Clinical Pharmacokinetics最新文献

{"title":"Population Pharmacokinetics of Elexacaftor, Tezacaftor and Ivacaftor in a Real-World Cohort of Adults with Cystic Fibrosis.","authors":"Paulette Magnas, Naïm Bouazza, Frantz Foissac, Léo Froelicher Bournaud, Gabrielle Lui, Nicolas Carlier, Jennifer Da Silva, Johanna Fesenbeckh, Reem Kanaan, Isabelle Honoré, Clémence Martin, Jean-Marc Treluyer, Pierre-Régis Burgel, Sihem Benaboud","doi":"10.1007/s40262-025-01516-1","DOIUrl":"10.1007/s40262-025-01516-1","url":null,"abstract":"<p><strong>Background and objectives: </strong>Elexacaftor-tezacaftor-ivacaftor (ETI), a combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, has become the therapeutic standard of care for most people with cystic fibrosis (pwCF). People with cystic fibrosis exhibit differences in CFTR genotypes and have important differences in phenotypic characteristics including age, body weight, pancreatic status, disease severity, and comorbidities. While these differences predict large interindividual variability (IIV) in ETI exposure, there is a unique dose regimen recommended for adults. This raises questions around the \"one-dose fits all\" strategy.</p><p><strong>Objectives: </strong>The aims of this study were to describe real-world population pharmacokinetics (Pop-PK) of ETI in adults with CF and identify factors associated with IIV.</p><p><strong>Method: </strong>As part of the ongoing French national observational cohort study the Pop-PK analysis included 552 plasma concentrations drawn routinely from 325 adults with CF.</p><p><strong>Results: </strong>A one-compartment model with first order absorption and elimination best represented all three compounds, and an additional lag-time for elexacaftor PK data. Large IIV was observed in ETI, with an area under the curve (AUC_0-24h for elexacaftor and tezacaftor, and AUC_0-12h for ivacaftor) ranging respectively, from 58.7-422.9 mg⋅h/L; 38.0-207.7 mg⋅h/L and 4.9-64.9 mg⋅h/L. The main sources of IIV identified in the final ETI Pop-PK models were body weight, age, exocrine pancreatic insufficiency and CFTR genotype.</p><p><strong>Conclusion: </strong>This study established the first ETI Pop-PK analysis in adults with CF and identified several covariates that explain IIV. Therapeutic drug monitoring may be beneficial for patients with a small body weight, older ages, carrying one ETI-responsive CFTR variant or those with no exocrine pancreatic insufficiency and especially for patients who combine these characteristics. Therapeutic drug monitoring may also prove to be useful in individuals experiencing adverse events, in those with reduced effectiveness, or to help manage non-adherence issues.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"959-971"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126500","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 Systematic Review and Classification of the Effects of P-glycoprotein Inhibitors and Inducers in Humans, Using Digoxin, Fexofenadine, and Dabigatran as Probe Drugs.","authors":"Claire Coumau, Chantal Csajka","doi":"10.1007/s40262-025-01514-3","DOIUrl":"10.1007/s40262-025-01514-3","url":null,"abstract":"<p><p>P-glycoprotein is a critical efflux transporter that may significantly affect the pharmacokinetics of various drugs by influencing their absorption, distribution and elimination. While European and American regulatory guidelines provide lists of P-glycoprotein modulators, they lack specificity concerning in vivo studies and clear guidance on inducers, creating uncertainty in their clinical relevance. A systematic search on in vivo clinical studies involving healthy volunteers using fexofenadine, dabigatran and digoxin as P-glycoprotein substrates has been performed in accordance with the PRISMA guidelines. A total of 151 studies assessing the impact of P-glycoprotein modulators on the concentration-time profile of P-glycoprotein substrates were retrieved. Additionally, data on the P-glycoprotein modulators' effect on cytochrome P450 3A4 induction or inhibition were also collected. P-gp modulators were classified as potent, moderate, weak or non-interactors for P-glycoprotein, with or without cytochrome P450 3A4 impact, on the basis of the area under the concentration-time curve ratio. This classification was adapted from the Food and Drug Administration criteria for cytochrome interactions. This systematic review identified 49 area under the plasma concentration-time curve ratio values corresponding to P-glycoprotein inhibitors, 23 to P-glycoprotein inducers and 131 to non-interactors. Of these, only 32.5% and 41.1% were classified as weak to potent, respectively. Only 0.7% of inhibitors and no inducers were classified as potent. This suggests that most P-glycoprotein modulators have a limited impact on drug exposure. The potential for interaction increases when P-glycoprotein modulators also affect cytochrome P450 3A4, which is the case for 59.9% of P-glycoprotein modulators. However, some moderate P-glycoprotein modulators may have clinically significant effects depending on the therapeutic margin of the substrate and the clinical context.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"849-863"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12158833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991626","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":"Prediction of Interspecies Translation for Targeting Delivery Coefficients of GalNAc-siRNA Silencing Apolipoprotein C-III Using a Mechanistic Minimal Physiologically Based Pharmacokinetic/Pharmacodynamic Model.","authors":"Zhiteng Tian, Hui Luo, Yantao Chu, Yanhong Liu, Shan Gao, Ling Song, Zhenzhen Yang, Dongyang Liu","doi":"10.1007/s40262-025-01513-4","DOIUrl":"10.1007/s40262-025-01513-4","url":null,"abstract":"<p><strong>Background and objective: </strong>The emerging N-acetylgalactosamine-small interfering RNA (GalNAc-siRNA) conjugates lead the way for liver-targeting delivery to exert gene-silencing therapeutic effects. To facilitate the drug development of GalNAc-siRNA, further detailed understanding of the key modality-specific mechanisms underlying the temporal discordance between pharmacokinetics and pharmacodynamics and how these processes can be extrapolated from animals to humans is needed.</p><p><strong>Methods: </strong>A mechanistic minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK-PD) model for an investigational new apolipoprotein C-III (APOC3)-silencing GalNAc-siRNA (RBD5044) was developed using available pharmacokinetic/pharmacodynamic (PK/PD) data. The aim was to explore hepatic-targeting delivery processes, the PK/PD relationship, and interspecies translation.</p><p><strong>Results: </strong>First, multiple PK/PD datasets from mice were satisfactorily fitted using the mPBPK-PD model. Second, we translated the mice model to the monkey model, validated it, and then extrapolated from mice and monkeys to humans to simulate the PK/PD characteristics. We then mechanistically summarized and proposed the essential in vivo delivery processes of GalNAc-siRNA after subcutaneous administration (termed \"ADUEB\": Absorption [into system circulation], Disposition [distribution to liver target and elimination], Uptake [into hepatocytes], Escape [from endosome and lysosome compartments], and Binding [with argonaute2 to form RNA-induced silencing complex]). The targeting delivery coefficients of these processes achieved with the model using RBD5044 and the published data of another GalNAc-siRNA (fitusiran) quantitatively reflected the delivery efficiency and rate-limiting factors in targeted hepatocytes.</p><p><strong>Conclusion: </strong>This study successfully constructed the mPBPK-PD model and conducted interspecies extrapolation for a GalNAc-siRNA targeting APOC3. Promising quantitative insights into a hepatic-targeted GalNAc-siRNA delivery system are provided to characterize the unique temporal disconnection of PK/PD properties and evaluate the key in vivo delivery processes. It will promote model-informed strategies and quantitative mechanistic understanding to support efficient drug development, evaluation, and clinical application of this modality in the future.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"865-883"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986550","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":"An Adult Population Pharmacokinetic Model to Simulate Subcutaneous Administration of a Fixed Dose of Furosemide in Adolescents with Heart Failure and Volume Overload.","authors":"Christoph P Hornik, Henry P Foote, Eric Kendig, John Mohr","doi":"10.1007/s40262-025-01515-2","DOIUrl":"10.1007/s40262-025-01515-2","url":null,"abstract":"<p><strong>Background: </strong>Subcutaneous furosemide administered with the On-Body Infusor could be useful in children with heart failure (HF) and congestion due to volume overload, but the appropriate dosing regimen is unknown.</p><p><strong>Objective: </strong>This study aimed to develop a population pharmacokinetic (popPK) model to determine the subcutaneous furosemide dosing regimen in children with HF who are appropriate for On-Body Infusor use.</p><p><strong>Methods: </strong>Samples collected from 15 adults with HF who received subcutaneous or intravenous furosemide in a randomized phase II/III study (NCT02329834) were used to develop the popPK model with covariates identified by forward inclusion and backward elimination; validation was by bootstrapping. The model was allometrically scaled from a 70-kg adult body weight to simulate furosemide pharmacokinetics in virtual adolescents aged 12-17 years by weight category (42.5-50.0, > 50-60, and > 60-70 kg) for subcutaneous furosemide 80 mg (30 mg over 1 h then 12.5 mg/h for 4 h).</p><p><strong>Results: </strong>Furosemide pharmacokinetics were best characterized using a two-compartment model with first-order absorption and elimination. After scaling to adolescents in subcutaneous dosing simulations, estimated furosemide clearance was 1.55 mL/min/kg. Estimated exposure (mean area under the plasma concentration-time curve at 24 h) was 16,800 µg⋅h/L in adolescents weighing 42.5-50.0 kg, 14,700 µg⋅h/L in adolescents weighing > 50-60 kg, and 13,000 µg⋅h/L in adolescents weighing > 60-70 kg versus 12,400 µg⋅h/L in adults.</p><p><strong>Conclusions: </strong>Simulated furosemide exposure was consistent with published values, supporting an 80-mg dose of subcutaneous furosemide (30 mg over the first hour, then 12.5 mg/h for 4 h) for adolescents aged 12-17 years with body weight ≥ 42.5 kg.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"899-908"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976122","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":"The Impact of Dietary Interventions on the Pharmacokinetics of Antifungal Drugs: A Systematic Review with Meta-analyses.","authors":"Agnieszka Wiesner-Kiełczewska, Paweł Zagrodzki, Paweł Paśko","doi":"10.1007/s40262-025-01511-6","DOIUrl":"10.1007/s40262-025-01511-6","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;Managing food-drug interactions may help to optimize the efficacy and safety of antifungal therapy. This systematic review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to evaluate how food, beverages, antacids, and mineral supplements influence the pharmacokinetic (PK) parameters or pharmacokinetic/pharmacodynamic (PK/PD) indices of 14 orally administered antifungal drugs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We considered all studies evaluating the effects of food, beverages, antacids, and mineral supplements on PK parameters and PK/PD indices of oral antifungal drugs for inclusion. We excluded in vitro, in silico, animal studies, reviews, and alcohol-related investigations. Searches were conducted in Medline (via PubMed), Embase, and Cochrane Library from database inception to June 2024. We evaluated the risk of bias using the National Institutes of Health (NIH) tool for before-after studies and the Cochrane tool for parallel and cross-over trials. We performed meta-analyses when two or more studies with comparable designs were available; otherwise, results were summarized qualitatively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The review included 73 studies from 68 reports. Only studies investigating the effect of dietary interactions on PK parameters were found. Meta-analyses were conducted for seven antifungal drugs, while qualitative synthesis covered the remaining drugs. Open-label, cross-over studies accounted for 58% of trials, aligning with Food and Drug Administration (FDA) recommendations. A high risk of bias appeared in 33% of studies, while only 7% showed low risk. Among 11 antifungals with food-effect data, seven (64%) exhibited clinically important interactions. High positive food effects (area under the concentration-time curve (AUC) or peak serum concentration (C&lt;sub&gt;max&lt;/sub&gt;) increased by &gt; 45%) were seen for griseofulvin, itraconazole capsules and tablets (except rice-based meals), and posaconazole immediate-release tablets and suspension. A moderate positive impact of high-fat meals (AUC or C&lt;sub&gt;max&lt;/sub&gt; increased in the range of 35-45%) occurred for ibrexafungerp and oteseconazole. A high negative food effect was observed on the absorption of voriconazole and itraconazole oral suspension or super bioavailable (SUBA) capsules (AUC or C&lt;sub&gt;max&lt;/sub&gt; decreased by &gt; 40%). Antacids strongly reduced itraconazole and ketoconazole absorption, while nutritional supplements improved posaconazole bioavailability. Acidic beverages such as Coca Cola substantially enhanced the absorption of itraconazole, ketoconazole, and posaconazole, whereas orange juice significantly reduced itraconazole bioavailability.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Interactions were influenced by such factors as drug physicochemical properties, type of dietary intervention, drug formulation, and patient characteristics. Although the review largely filled the existing gaps in r","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"815-848"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics for Belantamab Mafodotin Monotherapy and Combination Therapies in Patients with Relapsed/Refractory Multiple Myeloma.","authors":"Theodoros Papathanasiou, Josh Kaullen, Kishore Polireddy, Xi Chen, Yu Liu Ho, Adekemi Taylor, Herbert Struemper, Fernando Carreño, Geraldine Ferron-Brady","doi":"10.1007/s40262-025-01508-1","DOIUrl":"10.1007/s40262-025-01508-1","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;Belantamab mafodotin is an antibody-drug conjugate (ADC) comprising a monoclonal antibody targeting B-cell maturation antigen (BCMA) conjugated to the microtubule inhibitor monomethyl auristatin F via a protease-resistant maleimidocaproyl linker (cysteine maleimidocaproyl monomethyl auristatin F [cys-mcMMAF]). Belantamab mafodotin monotherapy population pharmacokinetics (PopPK) were previously described in relapsed/refractory multiple myeloma (RRMM). This analysis aimed to further characterize the PopPK of belantamab mafodotin ADC and cys-mcMMAF when administered intravenously in patients with RRMM using data from monotherapy and combination therapy studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Data from belantamab mafodotin monotherapy trials (DREAMM-2 [NCT03525678], DREAMM-3 [NCT04162210], DREAMM-12 [NCT04398745], DREAMM-14 [NCT05064358]) and combination trials with lenalidomide/dexamethasone (DREAMM-6 [NCT03544281]) or bortezomib/dexamethasone (DREAMM-6, DREAMM-7 [NCT04246047]) were used to develop PopPK models using non-linear mixed-effect modeling. The models described ADC pharmacokinetics using a linear, two-compartment model with decreasing clearance (CL) over time described by a sigmoidal time function, and cys-mcMMAF pharmacokinetics using a linear two-compartment model with cys-mcMMAF input rate governed by proteolytic ADC degradation that was modulated by a drug-to-antibody ratio that declined exponentially after each dose. Models were externally validated using DREAMM-8 (NCT04484623) study data (belantamab mafodotin plus pomalidomide/dexamethasone).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The analyses included 977 patients, with 8880 measurable ADC and 6354 measurable cys-mcMMAF concentrations. Final ADC model covariates included soluble BCMA (sBCMA), albumin, serum immunoglobulin G, body weight, and body mass index (BMI) all at baseline as well as race and combination therapy. The final cys-mcMMAF model included covariates of baseline sBCMA, serum immunoglobulin G, albumin, body weight, BMI, and race. Typical ADC parameter estimates were 0.926 L/day for initial CL, 10.8 L for steady-state volume of distribution, and 13.0 days for initial elimination half-life. Following monotherapy, CL was reduced by 33.2% to 0.619 L/day over time, resulting in an elimination half-life of 16.8 days. Following combination treatment, CL was reduced by 44.0% to 0.518 L/day, resulting in an elimination half-life of 19.1 days. Cys-mcMMAF had typical values of 642 L/day for CL and 12.3 L for the central volume of distribution. The models adequately described ADC/cys-mcMMAF pharmacokinetics as confirmed during external validation. Alternate models with β2 microglobulin in place of baseline sBCMA also described the pharmacokinetics well. Simulated cycle 1 ADC exposures were most affected by disease-related characteristics: greater disease burden resulted in lower exposure. Predicted cycle 1 ADC and cys-mcMMAF exposures were n","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"925-942"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186725","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":"Scoping Review of Paediatric Population Pharmacokinetic Models of Morphine.","authors":"Michael A Stokes, Noha A Kamel, Marino S Festa, Indy Sandaradura, Sophie L Stocker","doi":"10.1007/s40262-025-01477-5","DOIUrl":"10.1007/s40262-025-01477-5","url":null,"abstract":"<p><strong>Objective and purpose: </strong>This scoping review aimed to summarise all available population pharmacokinetic models of morphine and its metabolites (morphine-3-glucoronide [M3G], morphine-6-glucoronide [M6G]) in children and describe how morphine exposure varies across paediatric age groups and settings. Identifying the factors that contribute to pharmacokinetic variability may improve our understanding of a patient's pharmacodynamic response to morphine.</p><p><strong>Methods: </strong>We searched Embase and MEDLINE databases from inception to 8 March 2024 for paediatric population pharmacokinetic models of morphine and its metabolites. Two reviewers independently screened abstracts and full texts and extracted the data. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.</p><p><strong>Results: </strong>In total, 21 paediatric population pharmacokinetic models of morphine were identified; 12 studies also included morphine metabolites (M3G and/or M6G). Neonates and young children (< 6 years) were the most studied age groups (18/21; 86%), whereas older children (> 6 years) and adolescents (> 10 years) were included in only 6 of the 21 (29%) models. Morphine pharmacokinetics were most commonly described with two-compartment (52%) and one-compartment (38%) structure with first-order elimination. Several model covariates were identified: bodyweight, post-natal age for neonates, body temperature, therapeutic cooling, duration of mechanical ventilation, and genetic variation in drug transporters that mediate the uptake of morphine (e.g. OCT1).</p><p><strong>Conclusion: </strong>Several population pharmacokinetic models of morphine and its metabolites in paediatrics have been published across diverse patient groups. Bodyweight and age-related covariates emerged as the most common factors affecting clearance and distribution; other covariates, including mechanical ventilation, therapeutic cooling, and genetic variation, also impacted morphine pharmacokinetics. Further research should focus on validating the predictive accuracy of paediatric morphine models in different patient populations and the combined effect of covariates, such as those related to critical illness and genetic variation, on morphine pharmacokinetics.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"791-813"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Pharmacodynamics of Prusogliptin (DBPR108), a Once-Daily Dipeptidyl Peptidase-4 Inhibitor, in Patients with Type 2 Diabetes.","authors":"Wenfang Liu, Kexu Yang, Yang Lin, Chunyan Lu, Jingyi Liu, Huan Zhou, Juan Wang, Tianhao Zhang, Lingli Yao, Huanhuan Qi, Xiaofang Zhang, Rui Jia, Xiaoli Li, Shan Jing","doi":"10.1007/s40262-025-01501-8","DOIUrl":"10.1007/s40262-025-01501-8","url":null,"abstract":"<p><strong>Background and objective: </strong>DBPR108 (prusogliptin) is a novel, orally bioavailable dipeptidyl peptidase-4 (DPP-4) inhibitor. This study investigated the pharmacokinetics and pharmacodynamic characteristics of DBPR108 tablets in patients with type 2 diabetes.</p><p><strong>Methods: </strong>In this randomized, parallel-group, open-label, phase I study, Chinese adults with type 2 diabetes, glycated hemoglobin of 7.0-9.5%, and body mass index of 19-35 kg/m² were randomized 1:1:1 to once-daily DBPR108 50-, 100-, or 200-mg tablet groups. The primary endpoints included pharmacokinetic and pharmacodynamic characteristics after a single dose and multiple doses of DBPR108.</p><p><strong>Results: </strong>In total, 30 patients were randomized with 10 patients in each group. DBPR108 was quickly absorbed with median time to reach the maximum plasma concentration of 1.5-4 h at steady state. Exposure to DBPR108 at steady-state increased dose proportionally with mean maximum steady-state plasma DBPR108 concentration during dosage intervals of 119, 256, and 567 ng/mL in the 50-, 100-, and 200-mg groups, respectively. Accumulation ratio of DBPR108 ranged from 0.85 to 1.3, and steady state was reached after four continuous daily doses. After multiple doses of DBPR108, maximum inhibitory efficacy of DPP-4 increased with higher dose levels ranging from 62.1 to 89.4%. Active glucagon-like peptide-1 levels increased after DBPR108 administration. In addition, six patients experienced treatment-emergent adverse events without leading to treatment interruption or discontinuation.</p><p><strong>Conclusions: </strong>DBPR108 was well tolerated in Chinese patients with type 2 diabetes, and both the pharmacokinetic and pharmacodynamic profiles support once-daily dosage regimens of DBPR108 in future studies.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT05146869); registered 23 November 2021.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"703-713"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Systematic Review of Pharmacokinetic Studies of Colistin and Polymyxin B in Adult Populations.","authors":"Puteri Juanita Zamri, Sazlyna Mohd Sazlly Lim, Fekade Bruck Sime, Jason A Roberts, Mohd Hafiz Abdul-Aziz","doi":"10.1007/s40262-025-01488-2","DOIUrl":"10.1007/s40262-025-01488-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;The pharmacokinetics of polymyxins are highly variable and conventional dosing regimens may likely lead to sub-optimal exposures and outcomes, particularly in critically ill patients with multi-drug-resistant infections. The aim of this systematic review is to describe the published pharmacokinetic data and to investigate variables that have been shown to affect the pharmacokinetics of colistimethate sodium, colistin, and polymyxin B in adult populations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Sixty studies were identified. A total of 27 and 33 studies described the pharmacokinetics of colistin and polymyxin B, respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The most common dosing regimen for colistimethate sodium was a loading dose of 9 MIU, followed by 9 MIU/day in two to three divided doses, while for polymyxin B, a loading dose of 100-200 mg, followed by 50-100 mg every 12 h was given. Studies that used colistin sulfate instead of colistimethate sodium reported lower inter-individual variability, which may be attributed to the formulation of colistin sulfate being an active drug. The volume of distribution for colistin is typically lower in healthy individuals than in critically ill patients, owing to variations in physiological and pathological conditions. The clearance of colistimethate sodium in critically ill patients not undergoing dialysis was higher, around 13 L/h, compared with those receiving continuous renal replacement therapy, where clearance ranged from 2.31 to 8.23 L/h. In patients receiving continuous renal replacement therapy, clearance of colistin was higher compared with colistimethate sodium (2.06-6.63 L/h and 1.57-3.85 L/h, respectively). Colistin protein binding in critically ill patients ranged from 51% to 79%. The volume of distribution of polymyxin B was similar between critically ill and acutely ill patients, with range of 6.3-33.1 L and 6.22-38.6 L, respectively. Clearance of polymyxin B was also almost similar between critically ill and acutely ill patients (range of 1.27-2.32 L/h). There were two studies that reported free drug concentrations instead of the total drug concentrations of polymyxin B. In critically ill patients, protein binding ranged from 48.8% to 92.4% for polymyxin B. Creatinine clearance was the most common patient characteristic associated with altered clearance of colistimethate sodium and/or colistin, and polymyxin B.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Critically ill patients exhibit complex pharmacokinetics for colistin and polymyxin B, influenced by renal function, body weight, and clinical factors such as acute kidney injury, augmented renal clearance, serum albumin, and liver function. These factors necessitate individualized dosing adjustments to avoid toxicity and achieve therapeutic efficacy. Model-informed precision dosing provides a promising approach to optimize their use by integrating population pharmacokinetic parameters, patient-specific varia","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"655-689"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Hypothermic Temperature Control on Plasma and Soft Tissue Pharmacokinetics of Penicillin/Beta-Lactamase Inhibitor Combinations in Patients Resuscitated After Cardiac Arrest.","authors":"Alexandra-Maria Stommel, Peter Matzneller, Valentin Al Jalali, Beatrix Wulkersdorfer, Edith Lackner, Matthias Mueller, Christoph Dorn, Michael Holzer, Markus Zeitlinger","doi":"10.1007/s40262-025-01497-1","DOIUrl":"https://doi.org/10.1007/s40262-025-01497-1","url":null,"abstract":"<p><strong>Background and objectives: </strong>Penicillin/beta-lactamase inhibitors are often used to treat aspiration pneumonia in patients resuscitated after cardiac arrest (CA). The impact of hypothermic temperature control on the pharmacokinetics of amoxicillin/clavulanate (AMO/CLAV) and ampicillin/sulbactam (AMP/SULB) has not been studied. Our objective was to evaluate the effects of hypothermic temperature control on the plasma and soft tissue pharmacokinetics of AMO/CLAV and AMP/SULB, including pulmonary concentrations of AMP/SULB, in patients resuscitated after CA.</p><p><strong>Methods: </strong>This prospective clinical study involved ten adult patients after CA receiving either AMO/CLAV 2 g/0.2 g or AMP/SULB 2 g/1 g intravenously every 8 h. Patients underwent hypothermic temperature control (33 ± 1 °C) for 24 h, followed by normothermia. Plasma, urine, muscle, and subcutaneous pharmacokinetics were measured and plasma protein-binding assessed for each subject. Microdialysis determined unbound drug concentrations in soft tissues. The pulmonary concentration of AMP/SULB was analyzed in the epithelial lining fluid.</p><p><strong>Results: </strong>No significant differences in plasma pharmacokinetics or renal excretion of AMO/CLAV and AMP/SULB were observed between the two temperature conditions. Soft tissue concentrations showed no consistent trend. Pharmacokinetic/pharmacodynamic targets (time that the unbound plasma concentrations were above the minimal inhibitory concentration [MIC] for MIC up to 8 mg/L) were met but not for 16 mg/L. Pulmonary concentrations of AMP/SULB in the epithelial lining fluid showed no clear trend.</p><p><strong>Conclusion: </strong>This study indicates that hypothermic temperature control does not significantly affect plasma concentrations, soft tissue concentrations, or renal excretion of AMO/CLAV and AMP/SULB in patients resuscitated after CA. However, pulmonary concentrations of AMP/SULB exhibited interindividual variability.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"691-701"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}