Clinical Pharmacokinetics最新文献

{"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}

{"title":"Population Pharmacokinetics of Cefepime in Critically Ill Children and Young Adults: Model Development and External Validation for Monte Carlo Simulations and Model-Informed Precision Dosing.","authors":"Ronaldo Morales Junior, H Rhodes Hambrick, Tomoyuki Mizuno, Kathryn E Pavia, Kelli M Paice, Peter Tang, Erin Schuler, Kelli A Krallman, Luana Johnson, Michaela Collins, Abigayle Gibson, Calise Curry, Jennifer Kaplan, Stuart Goldstein, Sonya Tang Girdwood","doi":"10.1007/s40262-025-01485-5","DOIUrl":"10.1007/s40262-025-01485-5","url":null,"abstract":"<p><strong>Background and objective: </strong>This study aimed to develop a population pharmacokinetic model for cefepime in critically ill pediatric and young adult patients to inform dosing recommendations and to evaluate the model's predictive performance for model-informed precision dosing.</p><p><strong>Methods: </strong>Patients in the pediatric intensive care unit receiving cefepime were prospectively enrolled for clinical data collection and opportunistic plasma sampling for cefepime concentrations. Nonlinear mixed effects modeling was conducted using NONMEM. Allometric body weight scaling was included as a covariate with fixed exponents. Monte Carlo simulations determined optimal initial dosing regimens against susceptible pathogens. The model's predictions were evaluated with an external dataset.</p><p><strong>Results: </strong>Data from 510 samples across 100 patients were best fit with a two-compartment model with first-order elimination. Estimated glomerular filtration rate and cumulative percentage of fluid balance were identified as significant covariates on clearance and central volume of distribution, respectively. Internal validation showed no model misspecification. External validation confirmed that bias and precision for both population and individual predictions were within commonly accepted ranges. Monte Carlo simulations suggested that the usual dose of 50 mg/kg may require a 3-h infusion or a 6-h dosing interval to keep concentrations above the Pseudomonas aeruginosa minimum inhibitory concentration (≤ 8 mg/L) throughout the dosing interval for patients with normal or augmented renal clearance.</p><p><strong>Conclusion: </strong>A cefepime population pharmacokinetic model for critically ill pediatric patients was successfully developed, accounting for patient renal function, fluid status, and body size, using real-world data. The model was internally and externally validated for use in optimal dosing simulations and model-informed precision dosing.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"553-564"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482352","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 Safety of Navitoclax in Hepatic Impairment.","authors":"Maulik Patel, Jalaja Potluri, Thomas Marbury, Eric Lawitz, Juan Carlos Rondon, David M Hoffman, Satya R Siddani, Kennan C Marsh, Elaine J Kim, Muhammad Erfan Uddin, Rajeev M Menon, Akshanth R Polepally","doi":"10.1007/s40262-025-01484-6","DOIUrl":"10.1007/s40262-025-01484-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Navitoclax, an orally bioavailable B-cell lymphoma-2 (Bcl-2) family protein inhibitor, inhibits antiapoptotic Bcl-2 family proteins (with high affinity to Bcl-XL, Bcl-2, and Bcl-W). Navitoclax in combination with ruxolitinib has been investigated to treat patients with myelofibrosis (MF).</p><p><strong>Methods: </strong>Since navitoclax undergoes hepatic metabolism, we evaluated the pharmacokinetics (PK) and safety of single-dose navitoclax 50 mg in a phase 1 study in participants with mild (N = 6), moderate (N = 6), or severe (N = 1) hepatic impairment and matched participants with normal hepatic function (N = 7). All participants in this study were enrolled per Child-Pugh classification, with demographics matched per age, weight, and race.</p><p><strong>Results: </strong>Navitoclax maximum plasma concentration (C_max), area under the plasma concentration-time curve for time zero to infinity (AUC_0-∞), and terminal elimination half-life (t_1/2) in participants with mild or moderate hepatic impairment were comparable to participants with normal hepatic function. The change in C_max and AUC_0-∞ values in participants with mild and moderate hepatic impairment were within 25% of normal hepatic function. Overall, 2/20 (10%) participants receiving a 50 mg single dose reported grade 1 treatment-emergent adverse events of nausea (N = 1) and diarrhea (N = 1).</p><p><strong>Conclusions: </strong>In summary, no new safety issues were identified. On the basis of the pharmacokinetic results, no dose adjustment is required for patients with MF with mild or moderate hepatic impairment.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"611-617"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718259","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 and Safety of Levofloxacin for Treatment of Rifampicin-Resistant Tuberculosis During Pregnancy and the Postpartum Period: Results from IMPAACT P1026s.","authors":"Jennifer A Hughes, Mauricio Pinilla, Kristina M Brooks, Ahizechukwu C Eke, Alice Stek, Brookie M Best, Mark Mirochnick, Renee Browning, Lubbe Wiesner, Kathleen George, Kevin Knowles, Petra De Koker, James S Ngocho, Lee Fairlie, Nahida Chakhtoura, Anneke C Hesseling, Eric Decloedt, David E Shapiro, Marije van Schalkwyk","doi":"10.1007/s40262-025-01498-0","DOIUrl":"10.1007/s40262-025-01498-0","url":null,"abstract":"<p><strong>Background and objective: </strong>Treatment of rifampicin-resistant tuberculosis (RR-TB) often includes fluoroquinolones, but data on long-term exposure during and after pregnancy are limited. We examined the pharmacokinetics and safety of levofloxacin in an observational cohort of pregnant and postpartum women receiving treatment for RR-TB.</p><p><strong>Methods: </strong>Participants were enrolled in their second or third trimester and underwent intensive pharmacokinetic sampling to quantify levofloxacin plasma concentrations at 20-26 weeks' and 30-38 weeks' gestation and at 2-8 weeks postpartum. The levofloxacin plasma concentration target was 7 µg/mL. Pharmacokinetic parameters over 12 and 24 h were described using non-compartmental analysis and within-participant comparison during pregnancy versus postpartum. Adverse events were extracted from medical records. Infants were enrolled in utero and followed on study for 4-6 months after birth.</p><p><strong>Results: </strong>A total of 11 pregnant women, with a median age of 31 years, received RR-TB treatment including levofloxacin; 6 (55%) were living with HIV. In the second trimester, third trimester, and postpartum, median maximum plasma drug concentration values were 10.3, 10.6, and 10.6 µg/mL, and area under the concentration time curve over 12 h (AUC_0-12) were 69.0, 77.6, and 80.2 µg·h/mL, respectively. Compared with postpartum, median AUCs were lower and clearance was higher in the second but not the third trimester. Eight (72%) women and seven (64%) infants experienced severe or life-threatening adverse events or outcomes that were unlikely to be related to levofloxacin.</p><p><strong>Conclusions: </strong>Levofloxacin AUC_0-12 was lower in the second trimester than the third trimester of pregnancy and the postpartum period, but exposures overall were within target ranges. Further research is warranted to explore the clinical significance of these findings.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"619-630"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742485","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 Teicoplanin: A Systematic Review.","authors":"Jaap W A Mouton, Arnaud De Clercq, Peter De Paepe, Mirko Petrovic, Tania Desmet, Roger J Brüggemann, Jeroen A Schouten, Nynke G L Jager, Pieter A De Cock","doi":"10.1007/s40262-025-01483-7","DOIUrl":"10.1007/s40262-025-01483-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Teicoplanin is a glycopeptide antibiotic used to treat severe Gram-positive infections. This systematic review provides a comprehensive overview of the current knowledge on the pharmacokinetics of teicoplanin across the entire population, with the aim to identify gaps in the existing literature, prioritise pharmacokinetic research, and support optimal dosing strategies.</p><p><strong>Methods: </strong>A systematic literature search of the MEDLINE, Embase, Web of Science, and Scopus databases was conducted. Articles published until 1 October 2024 were identified as eligible when they included a pharmacokinetic analysis of teicoplanin. Relevant pharmacokinetic data were extracted from all included articles. Allometric scaling was carried out for reported values of clearance (CL) and volume of distribution (Vd) to an individual of 70 kg. Articles were categorised into eight subgroups. A qualitative assessment of the included studies was conducted using the clinical pharmacokinetic statement checklist.</p><p><strong>Results: </strong>In total, 85 articles were included in this review. Pharmacokinetic data for 186 healthy volunteers, 130 neonates, 788 children, 1434 adult patients, 48 older adults (≥ 65 years), 674 critically ill patients, 33 patients with impaired renal function, and 159 patients with extracorporeal elimination techniques were extracted for a total of 3452 subjects. Unbound concentrations were assessed in 7.1% of the articles. The Vd_scaled ranged from 1.5 to 583 L/70 kg. The CL_scaled ranged from 0.0073 to 6.38 L/h/70 kg. Covariates on drug disposition were identified in 55.3% of studies, 65.6% of which identified a relationship between renal function and CL. Target attainment was described in 42.4% of articles. Dosing recommendations were provided in 61.2% of all studies. Studies had an average quality score of 69.9% ± standard deviation 15.7.</p><p><strong>Conclusion: </strong>Individual dosing strategies based on renal function need to be developed, particularly in patients with immature or impaired renal function, using state-of-the art pharmacokinetic/pharmacodynamic modelling approaches. Since teicoplanin is highly plasma protein bound and it is suggested that total concentrations cannot be easily translated to unbound concentrations, future research should also include the measurement of unbound concentrations for pharmacokinetic and target attainment evaluation.</p><p><strong>Trial registration: </strong>Prospectively registered in PROSPERO.</p><p><strong>Trial registration number: </strong>CRD42023483334. Registration date: 03/12/2023.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"467-509"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596352","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":"Leveraging Clinical Data to Enhance the Performance Evaluation of Ceftriaxone Population Pharmacokinetic Models in Children.","authors":"Stef Schouwenburg, Tim Preijers, Alan Abdulla, Enno D Wildschut, Birgit C P Koch, Matthijs de Hoog","doi":"10.1007/s40262-025-01486-4","DOIUrl":"10.1007/s40262-025-01486-4","url":null,"abstract":"<p><strong>Introduction: </strong>Sepsis affects approximately 8% of pediatric intensive care unit (PICU) admissions in high-income countries. Ceftriaxone, a broad-spectrum beta-lactam antibiotic, is widely used for treating severe infections and bacterial meningitis in children. Despite its frequent use, limited studies address the population pharmacokinetic (popPK) of ceftriaxone in pediatrics. External validation of popPK models is essential to confirm their suitability for individualized dosing in PICU patients, enabling selection of the model best suited to this population.</p><p><strong>Methods: </strong>This study used data from the EXPAT Kids study, a prospective pharmacokinetics /pharmacodynamics (PK/PD) study. The included popPK models were implemented in NONMEM, with diagnostic goodness-of-fit and visual predictive check analyses performed to assess model accuracy. Predictive performance was evaluated using the relative prediction error, relative root mean square error, and mean (absolute) percentage error.</p><p><strong>Results: </strong>The predictive performance of the evaluated models varied widely. The included models showed only modest performance and generally seemed to overpredict ceftriaxone concentrations. Unbound ceftriaxone popPK models did not perform adequately. None of the models met all the predefined thresholds for accuracy and precision.</p><p><strong>Conclusions: </strong>Our external dataset comprised high ceftriaxone trough concentrations, indicating re-evaluation of current ceftriaxone dosing regimens to minimize the risk of overdosing and prevent toxicity. Future research should focus on the fine dosing balance for ceftriaxone, especially in patients with meningitis, by considering adequate exposure while preventing high trough concentrations. Model-informed precision dosing may enhance the use of the optimal individual dosage for critically ill children. However, our findings highlight the importance of externally evaluating ceftriaxone popPK models in the PICU population.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"585-598"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656236","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":"Opportunities for Precision Dosing of Cytotoxic Drugs in Non-Small Cell Lung Cancer: Bridging the Gap in Precision Medicine.","authors":"M P Kicken, M J Deenen, A J van der Wekken, B E E M van den Borne, M M van den Heuvel, R Ter Heine","doi":"10.1007/s40262-025-01492-6","DOIUrl":"10.1007/s40262-025-01492-6","url":null,"abstract":"<p><p>Precision dosing of classical cytotoxic drugs in oncology remains underdeveloped, especially in treating non-small cell lung cancer (NSCLC). Despite advancements in targeted therapy and immunotherapy, classical cytotoxic agents continue to play a critical role in NSCLC treatment. However, the current body surface area (BSA)-based dosing of these agents fails to adequately address interindividual variability in pharmacokinetics. By better considering patient characteristics, treatment outcomes can be improved, reducing risks of under-exposure and over-exposure. This narrative review explores opportunities for precision dosing for key cytotoxic agents used in NSCLC treatment: cisplatin, carboplatin, pemetrexed, docetaxel, (nab-)paclitaxel, gemcitabine, and vinorelbine. A comprehensive review of regulatory reports and an extensive literature search were conducted to evaluate current dosing practices, pharmacokinetics, pharmacodynamics, and exposure-response relationships. Our findings highlight promising developments in precision dosing, although the number of directly implementable strategies remains limited. The most compelling evidence supports using the biomarker cystatin C for more precise carboplatin dosing and adopting weekly dosing schedules for docetaxel, paclitaxel, and nab-paclitaxel. Additionally, we recommend direct implementation of therapeutic drug monitoring (TDM)-guided dosing for paclitaxel. This review stresses the urgent need to reassess conventional dosing paradigms for classical cytotoxic agents to better align with the principles of the precision dosing framework. Our recommendations show the potential of precision dosing to improve NSCLC treatment, addressing gaps in the current dosing of classical cytotoxic drugs. Given the large NSCLC patient population, optimising the dosing of these agents could significantly improve treatment outcomes and reduce toxicity for many patients.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"511-531"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566227","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":"Volume Kinetics of Gelofusine 4% During Vascular Surgery.","authors":"Cosmin Balan, Cristian Boros, Serban-Ion Bubenek-Turconi, Robert G Hahn","doi":"10.1007/s40262-025-01500-9","DOIUrl":"10.1007/s40262-025-01500-9","url":null,"abstract":"<p><strong>Objectives: </strong>The volume kinetics of a commercially available colloid fluid, Gelofusine, have not been studied previously.</p><p><strong>Methods: </strong>Intravenous Gelofusine 10 mL/kg was infused over 30 min in 15 patients undergoing vascular surgery. Of the 15 patients, 14 were classified as American Society of Anesthesiologists (ASA) class III status. The distribution and elimination of the infused volume was calculated with mixed-model kinetics based on 280 measurements of the hemoglobin-derived plasma dilution (19 per patient) collected over 180 min.</p><p><strong>Results: </strong>The expanded central fluid space volume (V_c, the plasma) amounted to 2.16 L (95% confidence interval [CI] 1.06-2.35) at baseline. The maximum volume expansion of V_c was 706 mL (95% CI 599-812) after infusing Gelofusine 800 mL. Elimination occurred with a half-life of 115 min (95% CI 110-124). Noradrenaline was infused in eight of the 15 patients, leading to a dose-dependent reduction in elimination half-life. For example, an infusion rate of 3 µg/min decreased the half-life to 60 min (- 48%). Distribution of the infused volume to the extravascular space was small (15%), and redistribution to the plasma was accelerated by noradrenaline. Mean arterial pressure and urinary creatinine were not statistically significant covariates, and the model was not strengthened by considering the urine output. Infusion protocols aiming to achieve steady state plasma volume expansion during surgery can begin with a fast infusion over 20 min, then decreasing the rate by 80%.</p><p><strong>Conclusion: </strong>The kinetics of Gelofusine was predictable in patients of American Society of Anesthesiologists class III status undergoing vascular surgery, with the fluid expanding the vascular space and the half-life shortened by noradrenaline.</p><p><strong>Trial registration: </strong>Retrospectively registered with ClinicalTrials.gov NCT06474052, June 24, 2024.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"599-610"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691196","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 Efsubaglutide Alfa in Healthy Subjects and Subjects with Type 2 Diabetes.","authors":"Yan-Ru Lou, Yu-Long Xu, Yifeng Xiong, Chenhui Deng, Qinghua Wang","doi":"10.1007/s40262-025-01475-7","DOIUrl":"10.1007/s40262-025-01475-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objectives: &lt;/strong&gt;Efsubaglutide alfa is a novel long-acting human glucagon-like peptide-1 receptor agonist. Clinical studies in patients with type 2 diabetes (T2D) have shown excellent glucose-lowering effects. This study aims to develop a population pharmacokinetic (popPK) model for efsubaglutide alfa to characterize its pharmacokinetic (PK) profile and assess the impact of intrinsic and extrinsic factors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A popPK model was developed using a nonlinear mixed-effects model (NONMEM) based on 4173 plasma concentration measurements of efsubaglutide alfa from 911 participants, including 36 healthy subjects and 875 patients with T2D, across four clinical trials. These trials involved once-weekly subcutaneous injections of efsubaglutide alfa at doses ranging from 0.375 mg to 9.0 mg, with treatment durations spanning from 1 to 24 weeks. Diagnostic plots, visual predictive checks, nonparametric bootstrap methods, and simulations were employed to validate the model's robustness and performance. Covariates were identified using stepwise covariate modeling.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A two-compartment model with first-order absorption and first-order elimination adequately described the PK characteristics of efsubaglutide alfa. Efsubaglutide alfa exhibited favorable absorption (K&lt;sub&gt;a&lt;/sub&gt; = 0.0255 per hour) and a relatively large apparent volume of distribution (V&lt;sub&gt;2&lt;/sub&gt;/F of 14.5 L with relative standard error [RSE] of 3%; V&lt;sub&gt;3&lt;/sub&gt;/F of 3.01 L). It showed moderate clearance (CL/F of 0.0680 L/h, RSE of 1%, inter-individual variability of 16.6%) and an extended half-life. In subjects with T2D, the geometric mean half-life was estimated between 182 and 215 h across the 1-3 mg dose range, supporting once-weekly or once-every-two-week dosing. Efsubaglutide alfa exposure increased proportionally with dose and remained consistent across studies. Baseline body weight (WT), baseline estimated glomerular filtration rate (eGFR), neutralizing antidrug antibody (Nab), STUDY, and planned dose (ARM) were identified as significant covariates for CL/F, while baseline WT and STUDY influenced V&lt;sub&gt;2&lt;/sub&gt;/F. Although baseline WT and eGFR affected exposure parameters (AUC&lt;sub&gt;ss&lt;/sub&gt;, C&lt;sub&gt;max,ss&lt;/sub&gt;, and C&lt;sub&gt;min,ss&lt;/sub&gt;), these effects were not clinically significant, suggesting no need for dose adjustment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The final popPK model, incorporating significant covariates (baseline WT, baseline eGFR, Nab, STUDY, and ARM), provided robust and precise PK parameter estimates, confirming its applicability in both healthy subjects and those with T2D. The minimal and clinically insignificant impact of baseline WT and eGFR on drug exposure supports the conclusion that no dose adjustment is necessary based on these factors. Moreover, the higher absorption rate constant suggests a rapid onset of action, and the extended half-life supports less frequent dosing, potential","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"533-552"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440071","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}