Clinical Pharmacokinetics最新文献

{"title":"A Phase IIa, Single-Blind, Placebo-Controlled, Parallel-Group Study to Assess Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Brensocatib in Adults with Cystic Fibrosis.","authors":"Michael W Konstan, James J Tolle, Emily DiMango, Patrick A Flume, Helen Usansky, Ariel Teper, Christina N Ramirez, Jimmy Flarakos, Jessica Basso, Sherry Li, Marcela Vergara","doi":"10.1007/s40262-025-01550-z","DOIUrl":"10.1007/s40262-025-01550-z","url":null,"abstract":"<p><strong>Background and objectives: </strong>Brensocatib, an oral, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1), reduces exacerbations and lung function decline in non-cystic fibrosis bronchiectasis (NCFBE). This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of brensocatib in adults with cystic fibrosis (CF), comparing these findings with data from previous trials in healthy adults and in those with NCFBE to inform dose selection for future clinical trials.</p><p><strong>Methods: </strong>A phase IIa, single-blind, randomized, placebo-controlled trial was conducted to assess the PK, PD, safety, and tolerability of brensocatib in adults with CF. Participants were randomly assigned to receive once-daily brensocatib (10 mg, 25 mg, or 40 mg) or placebo for 28 days. The study planned enrollment of up to 34 adults, stratified on the basis of their CF transmembrane conductance regulator (CFTR) modulator use, to evaluate the PK profile of brensocatib and its safety compared with placebo. Primary PK parameters, including maximum plasma concentration (C_max), time to maximum concentration (T_max), area under the concentration-time curve from 0 to 24 h (AUC_0-24), and half-life (t_1/2), were determined on day 1 and day 28. Dose-dependency of brensocatib exposure was analyzed, and safety and tolerability were assessed through treatment-emergent adverse events. Data from participants were compared with previous data from healthy adults and from those with NCFBE.</p><p><strong>Results: </strong>A total of 29 participants were randomized to treatment, with 21 stratified to the CFTR modulator group. Baseline characteristics were similar among cohorts. Mean age was 37.9 (standard deviation (SD) 14.6) years, and most participants exhibited mild-to-moderate lung disease. PK analysis showed dose-dependent and predictable brensocatib exposure, with comparable profiles between participants with and without use of CFTR modulators. In addition, PK profiles in participants were comparable to those of healthy adults and of those with NCFBE. Pharmacodynamic analysis revealed dose-dependent reduction in neutrophil serine protease (NSP) activity, reaching saturation around the 25-mg dose, particularly in blood. Brensocatib at all doses was well tolerated with no new identified safety signals.</p><p><strong>Conclusions: </strong>Brensocatib demonstrated consistent PK profiles independent of CFTR therapy and comparable to those of healthy and NCFBE adults. Brensocatib reduced blood and sputum NSP levels. The safety profile was comparable to previous studies, with no new safety concerns identified, supporting the use of similar dosing for adults with CF as for other populations. These findings advocate for further investigation of brensocatib in CF.</p><p><strong>Clinical trial registration: </strong>NCT05090904.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1561-1574"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768508","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":"Importance of Lysosomal Trapping and Plasmodium Parasite Infection on the Pharmacokinetics of Pyronaridine: A Physiologically Based Pharmacokinetic Model-Based Study.","authors":"Wan-Yu Chu, Wietse M Schouten, Hypolite Muhindo Mavoko, Japhet Kabalu Tshiongo, Doudou Malekita Yobi, Freddy-Arnold Kabasele, Gustave Kasereka, Vivi Maketa, Esperança Sevene, Anifa Vala, Jangsik Shin, Umberto D'Alessandro, Kassoum Kayentao, Alwin D R Huitema, Thomas P C Dorlo","doi":"10.1007/s40262-025-01581-6","DOIUrl":"https://doi.org/10.1007/s40262-025-01581-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Pyronaridine is a blood schizonticide with a high blood-to-plasma ratio, effective against Plasmodium parasites. As a lipophilic, moderately strong base, it accumulates in low-pH compartments such as lysosomes and parasite food vacuoles, leading to tissue accumulation and differences in drug exposure between healthy individuals and patients with malaria. This study applied physiologically based pharmacokinetic (PBPK) modeling to evaluate the effects of lysosomal sequestration, red blood cell (RBC) accumulation, and parasitemia on pyronaridine pharmacokinetics.</p><p><strong>Methods: </strong>Data were available from a phase I clinical trial and the PYRAPREG study. PBPK models were developed in PK-Sim® and MoBi®. A standard multicompartment structure was expanded by adding lysosome compartments to relevant organs. To account for malaria infection, Plasmodium parasite compartments were incorporated into RBCs, with volume scaled by parasitemia.</p><p><strong>Results: </strong>Data from 52 healthy individuals and 25 patients with malaria were used for model optimization. Incorporating lysosomal sequestration was essential for capturing pyronaridine distribution. In patients with malaria, incorporating low hemoglobin (Hb) and drug accumulation in the parasite compartment enabled an adequate description of whole blood pharmacokinetics. Simulations showed that free pyronaridine concentrations in the parasite compartment were over 10-fold higher than that in whole blood. Higher parasitemia was associated with increased area under the curve (AUC)_0-24h and C_max, mainly on day 1, as parasitemia decreased rapidly. However, the subsequent decrease in Hb had the opposite effect, lowering AUC_0-24h and C_max on the following days.</p><p><strong>Conclusions: </strong>This study demonstrates the value of PBPK modeling in elucidating key pharmacokinetic mechanisms, revealing the critical roles of lysosomal sequestration, Hb level, and parasitemia in pyronaridine disposition.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198571","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":"Prediction of Maternal and Fetal Exposure to Escitalopram, Sertraline, and Paroxetine by Combining Human Ex Vivo Placenta Perfusion Data and Physiologically Based Pharmacokinetic Modeling.","authors":"Laure-Hélène Préta, Naïm Bouazza, Frantz Foissac, Léo Froelicher, Saïk Urien, Victoria Buth, Sihem Benaboud, Jean-Marc Tréluyer, Gabrielle Lui","doi":"10.1007/s40262-025-01574-5","DOIUrl":"https://doi.org/10.1007/s40262-025-01574-5","url":null,"abstract":"<p><strong>Background: </strong>Depression is common in pregnant women, and selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants during pregnancy. Pregnancy is a period of major physiological changes that impact drug pharmacokinetics (PK). To date, there is limited information about the placental transfer of antidepressants, and differences in fetal exposure between drugs are poorly characterized.</p><p><strong>Aims: </strong>We aimed to develop physiologically based pharmacokinetic (PBPK) models to assess maternal and fetal exposure to sertraline, escitalopram and paroxetine across pregnancy.</p><p><strong>Methods: </strong>Transplacental parameters from ex vivo human placenta perfusion experiments were estimated using mixed-effects modeling in Monolix and integrated in pregnancy PBPK models in Simcyp PBPK Simulator. After evaluation of the models by comparison with observed data from literature, maternal PK profiles and fetal exposure at different trimesters of pregnancy were simulated.</p><p><strong>Results: </strong>The pregnancy PBPK models accurately predicted maternal and fetal concentration time-courses of SSRIs. Simulations showed a decrease in maternal concentrations during pregnancy for all three SSRIs, affecting both total and unbound concentrations. In the third trimester, residual concentrations were predicted to decrease by 56% and 43% for sertraline, 55% and 49% for escitalopram, and 90% and 88% for paroxetine, for total and unbound concentrations respectively. Cord blood-to-maternal plasma area-under-curve (fm AUC) ratios over 24 h were calculated based on model predictions. By late pregnancy, fm AUC ratios were 0.45 for sertraline, 0.91 for escitalopram, and 0.58 for paroxetine.</p><p><strong>Conclusions: </strong>Quantitative prediction of antidepressants exposure using PBPK modeling integrating ex vivo data will help to better understand the impact of pregnancy-related physiological changes on the PK of these drugs and support evidence-based pharmacotherapy for depression during pregnancy.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173604","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":"A Physiologically Based Pharmacokinetic Model for the Prediction of Plasma and Bone Tissue Exposure after Prophylactic Administration of Ampicillin/Sulbactam in Patients with Osteonecrosis of the Jaw.","authors":"Maximilian Stapf, Anton Straub, Valentin Steinacker, Stefan Hartmann, Oliver Scherf-Clavel","doi":"10.1007/s40262-025-01582-5","DOIUrl":"https://doi.org/10.1007/s40262-025-01582-5","url":null,"abstract":"<p><strong>Background and objective: </strong>The combination of ampicillin (AMP) together with sulbactam (SBC) is a widely used choice for infection prophylaxis in the context of numerous surgical procedures, especially those performed in the field of maxillofacial surgery. Since the pharmacokinetic behavior of these two substances in body tissues is not known in detail owing to sparse tissue data in the literature, the aim of this work was to develop a physiologically based pharmacokinetic (PBPK) model that can predict the concentration versus time courses of AMP and SBC after intravenous administration in plasma, especially bone tissue. Furthermore, the effectiveness of an established prophylaxis regimen based on the developed PBPK model was to be evaluated.</p><p><strong>Methods: </strong>A PBPK model for middle-aged and elderly populations was created using PK-Sim^® software. A total of nine human clinical studies which included data from plasma, lung, skin, and bone tissue were utilized to verify the model. In addition to the physicochemical properties and ADME (Absorption, Distribution, Metabolism, and Excretion) characteristics of AMP and SBC, the measured drug concentrations from the clinical studies were used for development and validation. The performance of the model was evaluated on the basis of established fold error acceptance criteria for selected pharmacokinetic parameters. Here, the model predictions were compared with the observed values.</p><p><strong>Results: </strong>The final PBPK model for AMP and SBC could well describe the measured mean concentrations in plasma and in the different body tissues, as these fell within the predicted 5th-95th percentile range for the most part. This applies to 97% of the AMP and 88% of the SBC measurements. Exactly 81% of the fold error values of the pharmacokinetic parameters are within the twofold acceptance criterion. Overall, the average fold errors for the evaluated pharmacokinetic parameters were within the range of 1.01-1.43.</p><p><strong>Conclusions: </strong>In this work, we present the first PBPK model that simultaneously predicts AMP and SBC in plasma and various tissues. In addition to observed plasma data, the model was also developed and verified with experimentally measured data from the above-mentioned tissues. This allowed a significant limitation of previous PBPK models to be overcome. The effectiveness of established prophylaxis regimes is demonstrated through our model, whereby it must be assumed, owing to measured data for bone tissue, that some individuals do not reach the target values for adequate prophylaxis.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181837","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 of Fentanyl-Emerged Adverse Events and Pharmacokinetics in Neonates: A Physiologically Based Pharmacokinetic Modeling Approach.","authors":"Walaa Yousef Bassyouni Mahdy, Kazuhiro Yamamoto, Risa Joji, Mari Hashimoto, Ruka Nakasone, Kazumichi Fujioka, Kotaro Itohara, Yumi Kitahiro, Tomohiro Omura, Ikuko Yano","doi":"10.1007/s40262-025-01573-6","DOIUrl":"https://doi.org/10.1007/s40262-025-01573-6","url":null,"abstract":"<p><strong>Background: </strong>Despite its common use for analgesia in neonatal intensive care units, the optimal dosing and safety profile of fentanyl, particularly regarding suspected fentanyl-emerged adverse events (FEAEs), such as hypotension, desaturation, and oliguria, are not well-defined.</p><p><strong>Objective: </strong>This study aimed to develop an optimal therapeutic monitoring and dosing strategy for fentanyl for neonates. A physiologically based pharmacokinetic (PBPK) model for predicting fentanyl pharmacokinetics across various populations, including preterm and term neonates, was developed, and the relationship between predicted fentanyl exposure and FEAE incidence in neonates was assessed.</p><p><strong>Methods: </strong>A PBPK model was developed and validated against the observed values in the literature. The model's predictive accuracy for fentanyl pharmacokinetics and association with FEAE incidence in an external retrospective cohort of Japanese neonates was evaluated using the predicted concentrations and pharmacokinetic parameters estimated by PBPK simulation.</p><p><strong>Results: </strong>The PBPK model exhibited reasonable predictive performance for serum fentanyl concentrations in actual neonatal patients (mean error: 9.27% [standard error: 5.06%], root mean squared error: 54.7%). The incidence of any FEAE, particularly oxygen desaturation, was associated with the fentanyl concentration-to-dose ratio, but not with some exposure parameters, such as the area under the curve and maximum concentration. The recommended reduced infusion rate allowed serum fentanyl concentrations to fall within the ranges established by the reported values and our data.</p><p><strong>Conclusions: </strong>Our PBPK model and proposed dosing strategy may contribute to safer and more effective fentanyl use in neonates.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147966","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":"PEGylated Proteins: How Much Does Molecular Weight Matter?","authors":"Diego Maria Michele Fornasari","doi":"10.1007/s40262-025-01568-3","DOIUrl":"https://doi.org/10.1007/s40262-025-01568-3","url":null,"abstract":"<p><p>Polyethylene glycols (PEGs) are inert polymers of repeating ethylene oxide subunits. Attaching PEGs to therapeutic proteins may reduce the protein's immunogenicity and antigenicity, improve solubility and stability, slow protein degradation, and increase the half-life (t_½). This usually results in less frequent administration, improved quality of life and convenience, and potentially better adherence and lower costs. The advantages and disadvantages of PEGylated proteins differ according to the structure of the PEG moiety, particularly its molecular weight. The larger the PEG molecular weight, the longer the t_½ and time to steady state. PEGs have low toxicity and undergo minimal metabolism. The PEG moiety usually undergoes renal elimination and is excreted in urine, but with greater molecular weights, renal elimination declines and biliary excretion increases. Because PEG molecules are not broken down, there is potential for PEGs to accumulate in the cytoplasm, forming vacuoles, mostly in macrophages, although this does not affect their function. The risk of vacuolation increases with molecular weights > 30 kDa. However, even high molecular weight PEGs are used at doses markedly lower than the European Medicines Agency safety threshold for paediatric use. People can develop antibodies to PEGs, and this may increase the overall clearance of the PEGylated protein if antibody levels are sufficiently high (> 500 ng/mL according to one modelling study). In conclusion, it is important for physicians to understand how PEG molecular weight and architecture can impact stability, immunogenicity, glomerular filtration and cellular uptake, to better understand the overall safety, efficacy and pharmacological profile of PEGylated proteins.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174004","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":"Exposure-Response Analysis of Efsubaglutide Alfa in Patients with Type 2 Diabetes Treated with Metformin.","authors":"Qinghua Wang, Fan Jiang, Yulong Xu, Yuyang Lei, Li Zhang, Xiaodong Sun","doi":"10.1007/s40262-025-01569-2","DOIUrl":"https://doi.org/10.1007/s40262-025-01569-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>Efsubaglutide alfa is a long-acting GLP-1 receptor agonist and is designed by fusion of two human GLP-1 molecules with IgG2 Fc via a natural immunoglobulin hinge region. This study evaluates the exposure-response (E-R) relationship of efsubaglutide alfa in patients with type 2 diabetes (T2D) treated with metformin.</p><p><strong>Methods: </strong>Data were derived from an operational seamless design of randomized, double blind, placebo clinical trial (YN011-302) involving 406 subjects with T2D on stable metformin therapy. Participants received weekly subcutaneous injections of 1 mg or 3 mg efsubaglutide alfa, or placebo. The trial included a 24-week double-blind period and a 28-week open-label period.</p><p><strong>Results: </strong>Participants had a median age of 55.0 years, mean body weight of 73.7 kg, fasting plasma glucose (FPG) of 9.72 mmol/L, and glycated hemoglobin (HbA1c) of 8.63%. A robust inverse correlation was observed between efsubaglutide alfa exposure and improvements in HbA1c, FPG, glucose area under the curve (AUC) during mixed-meal tolerance test (MMTT), body weight, and body mass index. Efsubaglutide alfa exposure also positively correlated with C-peptide AUC during MMTT, indicating improved beta-cell function. The E-R model indicates that doubling steady-state trough concentrations (C_min,ss) reduced HbA1c by 0.211%, while every 100 ng/mL increase in C_avg,ss led to 0.5 kg reduction in body weight at Week 24. Baseline HbA1c was a predictor of treatment response. Safety analysis revealed a positive correlation between exposure and gastrointestinal adverse events, which decreased over time, suggesting tolerance development.</p><p><strong>Conclusions: </strong>Efsubaglutide alfa, combined with metformin, significantly improves glycemic control and weight management, with an acceptable safety profile. This E-R model provides insights for dose optimization and trial design, and supports its use as an effective add-on therapy for patients with T2D, as indicated in the drug specification.</p><p><strong>Trial registration: </strong>The trials were registered at Clinicaltrials.gov (identifier: NCT04998032).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130083","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 Pharmacokinetic Analysis of Balcinrenone in Healthy Participants and Participants with Heart Failure and Chronic Kidney Disease.","authors":"Joanna Parkinson, Magnus Åstrand, Johanna Melin, Hans Ericsson","doi":"10.1007/s40262-025-01572-7","DOIUrl":"https://doi.org/10.1007/s40262-025-01572-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Balcinrenone is a novel mineralocorticoid receptor modulator which, based on preclinical data, maintains cardio-renal benefits without increasing hyperkalemia risk. Balcinrenone is developed in combination with dapagliflozin for the treatment of heart failure (HF) with impaired kidney function and chronic kidney disease (CKD). The aim of this work was to apply a population pharmacokinetic (popPK) approach to describe the pharmacokinetics (PK) of balcinrenone, and to quantify the effects of intrinsic and extrinsic factors on balcinrenone PK.</p><p><strong>Methods: </strong>The assessment was based on data from six clinical studies in healthy participants (NCT03843060, NCT03804645, and NCT04798222), participants with renal impairment (NCT04469907), and participants with HF and CKD (NCT03682497 and NCT04595370) using the immediate-release capsule formulation (chosen for phase 3 studies).</p><p><strong>Results: </strong>Food state (i.e., taking balcinrenone with or without food), renal function (estimated glomerular filtration rate [eGFR], incorporated using power function of eGFR on apparent clearance), and study type (phase 1 studies with mainly healthy participants or phase 1b/2b studies in patients with HF and CKD) were identified as covariates on balcinrenone exposure (area under the curve at steady-state [AUC_ss]). The magnitude of the impact of food state on balcinrenone exposure was minor, with a 1.13-fold (95% confidence interval [CI] 1.06-1.21) increase in AUC_ss when balcinrenone was taken with food compared with in a fasted state. Participants with a lower eGFR were observed to have higher exposure: those with an eGFR of 25 mL/min/1.73 m² had a 1.44-fold (95% CI 1.22-1.69) increase in balcinrenone AUC_ss compared with participants with an eGFR of 60 mL/min/1.73 m². Participants from phase 1 studies were estimated to have a 0.49-fold (95% CI 0.41-0.60) lower exposure compared with patients from phase 1b/2b studies.</p><p><strong>Conclusions: </strong>Participants with HF and CKD were observed to have approximately 50% lower apparent clearance compared with healthy participants and those with renal impairment, after adjusting for differences in eGFR. This may indicate that factors other than renal function may impact the apparent clearance of balcinrenone. The impact of the covariates on balcinrenone exposure (AUC_ss) in the intended patient population was less than 50% relative to a reference participant.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079661","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":"Modeling Whole-Body Dynamic PET Microdosing Data to Predict the Whole-Body Pharmacokinetics of Glyburide in Humans.","authors":"Léa Comin, Solène Marie, Moreno Ursino, Sarah Zohar, Nicolas Tournier, Emmanuelle Comets","doi":"10.1007/s40262-025-01562-9","DOIUrl":"https://doi.org/10.1007/s40262-025-01562-9","url":null,"abstract":"<p><strong>Introduction: </strong>Whole-body dynamic (WB4D) positron emission tomography (PET) imaging data using radiolabeled analogs of drugs are mostly analyzed using descriptive approaches, with no relationship to traditional pharmacokinetic studies based on blood sampling. Here, we build a pharmacokinetic (PK) model from WB4D PET data obtained using a microdose of radiolabeled glyburide ([¹¹C]glyburide) in humans, aiming to describe the biodistribution of this drug and compare estimated pharmacokinetic parameters with the parameters obtained in standard PK studies.</p><p><strong>Methods: </strong>The present work analyzes data acquired over 40 min after injection of [¹¹C]glyburide in 16 healthy subjects using non-linear mixed-effect models (NLMEM). In 10 subjects, a second PET acquisition was performed after rifampicin administration, which may cause a drug-drug interaction and inhibit the liver uptake transport of glyburide. Arterial blood, liver, kidneys, pancreas, and spleen kinetics were modeled using NLMEM. The model-building strategy involved selecting the structural model using baseline [¹¹C]glyburide PET data and then selecting the covariate model (rifampicin, age, and gender) and refining the structure of the interindividual variability model using both administration periods. Model selection was based on the corrected Bayesian information criterion and implemented in Monolix software.</p><p><strong>Results: </strong>The final model included seven compartments, with two compartments each for the Liver and kidneys to account for within-tissue exchanges. Rifampicin decreased the Liver distribution by 261%.</p><p><strong>Discussion: </strong>The estimated central volume of distribution (V = 3.6 L) and elimination rate (k = 0.8 h^-1) were consistent with the known pharmacokinetics of glyburide, which is a promising first step in leveraging microdose data to study the WB4D biodistribution.</p><p><strong>Registration: </strong>EudraCT identifier no. 2017-001703-69.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074584","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 Pharmacokinetic Modeling of Canagliflozin in Advanced Chronic Kidney Disease.","authors":"Elias John Elenjickal, Thomas A Mavrakanas, Ari Gritsas, Rita S Suri, Amélie Marsot","doi":"10.1007/s40262-025-01571-8","DOIUrl":"https://doi.org/10.1007/s40262-025-01571-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objectives: &lt;/strong&gt;Canagliflozin is an orally active, selective, reversible sodium-glucose cotransport-2 (SGLT-2) inhibitor used in patients with chronic kidney disease (CKD) to prevent cardiovascular (CV) events and CKD progression. Its initiation is currently not recommended in advanced CKD [estimated glomerular filtration rate (eGFR) &lt; 20 mL/min per 1.73 m&lt;sup&gt;2&lt;/sup&gt;], end-stage kidney disease, or in those on kidney replacement therapies due to insufficient clinical and safety data. This study aimed to develop a population pharmacokinetic (popPK) model using data from patients with advanced CKD, including those on maintenance hemodialysis (HD), to characterize the steady-state pharmacokinetics (PK) of canagliflozin at 100 mg and 300 mg doses, and to assess the impact of significant covariates on its PK.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;PK data were obtained from a single-center, prospective, single-arm, open-label interventional study conducted in two cohorts. The first cohort was a detailed PK sampling done in 10 patients receiving intermittent HD for at least 3 months and the second cohort included sparse PK sampling in 13 patients with advanced CKD, not yet on dialysis. Canagliflozin PK parameters were modeled using nonlinear mixed-effects modeling (NONMEM&lt;sup&gt;®&lt;/sup&gt; version 7.5) with the first-order conditional estimation method with interaction. Model performance was evaluated using goodness of fit plot, bootstrap (n = 1000), and normalized prediction distribution error (NPDE). Model-based simulations were performed using the final model to predict concentration-time profiles at steady state, evaluate the impact of significant covariates on predicted steady-state area under the curve (AUC), and compare PK profiles between patients with non-dialysis CKD and those with hemodialysis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A total of 332 PK observations from 23 patients were analyzed. The mean age of the cohort was 67 ± 15 years with a mean body mass index of 27 ± 5 kg/m&lt;sup&gt;2&lt;/sup&gt;. A two-compartment popPK model of canagliflozin with lag-time, sequential zero- and first-order absorption, and first-order elimination was developed. Age was a significant covariate of the absorption rate constant (K&lt;sub&gt;a&lt;/sub&gt;), which increased with age. Sex was a significant covariate for the apparent volume of distribution (V/F), which was lower in women (80.7 L in men and 49.1 L in women). Model-based simulations demonstrated that steady-state AUC was 66% higher in women compared with men. Additionally, AUC increased approximately threefold in both sexes when the canagliflozin dose was escalated from 100 mg to 300 mg. Notably, eGFR was not a determinant of steady state exposure.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The developed model demonstrates that steady state canagliflozin exposure is higher in women and with use of higher dose, whereas eGFR does not meaningfully alter drug exposure in patients with advanced CKD. Model-based simula","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063477","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}