Clinical Pharmacokinetics最新文献

{"title":"Pharmacokinetics, Pharmacodynamics and Safety of Fultagliptin Benzoate Tablets, a DPP-4 Inhibitor, in Patients With Varying Degrees of Renal Insufficiency and Matched Healthy Volunteers: A Phase I Clinical Trial.","authors":"Yue Chen, Chao Hu, Xiaotao Cao, Yuchun Men, Ying Wang, Ruijie Zhang, Hongyu Guan, Lihong Shi, Fang Liu, Jia Miao","doi":"10.1007/s40262-026-01622-8","DOIUrl":"10.1007/s40262-026-01622-8","url":null,"abstract":"<p><strong>Background: </strong>DPP-4 inhibitors are a class of oral hypoglycemic drugs commonly used in the treatment of type 2 diabetes mellitus (T2DM). Fultagliptin benzoate is a novel and high-selective DPP-4 inhibitor. The renal excretion of many medications, including DPP-4 inhibitors, can be altered in patients with renal impairment. This study investigates the pharmacokinetics, pharmacodynamics, and safety of fultagliptin benzoate tablets in mild and moderate renal impairment (RI) compared with normal renal function to ensure safety and efficacy across these groups.</p><p><strong>Methods: </strong>A single-dose, non-randomized, open-label, and parallel-control phase I study was performed. Pharmacokinetics, pharmacodynamics, and safety of fultagliptin benzoate tablets were evaluated.</p><p><strong>Results: </strong>A total of 18 participants were enrolled and completed the study. After oral administration of a single dose of fultagliptin benzoate tablets 12 mg under fasted conditions, fultagliptin was absorbed with median time to reach peak concentration (T_max) of 4.50, 3.00, and 5.50 hours in healthy participants, patients with mild RI, and patients with moderate RI, respectively, and eliminated with mean elimination half-life (t_½) of 32.27, 40.22, and 46.38 h, respectively. Compared with healthy participants, patients with mild RI had similar peak concentration (C_max), while area under the concentration-time curve from time zero to the last measured concentration (AUC_0-t) and AUC from time zero to infinity (AUC_0-∞) increased by 24.7% and 25.0%, respectively. In patients with moderate RI, C_max, AUC_0-t, and AUC_0-∞ increased by 27.5%, 86.4%, and 87.9%, respectively. Comparing the renal clearance rate (CL_R) with that of the healthy participants (8.96 ± 2.24 L/h), the CL_R values (mean ± SD) of patients with mild RI and patients with moderate RI were 6.615 ± 1.34 L/h and 4.54 ± 1.20 L/h, respectively, which were approximately 73.8% and 50.6% of that of the healthy participants. For pharmacodynamic biomarkers, the DPP-4 inhibition rate (E_max) in all groups of participants was > 90%. The duration of DPP-4 inhibition rate over 80% in the three groups showed an increasing trend. Fultagliptin benzoate tablets were well tolerated in all participants during the study.</p><p><strong>Conclusion: </strong>In patients with mild RI, the small increase in exposure to fultagliptin was not considered clinically relevant. Although a significant increase in exposure was observed in patients with moderate RI without eliciting issues related to efficacy and safety, a half-dose reduction may be considered for the protection of participants.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT06883656); registered 12 March 2025 (retrospectively registered).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"545-556"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141360","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":"Model-Based Alternative Dosing Strategies for Subcutaneous Nivolumab to Improve Cost Effectiveness.","authors":"Yan Wang, Laura H Bukkems, Rob Ter Heine, J G C van Hasselt, S L W Koolen, J J M A Hendrikx, Tom Van der Hulle, Ellen Kapiteijn, Juliette Zwaveling, Annemarie Becker, Michel M van den Heuvel, Willemijn S M E Theelen, Thijs H Oude Munnink, Egbert F Smit, Henk-Jan Guchelaar, Dirk Jan A R Moes","doi":"10.1007/s40262-025-01610-4","DOIUrl":"10.1007/s40262-025-01610-4","url":null,"abstract":"<p><strong>Background: </strong>The increasing use of the immune checkpoint inhibitor nivolumab places a significant financial burden on healthcare systems, contributes to environmental concerns, and strains hospital capacities. The nivolumab average exposure and exposure variation of a fixed subcutaneous (SC) dosing regimen (1200 mg every 4 weeks) is significantly higher compared with 3-mg/kg every 2 weeks intravenous dosing.</p><p><strong>Objectives: </strong>We aimed to develop alternative dosing regimens for SC nivolumab to reduce drug expenses and lower the treatment burden for patients while ensuring effective exposure.</p><p><strong>Methods: </strong>Population pharmacokinetic simulation was conducted using a population pharmacokinetic model developed by the license holder to explore alternative SC regimens. In this process, patients were divided into three weight groups: less than 60 kg, 60-90 kg, and more than 90 kg. Furthermore, two experimental progressive alternative dosing regimens were developed, one based on a minimum effective concentration-driven approach. The second progressive alternative regimen was based on using the 1200-mg SC formulation as an intravenous infusion.</p><p><strong>Results: </strong>We developed an alternative bodyweight-based regimen consisting of SC 1200 mg every 7 weeks (<60 kg), 1200 mg every 6 weeks (60-90 kg), and 1200 mg every 5 weeks (>90 kg). This new alternative dosing regimen would save an average of €24,345 (35%) per patient per year compared with SC 1200 mg every 4 weeks. The results for the first experimental, progressive, extended-interval dosing regimen for patients with melanoma indicate that 95% of patients exceed a steady-state trough concentration of 2.5 mg/L when administered SC 1200 mg every 10 weeks. This dosing regimen would decrease the yearly cost from €68,870 to €27,548 (60% less) per patient per year. The second experimental progressive regimen using SC 1200 mg as an intravenous administration every 7 weeks leads to a potential saving of €29,516, which is a 43% decrease compared with the SC 1200-mg approved regimen.</p><p><strong>Conclusions: </strong>The developed dosing regimen with a bodyweight-dependent interval offers a cost-effective and patient-friendly method to optimize SC nivolumab use while ensuring adequate exposure, which can be directly implemented in clinical practice. Moreover, the two experimental progressive proposed regimens provide a rationale for a clinical non-inferiority study in which alternative dose regimens are compared to standard dosing according to the drug label.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"621-632"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951660","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":"Systemic Pharmacokinetic Principles of Therapeutic Peptides.","authors":"Pär Nordell, Rasmus Jansson-Löfmark, Peter Gennemark","doi":"10.1007/s40262-025-01615-z","DOIUrl":"10.1007/s40262-025-01615-z","url":null,"abstract":"<p><strong>Introduction: </strong>Peptide-based therapeutics represent a rapidly expanding class of drugs. Endogenous peptides typically exhibit short elimination half-lives due to proteolytic cleavage and renal filtration. However, modifications such as amino acid substitutions and fatty-acid conjugation can significantly prolong their half-lives, enabling, for example, once weekly dosing. This study revisits the systemic pharmacokinetics of peptide drugs using classical pharmacokinetic principles and elucidates the scaling of peptide pharmacokinetics across species.</p><p><strong>Methods: </strong>Preclinical and clinical pharmacokinetic data were collected from published literature and AstraZeneca internal sources, covering four unconjugated peptides (teduglutide, apraglutide, pramlintide, and exenatide) and five fatty-acid conjugated peptides (tirzepatide, cotadutide, liraglutide, semaglutide and pemvidutide). Algebraic equations for clearance, volume of distribution, and plasma half-life were derived.</p><p><strong>Results: </strong>Theoretical predictions from these models were broadly consistent with collected data; however, there was a tendency to overpredict the volume of distribution. Furthermore, for each peptide drug, these pharmacokinetic parameters were well described by inter-species allometric relationships. The allometric exponents for apparent clearance ranged from 0.58 to 0.88 (geometric mean: 0.72; n = 9; R² ≥ 0.93), while those for apparent volume of distribution ranged from 0.89 to 1.1 (geometric mean: 0.98; n = 8; R² ≥ 0.88). Notably, there were no differences in scaling exponents between unconjugated and fatty-acid conjugated peptides.</p><p><strong>Conclusion: </strong>In summary, our results underscore that the systemic pharmacokinetics of peptide drugs generally follow size-related physiological scaling patterns and provide quantitative tools to facilitate translational assessments in the drug discovery process.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"571-582"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141372","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":"Utilization of Apixaban Pharmacokinetics for Dose Optimization in High-Risk Elderly Patients.","authors":"Rachel Goldstein, Khaled Sandouka, Lana Zighan, Shaul Ya'ari, Meir Bialer, Mordechai Muszkat","doi":"10.1007/s40262-026-01625-5","DOIUrl":"10.1007/s40262-026-01625-5","url":null,"abstract":"<p><strong>Background and objective: </strong>Direct oral anticoagulants have largely replaced vitamin K antagonists, for example, warfarin, because of their favorable safety profile and predictable pharmacokinetics, with apixaban being the most widely used direct oral anticoagulant. Although routine therapeutic drug monitoring is not required, measuring apixaban plasma concentrations may be useful in high-risk clinical scenarios. This aim of this study was to evaluate the impact of a repeat apixaban concentration measurement combined with a pharmacokinetic analysis and dose adjustment on drug concentrations and clinical outcomes.</p><p><strong>Methods: </strong>We conducted a retrospective observational cohort study at Hadassah Mount Scopus Hospital, including elderly patients hospitalized between January 2020 and September 2024 with prescriptions for apixaban. Patients with two appropriately timed, maximum apixaban plasma concentrations within 90 days were analyzed.</p><p><strong>Results: </strong>A total of 127 patients were included (median age 79 years, maximum age 97 years; 51% female). At baseline, 16% had subtherapeutic apixaban plasma concentrations and 20% had supratherapeutic concentrations. Female sex was associated with subtherapeutic concentrations while a standard dose (10 mg/day) of apixaban was associated with supratherapeutic plasma concentrations. Dose adjustment was more common in patients with standard dose therapy and in patients with an out-of-range baseline apixaban measurement with adjusted odds ratio of 6.1 and 95% confidence interval of 2.2-16.9 and 4.9 (95% confidence interval 1.9-12.7), respectively. In patients who had undergone repeated apixaban maximum plasma concentration measurements, we found 24 bleeding events and six thrombotic or embolic events within a 1-year follow-up from the second maximum plasma concentration measurement. Bleeding events were more common in patients whose maximum plasma concentration was out of the therapeutic range (28% vs 15%), CONCLUSIONS: Dose adjustment based on apixaban plasma concentration monitoring increased the proportion of patients who have apixaban concentrations within the therapeutic range. In high-risk elderly patients, an apixaban concentration measurement coupled with active intervention (e.g., dose adjustment) is likely to be clinically beneficial in avoiding bleeding and thromboembolic events.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"609-620"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146194254","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":"Optimising Paediatric Medication Adherence Through Innovative Drug Formulations and Delivery Systems.","authors":"Nokwanda Nhlanzeko Ngcobo","doi":"10.1007/s40262-026-01630-8","DOIUrl":"10.1007/s40262-026-01630-8","url":null,"abstract":"<p><p>Medication adherence remains a significant challenge in healthcare, particularly in paediatric populations, where non-adherence has a substantial impact on therapeutic outcomes and contributes to increased healthcare costs. This manuscript emphasises the central role of drug formulations and delivery systems in shaping adherence behaviours in children. Given the unique pharmacokinetic characteristics of paediatric patients, formulation design has a critical impact on medication efficacy, safety and acceptability. By integrating pharmacological considerations with innovative formulation strategies and tailored care approaches, this work provides practical and evidence-informed pathways to enhance medication adherence and improve clinical outcomes in paediatric care.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"515-526"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509995","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":"Exposure-Response Relationships of Antibody Drug Conjugates in Solid Tumours.","authors":"Merel J J Lucassen, Pauline L M Buitelaar, Bart A W Jacobs, Tim Schutte, Neeltje Steeghs, Alwin D R Huitema","doi":"10.1007/s40262-026-01633-5","DOIUrl":"https://doi.org/10.1007/s40262-026-01633-5","url":null,"abstract":"<p><p>Over the last decade, there has been an increase in development of antibody drug conjugates (ADCs), a drug class designed to bring chemotherapeutic agents to tumour sites. The pharmacokinetics of ADCs are complex, due to their multifaceted structure consisting of an antibody linked to a (chemotherapeutic) payload. This review provides an overview of the pharmacokinetics of approved ADCs for patients with solid tumours in relation to toxicity and/or efficacy outcomes. Due to the complex nature and in vivo modifications of an ADC, the pharmacokinetic exposure is measured partially or with surrogate entities. These entities include the calculated drug-to-antibody ratio (DAR)-corrected ADC, measured conjugated antibody, total antibody and/or free payload concentration. A clear exposure-efficacy and exposure-toxicity relation was evident for the majority of ADCs. A higher exposure of almost all ADCs approved for patients with solid tumours, specifically the conjugated antibody entity, was related to higher objective response rates. A higher exposure of the free circulating cytotoxic payload and of the surrogate entities of ADC exposure, of ADCs with cleavable linkers, was related to toxicity. This is unsurprising as a higher circulating payload may induce toxicities associated with the related chemotherapeutic compound. Non-cleavable linkers increase the plasma stability compared to cleavable linkers, resulting in the absence of an (systemic) exposure-toxicity relation. The exposure-response relations for efficacy and toxicity seem apparent based on current literature, but quantification of all ADC components should be considered to fully elucidate the exposure-response relations. This is a crucial next step for dose optimisation and development of a new generation of this important new therapeutic class.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590424","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":"Nomograms for Therapeutic Drug Monitoring of High-Dose Amikacin in Critically Ill Patients: Insights from a Population Pharmacokinetic Analysis and Dosing Simulation.","authors":"Thi Cuc Nguyen, Dinh Van Le, Hoang Anh Nguyen, Nguyen Tran Nam Tien, Thi Hong Ngoc Nguyen, Dinh Hoa Vu, Hoang Anh Nguyen, Hong Nhung Pham, Cong Tan Nguyen, Dang Minh Vuong Nguyen, The Thach Pham, Ngoc Son Do, Quoc Tuan Dang, Xuan Co Dao, Jan-Willem C Alffenaar","doi":"10.1007/s40262-026-01621-9","DOIUrl":"10.1007/s40262-026-01621-9","url":null,"abstract":"<p><strong>Background and objective: </strong>This study evaluated the probability of pharmacokinetic/pharmacodynamic efficacy target attainment and developed a dosing interval identification nomogram to minimize toxicity risks of high-dose amikacin.</p><p><strong>Methods: </strong>Therapeutic drug monitoring was performed in critically ill patients receiving high-dose (30 mg/kg) amikacin intravenously. Population pharmacokinetic modeling and Monte Carlo simulation were performed in NONMEM^® 7.5.1. The probability of target attainment and the cumulative fraction of response for the local Klebsiella pneumoniae population were assessed using maximum concentration/minimum inhibitory concentration ≥ 8 as the efficacy target. Nomograms stratified by the renal function group were established to guide dosing intervals to avoid exceeding the toxicity minimum concentration threshold of 2.5 mg/L.</p><p><strong>Results: </strong>A total of 251 patients with 488 amikacin concentrations were included. The amikacin pharmacokinetics was best described by a two-compartment model. The creatinine clearance and adjusted body weight were significant covariates for clearance and the central volume of distribution, respectively. Amikacin 30 mg/kg achieved a probability of target attainment > 90% for minimum inhibitory concentrations < 8 mg/L and around 80% for minimum inhibitory concentrations of 8 mg/L. This regimen showed a cumulative fraction of response of 63.5% for K. pneumoniae, while attaining a cumulative fraction of response of 96.8% for susceptible isolates. The 30-mg/kg nomograms in patients with creatinine clearance < 60 and ≥ 60 mL/min showed accurate dosing intervals with around 90% of virtual patients for the post-infusion period from 20 to 32 h and from 6 to 32 h, respectively.</p><p><strong>Conclusions: </strong>Nomogram-aided dosing interval adjustment of high-dose amikacin (30 mg/kg) maximized the efficacy and safety target attainment for critically ill patients with infections caused by susceptible K. pneumoniae.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"557-570"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141344","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":"Evaluation and Improvement of Specialized Vancomycin Pharmacokinetic Models for Pediatric Cardiovascular Intensive Care Unit and Pediatric Oncology Patients.","authors":"Michael G McCarthy, Ron J Keizer, Jasmine H Hughes","doi":"10.1007/s40262-026-01623-7","DOIUrl":"10.1007/s40262-026-01623-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Dose optimization of vancomycin in distinct pediatric subpopulations is inherently complex due to altered vancomycin pharmacokinetics associated with certain conditions or circumstances, such as cancer or postoperative cardiac surgery. Numerous population pharmacokinetic models have been developed that aim to capture these alterations; however, it is currently unclear whether these specialized models are necessary, or if covariates in a well-specified general model can adequately capture pharmacokinetic variation between special subpopulations. Here, we conduct an external evaluation comparing the predictive performance of published general and specialized population pharmacokinetic models in pediatric oncology and pediatric cardiovascular intensive care unit (CVICU) patients in order to address this question, and guide model selection decisions for model-informed precision dosing of vancomycin in these subpopulations.</p><p><strong>Methods: </strong>The predictive error, bias, and accuracy of two general, six oncology-supporting, and three CVICU-supporting pharmacokinetic models were compared in two multi-site data sets of pediatric oncology (N = 371, 1392 drug levels, 20 sites) and pediatric CVICU (N = 219, 1136 drug levels, 11 sites) patients, respectively. The best performing model(s) in each subpopulation were refit to evaluate whether predictive performance could be further improved over the published models.</p><p><strong>Results: </strong>We find that although specialized models performed better than general population models for pediatric CVICU patients, a general model (Colin 2019) performed better than all specialized models for pediatric oncology patients. We additionally report a refit version of the Shimamoto 2024 model for pediatric CVICU patients, which performed better than all published CVICU-supporting models in our data set.</p><p><strong>Conclusion: </strong>Population pharmacokinetic models developed on distinct pediatric subpopulations are not necessarily more fit-for-purpose than models developed on a general population. Both well-specified general models and specialized models may be capable of achieving suitable clinical performance in these subpopulations, and this assessment of model fit-for-purpose must be made on a case-by-case basis.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"527-543"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141338","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":"Correction: Model‑Based Alternative Dosing Strategies for Subcutaneous Nivolumab to Improve Cost Effectiveness.","authors":"Yan Wang, Laura H Bukkems, Rob Ter Heine, J G C van Hasselt, S L W Koolen, J J M A Hendrikx, Tom Van der Hulle, Ellen Kapiteijn, Juliette Zwaveling, Annemarie Becker, Michel M van den Heuvel, Willemijn S M E Theelen, Thijs H Oude Munnink, Egbert F Smit, Henk-Jan Guchelaar, Dirk Jan A R Moes","doi":"10.1007/s40262-026-01627-3","DOIUrl":"10.1007/s40262-026-01627-3","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"633"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442878","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":"Single Saliva Sample Model-Informed Precision Dosing of Levofloxacin for Multidrug-Resistant Tuberculosis.","authors":"Thi A Nguyen, Tri P Nguyen, Anh T Nguyen, Luong V Dinh, Hoa B Nguyen, Hoa D Vu, Tram N B Nguyen, Dang Vu, Greg J Fox, Jan-Willem C Alffenaar, Sophie L Stocker","doi":"10.1007/s40262-026-01619-3","DOIUrl":"10.1007/s40262-026-01619-3","url":null,"abstract":"<p><strong>Background and objectives: </strong>Levofloxacin is an essential drug in multidrug-resistant tuberculosis (MDR-TB) treatment, but high pharmacokinetic variability necessitates therapeutic drug monitoring (TDM) to optimise exposure and improve outcomes. Traditional TDM requires invasive blood sampling, limiting feasibility. Saliva sampling, a non-invasive matrix may simplify implementation. We aimed to develop a levofloxacin population pharmacokinetic (popPK) model integrating plasma and saliva data, and to evaluate saliva-based limited sampling strategies to support model-informed TDM for levofloxacin in practice.</p><p><strong>Methods: </strong>Adults receiving oral levofloxacin for ≥ 7 days had plasma and saliva samples collected at 0, 2, and 5 h post-dose. A plasma-and-saliva popPK model was developed using NONMEM, including covariate evaluation. Predictive performance of saliva-based limited sampling strategies for estimating plasma AUC₂₄ was assessed using Bayesian estimation and Monte Carlo simulations.</p><p><strong>Results: </strong>A total of 57 patients with 342 paired plasma-saliva samples were evaluated. One-compartment model incorporating saliva bio-compartment with first-order absorption (with a lag time) and elimination best described the data. No significant covariates were identified. Simulations showed that the three-point saliva strategy (0, 2, 5 h) predicted plasma AUC₂₄ within clinically acceptable limit (< 15% prediction error). A single 2-h sample yielded comparable accuracy. Two- and three-sample saliva strategies up to 16 h post-dose also showed clinically acceptable accuracy.</p><p><strong>Conclusions: </strong>The developed popPK model enables reliable estimation of levofloxacin exposure from limited saliva samples. A single 2-h post-dose saliva concentration may support model-informed levofloxacin TDM in routine MDR-TB care. This approach may be beneficial in settings where plasma-based TDM is logistically or ethically challenging.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"583-594"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156412","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}