Clinical Pharmacokinetics最新文献

{"title":"Single Saliva Sample Linezolid Dosing for Multidrug-Resistant Tuberculosis: A Population Pharmacokinetic Modelling of Plasma and Saliva.","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/s40262-026-01626-4","DOIUrl":"10.1007/s40262-026-01626-4","url":null,"abstract":"<p><strong>Background and objective: </strong>Therapeutic drug monitoring (TDM) of linezolid for treating multidrug-resistant tuberculosis (MDR-TB) is recommended but is hindered by the invasive and logistical challenges of plasma sampling. Saliva is a promising alternative, but a saliva pharmacokinetic model to inform dosing is lacking. This study aimed to develop a saliva-based population pharmacokinetic (popPK) model and evaluate limited sampling strategies for linezolid in MDR-TB.</p><p><strong>Methods: </strong>Plasma and saliva samples were collected at pre-dose, 2-, and 5-h post-dose from adults treated with linezolid for ≥ 7 days. A saliva-plasma popPK model was developed in NONMEM with covariate analysis. Bayesian estimation and Monte Carlo simulations were used to evaluate the predictive performance of saliva limited sampling strategies for predicting plasma AUC_0-24. A ±20% bias versus reference was considered acceptable.</p><p><strong>Results: </strong>One-compartment plasma model incorporating a saliva hypothetical effect compartment with first-order absorption and elimination best described the data (102 paired saliva-plasma samples, 17 patients). Body weight influenced volume of distribution with an exponent of 1.1 (95% CI 1.01-1.18). The three-sample (pre-dose, 2-, and 5-h) saliva strategy adequately predicted plasma AUC_0-24 with < 5% median bias. A single saliva sample at pre-dose or 2 h post-dose provided accurate plasma AUC_0-24 predictions (< 5% median bias).</p><p><strong>Conclusions: </strong>The validated model enables reliable estimation of plasma AUC_0-24 using limited saliva samples. A single saliva sample (pre-dose or 2 h post-dose) can accurately predict plasma AUC_0-24, supporting saliva-based TDM as a practical alternative to plasma-based monitoring of linezolid in MDR-TB.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"719-730"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472846","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/Pharmacodynamic Modeling of Therapeutic Enzymes in Lysosomal Storage Diseases.","authors":"Ina Barzel, Ans T van der Ploeg, W W M Pim Pijnappel, P Hugo M van der Kuy, Johanna M P van den Hout, Tim Preijers","doi":"10.1007/s40262-026-01636-2","DOIUrl":"10.1007/s40262-026-01636-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Lysosomal storage diseases (LSDs) are rare genetic disorders treated with enzyme replacement therapy (ERT). However, treatment outcomes are highly variable, reflecting the complexities of therapeutic enzyme pharmacology, patient heterogeneity and therapy response. Population pharmacokinetic/pharmacodynamic (popPK/PD) modeling can help characterize this variability, identify covariates, and optimize dosing strategies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;This review aimed to provide a comprehensive overview of published popPK and popPD models of therapeutic enzymes in LSDs, summarize modeling strategies and study characteristics, and evaluate the quality of the available models.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A systematic search of Medline, Embase, and Web of Science (inception-March 2025) identified studies reporting popPK and/or popPD models of therapeutic enzymes in patients with LSDs. Data on study characteristics, structural and statistical model choices, covariate analyses, and evaluation methods were extracted and compared.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;This review included studies describing 6 popPK models and 3 popPD models of therapeutic enzymes in LSD. All models were developed using the nonlinear mixed-effects (NLME) modeling approach. The PK characteristics were adequately described using a two-compartment model in three studies, a three-compartment model in two studies, and a one-compartment model in one study. Three studies additionally assessed PK parameters in monocytes, leukocytes, and cerebrospinal fluid (CSF). Among all tested covariates, total body weight (TBW) was identified as a significant predictor for clearance (CL) and volume of distribution in the central compartment (V&lt;sub&gt;c&lt;/sub&gt;) in three studies. In one study evaluating PK parameters in CFS, age-based scaling was applied instead of weight-based allometric scaling to improve model fit. PopPD models were limited, with exposure-response relationships described either by an inhibitory maximal effect (I&lt;sub&gt;max&lt;/sub&gt;) model or by a longitudinal logistic regression model with a first-order Markov element.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;PopPK modeling of therapeutic enzymes in LSDs is relatively well established. However, progress in popPD modeling remains limited. Existing models support the use of indirect response and maximum effect (E&lt;sub&gt;max&lt;/sub&gt;) models to describe the delayed and saturable effects of ERT, and innovative approaches such as intracellular PK assessment and Markov modeling illustrate the potential of advanced pharmacometric methods. Nevertheless, there remains a need to further clarify the role of drug concentration measurements in target cells, to characterize CNS distribution in LSDs affecting the brain following intrathecal administration of ERTs and intravenous administration of a novel fusion protein, and to identify robust PD biomarkers in defining exposure-response relationships of therapeutic enzymes in LSD","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"647-664"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834314","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 Modeling of Encorafenib in Healthy Participants and Patients with BRAF V600-Mutant Solid Tumors: A Semi-mechanistic Autoinduction Model.","authors":"Derek Z Yang, Erik M Hahn, Joseph Piscitelli, Yazdi K Pithavala, Jennifer E Hibma","doi":"10.1007/s40262-025-01608-y","DOIUrl":"10.1007/s40262-025-01608-y","url":null,"abstract":"<p><strong>Background and objective: </strong>Encorafenib is a potent and selective adenosine triphosphate-competitive BRAF V600-mutant kinase inhibitor. Encorafenib is approved for multiple indications in combination with binimetinib or cetuximab. This analysis aimed to develop a global population pharmacokinetics (popPK) model characterizing encorafenib disposition across tumor types.</p><p><strong>Methods: </strong>The popPK analysis was based on nine phase 1 to 3 studies in participants with melanoma, colorectal cancer (CRC), non-small cell lung cancer, or other solid tumors, and healthy participants. A total of 1310 participants who received encorafenib as monotherapy or in combination were included. Nonlinear mixed effects modeling was performed using NONMEM v7.5.0. A semi-mechanistic enzyme turnover model was assessed to quantify the autoinduction effect. Stepwise covariate modeling using Perl-speaks-NONMEM (version 5.3.0) evaluated a broad range of covariates.</p><p><strong>Results: </strong>A two-compartment model with first-order absorption and concentration-dependent autoinduction successfully characterized the concentration-time profile of encorafenib. Encorafenib apparent clearance (CL/F) was estimated to be 12.2 L/h after the first dose in a typical adult and increased by 186% to 35 L/h at steady state. This model indicates that maximum autoinduction is expected within 14 days of daily dosing (autoinduction half-life 64 h). Age and tumor type (melanoma, metastatic CRC, other [healthy, lung tumors, other solid tumors]) on CL/F and body weight on volume of distribution were significant covariates; these effects were not determined to be clinically significant.</p><p><strong>Conclusions: </strong>This model successfully described the PK of encorafenib over time and across tumor types. No dose modifications are suggested on the basis of intrinsic or extrinsic factors evaluated.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"693-707"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442857","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":"Pharmacokinetic Comparability Assessment of Tixagevimab and Cilgavimab Developed for COVID-19 Prevention and Treatment Using Standard Exposure Metrics and Partial Area Under the Curve.","authors":"Huixia Zhang, Weifeng Tang, Samuel Sadow, Roberta Baronio, Antonella Nadia Tullio, Lauren Hirao, Vitalina Dzutseva, Cecil Chi-Keung Chen, Alexandre Kiazand, Lee-Jah Chang, Taylor S Cohen, Michael Gibbs","doi":"10.1007/s40262-026-01631-7","DOIUrl":"10.1007/s40262-026-01631-7","url":null,"abstract":"<p><strong>Background and objective: </strong>AZD7442 is a combination of extended half-life monoclonal antibodies (mAbs; tixagevimab and cilgavimab), developed to neutralize SARS-CoV-2. This open-label Phase 1 study compared pharmacokinetics (PK) of three AZD7442 formulations in which component mAbs were (1) co-formulated versus separately formulated and (2) derived from clonal cell line or cell pool material when separately formulated.</p><p><strong>Methods: </strong>Healthy adults were randomized 1:1:1 to receive intramuscular (IM) AZD7442 300 mg (150 mg each of tixagevimab and cilgavimab) via one injection of co-formulated tixagevimab and cilgavimab from clonal cell line material (treatment A), or two sequential injections of tixagevimab and cilgavimab formulated separately either from clonal cell line (treatment B) or cell pool material (treatment C). Serial blood samples were collected up to 360 days post-dose to evaluate serum concentrations and anti-drug antibody responses. Standard exposure metrics (C_max, AUC_last and AUC_inf) were used for PK comparability assessment between treatments (A vs B, B vs C and A vs C). A post hoc analysis using partial area under the curve (pAUC) was also conducted.</p><p><strong>Results: </strong>In total, 224 participants were randomized and dosed. Serum concentration-time profiles overlapped post dosing across treatments. Median time to reach peak concentration occurred within 2 weeks with mean terminal half-life 74-84 days. Pharmacokinetic comparability for tixagevimab, cilgavimab and AZD7442 was demonstrated between treatments, with geometric mean ratios (GMR) and 90% CI within 0.8000-1.2500 using traditional exposure metrics (C_max, AUC_last and AUC_inf) and partial AUCs (pAUCs; AUC_0-d30, AUC_0-d60, AUC_0-d90, or AUC_0-d180), except for comparison of treatment A versus B for tixagevimab, where the lower 90% CI bound for AUC_last GMR (0.7933) was slightly below the pre-defined threshold of 0.8000. Low immunogenicity and acceptable safety profiles were observed across treatments.</p><p><strong>Conclusions: </strong>Pharmacokinetic comparability of tixagevimab, cilgavimab and AZD7442 was demonstrated between the different treatments based on analyses using traditional bioequivalence metrics or pAUCs. Partial AUC could serve as an exposure metric when evaluating PK comparability for extended half-life mAbs.</p><p><strong>Trial registry: </strong>Clinical trials registration number: ClinicalTrials.gov NCT05166421.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"747-761"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590399","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":"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":"Leveraging Model-Informed Drug Development to Predict Asciminib Efficacy in Second-Line Treatment of Chronic Myeloid Leukemia in Chronic Phase.","authors":"Sherwin K B Sy, Deok Yong Yoon, Yiqun Yang, Christelle Darstein, Kohinoor Dasgupta, Shruti Kapoor, Shengyuan Wu, Yasunori Kawakita, Matthias Hoch, Kai Grosch","doi":"10.1007/s40262-025-01616-y","DOIUrl":"10.1007/s40262-025-01616-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>The efficacy of asciminib was proven in newly diagnosed (first-line, 1L) patients with Philadelphia-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) and in patients treated with at least two prior tyrosine kinase inhibitors (third-line, 3L+). Given that no randomized controlled trial has been conducted for second-line (2L) patients with CML, this analysis aims to infer the efficacy of asciminib in the 2L setting using the 80 mg once-daily dosing regimen and to support the use of asciminib in patients with CML-CP irrespective of line of therapy.</p><p><strong>Methods: </strong>Data (n = 430) were used from three studies, including first-in-human and ASCEMBL in 3L+ and ASC4FIRST in 1L trials, to evaluate the effect of line of therapy on efficacy on the basis of the time-course of BCR::ABL1 mRNA transcripts. Previously adapted to characterize the effect of nilotinib as a 1L and 2L therapy on a CML surrogate marker, the model has three compartments representing quiescent leukemic stem cells and proliferating drug-susceptible and resistant bone marrow cells, wherein the effect of asciminib was modeled as an enhancement of the elimination of susceptible cells.</p><p><strong>Results: </strong>Asciminib efficacy in 2L was inferred from 1L by borrowing information from nilotinib data. A credibility assessment showed robust prediction accuracy and precision of the model with external 2L data from the ASC2ESCALATE study (n = 36). Major molecular response (MMR) rates in 2L were predicted to be 61-67% at week 48 and 70-76% at week 96, with the 80 mg total daily dose.</p><p><strong>Conclusions: </strong>A model-informed drug development (MIDD) approach was applied to predict 2L efficacy and supported global regulatory approval of asciminib across treatment lines, despite limited clinical data in 2L.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"595-608"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, Pharmacodynamics and 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":"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}