduction of primary resistance by using a mixture model improved the model fit significantly. Tumor growth and decay rates differed between mRCC and STS but showed no pazopanib exposure dependency across the studied range, suggesting maximal tumor inhibition at current exposure levels.</p><p><strong>Conclusions: </strong>These findings suggest that an initial pazopanib dose of 600 mg fasted, followed by model-informed precision dosing to maintain C_min,ss between 20 and 34 mg/L, may improve efficacy-toxicity balance and mitigate treatment interruptions.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"715-728"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980336","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":"Variability in Meropenem Distribution and Clearance in Children with Sepsis: Population-Based Pharmacokinetics with Assessment of Renal Biomarkers.","authors":"Jennifer Le, Julie Huynh, Brandon Vo, Annie Mai, Robert H Mak, Jeremiah D Momper, Edmund V Capparelli, Helen Harvey, Sean Avedissian, Erin Bradley, Amy Sitapati, Karandeep Singh, John S Bradley","doi":"10.1007/s40262-025-01495-3","DOIUrl":"https://doi.org/10.1007/s40262-025-01495-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Meropenem dosing to achieve therapeutic exposure in critically ill children with sepsis is challenging due to a spectrum of renal function, from augmented renal clearance (ARC) to acute kidney injury (AKI). The objective of this study was to define meropenem plasma concentrations and pharmacodynamic exposure metrics in children with septic shock during the first 3 days of PICU hospitalization.</p><p><strong>Methods: </strong>We prospectively evaluated meropenem clearance (CL_MERO) and volume of distribution (V_1-MERO), innovatively assessing renal biomarkers (serum creatinine [SCr], serum cystatin C [SCys], and neutrophil gelatinase-associated lipocalin [SNgal]), in infants aged ≥ 4 weeks and children on intravenous (IV) meropenem 20 mg/kg every 8 h from 2019 to 2023. Cases with sepsis were matched to controls without sepsis.</p><p><strong>Results: </strong>Analysis included 27 participants (19 cases and 8 controls) with 309 meropenem serum concentrations. Median age was 11.8 (range 0.6-19.6) years, weight 36.3 (7.2-98.0) kg, SCr 0.33 (0.09-2.57) mg/dL, SCys 451.1 (178.3-1824.1) ng/mL, and SNgal 180.7 (23.2-1403.0) ng/mL. A 2-compartment, population pharmacokinetic (PK) model via NONMEM best described data, with weight on V_MERO and allometric scaling on CL_MERO. Using the final model with SCys in V_1-MERO and estimated glomerular filtration rate (eGFR)-MS in CL_MERO, the median V_1-MERO was 0.23 (range 0.07-0.57) L/kg and CL_MERO 0.15 (0.05-0.49) L/h/kg, with eGFR-MS 139 (23-365) mL/min/1.73 m² from AKI to ARC. Meropenem clearance, V_1-MERO and eGFR-MS were significantly decreased in cases versus controls, with higher variability of eGFR-MS in cases.</p><p><strong>Conclusion: </strong>Wide variation in meropenem concentrations in children with sepsis as compared to those without sepsis prompt close monitoring of GFR and drug concentrations in this population.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"769-777"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984154","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 Pharmacokinetics and Pharmacodynamics of Fepixnebart (LY3016859) and Epiregulin in Patients with Chronic Pain.","authors":"Douglas E James, Jason Bailey, Jan-Stefan van der Walt, Julia Winkler, Rik Schoemaker","doi":"10.1007/s40262-025-01506-3","DOIUrl":"10.1007/s40262-025-01506-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Fepixnebart (LY3016859), a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and tumor growth factor-α, is being developed as a novel analgesic to treat broad-spectrum chronic pain. Early phase clinical studies demonstrated fepixnebart has nonlinear pharmacokinetics in healthy subjects and patients with diabetic nephropathy. This population pharmacokinetic analysis used data from three 26-week, phase 2, proof-of-concept studies in osteoarthritis, diabetic peripheral neuropathic pain (DPNP), and chronic low back pain (CLBP) to characterize the pharmacokinetics of fepixnebart and predict its target engagement by epiregulin. Covariate relationships were also assessed.</p><p><strong>Methods: </strong>Population analysis was performed using nonlinear mixed-effects modeling software. Covariate relationships were explored graphically by plotting potential covariates versus parameters of interest. Simulated target engagement was predicted using the phase 2 dose regimen for fepixnebart (750 mg intravenous starting dose, followed by 500 mg every 2 weeks).</p><p><strong>Results: </strong>The median simulated target engagement at 2 weeks after the last dose of fepixnebart was predicted to be 92.0%, with 90% of predictions between 86.0 and 96.2% and 68.5% of subjects predicted to exhibit target engagement exceeding 90%.</p><p><strong>Conclusions: </strong>The phase 2 dose regimen is adequate to test the analgesic effect of fepixnebart in patients with osteoarthritis, DPNP, and CLBP. In the final model, female sex and higher glomerular filtration rate were associated with higher clearance, female sex was associated with larger volume of distribution of the central compartment (V_c) than male sex, and DPNP was associated with lower V_c than CLBP. There were no significant effects on the concentration of fepixnebart at which its effect on epiregulin is half-maximal (EC₅₀).</p><p><strong>Trail registry: </strong>ClinicalTrials.gov: NCT04529096, NCT04476108, and NCT04456686.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"757-767"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994211","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 Pharmacokinetics of Tarlatamab, a Half-Life Extended DLL3-Directed Bispecific T-Cell Engager in Patients with Previously Treated Small Cell Lung Cancer.","authors":"Stephanie Kong, Mukul Minocha, Po-Wei Chen, Pablo Martinez, Erik S Anderson, Amanda Parkes, Brett E Houk, Chih-Wei Lin","doi":"10.1007/s40262-025-01499-z","DOIUrl":"10.1007/s40262-025-01499-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Tarlatamab is a first in class, half-life extended delta-like ligand 3 (DLL3) directed bispecific T-cell engager (BiTE®) immunotherapy that has shown durable efficacy in patients with previously treated small cell lung cancer (SCLC). The purpose of this analysis was to develop a population pharmacokinetic (PK) model for tarlatamab.</p><p><strong>Methods: </strong>This analysis includes data from 420 patients with previously treated small cell lung cancer (8509 samples) pooled across the Phase 1 DeLLphi-300 study (dose range 0.003-100 mg every 2 weeks and 200 mg every 3 weeks) and Phase 2 DeLLphi-301 study (10 mg and 100 mg every 2 weeks). The data were analyzed using a nonlinear-mixed effects modeling approach implemented in NONMEM (v7.5) software and validated using standard statistical approaches. The effects of intrinsic and extrinsic factors on PK parameters and exposures of tarlatamab were evaluated, and the impact of identified covariates were further assessed using simulations.</p><p><strong>Results: </strong>Tarlatamab serum concentration data were best described by a two-compartment model with linear elimination. Tarlatamab clearance (CL) and central volume of distribution (V_C) were 0.649 L/day and 3.44 L, respectively, for a typical 73-kg individual. The model-estimated median terminal phase elimination half-life was 11.2 days. Tarlatamab pharmacokinetics were not impacted by age, sex, ethnicity, estimates of renal and hepatic function, prior lines of therapy, or baseline disease status. The presence of antidrug antibody (ADA) at any time during the study and bodyweight were found to be statistically significant covariates on CL, and Asian race and bodyweight were found to be statistically significant covariates on V_C; however, they did not lead to a clinically meaningful impact on exposures.</p><p><strong>Conclusions: </strong>The pharmacokinetics of tarlatamab was well-described by a two-compartment model with linear elimination. No clinically significant differences were observed on the basis of age, sex, bodyweight, race, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status, or emergence of ADA. These results support that no dose adjustment is required on the basis of any of the evaluated covariates.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"729-741"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968022","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}