Clinical Pharmacokinetics最新文献

{"title":"A Novel Approach to Evaluating the Design of Pediatric Pharmacokinetic Studies Focused on Accurate Dose Selection.","authors":"Yuanxi Zou, Jerry Nedelman, Mats O Karlsson, Elin M Svensson","doi":"10.1007/s40262-025-01542-z","DOIUrl":"https://doi.org/10.1007/s40262-025-01542-z","url":null,"abstract":"<p><strong>Background and objective: </strong>In pediatric trial design, it is particularly essential to maximize data utilization and ensure robust designs while minimizing sample collection. A common criterion to justify pediatric pharmacokinetic study designs is based on parameter precision (PP) evaluation, recommended by the US Food and Drug Administration. Here, we propose an alternative approach to design evaluation based on accuracy for dose selection (ADS).</p><p><strong>Methods: </strong>This work was conducted using a simulation-and-reestimation framework, based on a real-case scenario of designing the single-dose pharmacokinetic study of the anti-tuberculosis (TB) drug pretomanid, with the aim of selecting doses for the next multidose long-term study. The study powers were computed using the ADS approach under scenarios with (1) real-case conditions, (2) high variabilities, (3) available options of tablet doses for selections. The study power using a PP approach was computed to compare with the ADS approach.</p><p><strong>Results: </strong>The ADS approach suggested that the design selected accurate doses with study power >80% in almost all dosing weight groups, whereas the PP approach found the design underpowered for clearance. The ADS-based power was decreased to ~65% in the smallest weight groups given high variability. Varying the options of dose levels affected the ADS-based power non-monotonically, although fewer levels generally yielded higher power.</p><p><strong>Conclusion: </strong>The ADS approach practically evaluates the precision in dose selection, providing a directly relevant decision criterion for designing pediatric pharmacokinetic studies and could be an alternative for power evaluation when the study is focused on determining doses using discrete tablet sizes.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526687","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 of Sufentanil After Epidural Administration During the Course of Extensive Abdominal Surgery.","authors":"Agnieszka Bienert, Agnieszka Borsuk-De Moor, Paulina Okuńska, Justyna Ber, Danuta Siluk, Małgorzata Waszczuk, Krzysztof Kusza, Tomasz Bartkowiak, Jakub Szrama, Anna Kluzik, Tomasz Koszel, Paweł Wiczling","doi":"10.1007/s40262-025-01543-y","DOIUrl":"https://doi.org/10.1007/s40262-025-01543-y","url":null,"abstract":"<p><strong>Background and objective: </strong>Epidural sufentanil is widely used for intraoperative analgesia and is recognized as a safe and effective route of administration when carefully monitored and administered at the lowest effective doses. Optimizing drug dosing requires a precise understanding of its pharmacokinetics. While it is known that sufentanil concentrations in the blood decline more slowly after epidural administration compared with intravenous administration, and the flip-flop phenomenon has been observed in this context, a pharmacokinetic model accounting for this phenomenon has not yet been described.</p><p><strong>Methods: </strong>This study aimed to develop a pharmacokinetic model of sufentanil following epidural administration, with a focus on its absorption from the epidural space. The study was performed in 23 patients, aged 30-83 years with an American Society of Anesthesiologists (ASA) classification of 2-3, undergoing major abdominal (oncologic and non-oncologic) surgery under general anesthesia and epidural analgesia. Blood samples were collected, and sufentanil concentrations were measured at time points ensuring coverage of the absorption phase. Population analysis was performed using a full Bayesian approach implemented in Stan/Torsten programs with the \"cmdstanr\" and \"bbr.bayes\" packages in RStudio.</p><p><strong>Results: </strong>The Bayesian approach helped incorporate prior information about sufentanil disposition. A two-compartment disposition model with two-compartmental absorption best described the data, featuring a fast absorption rate constant into plasma and the peripheral compartment, and a slow redistribution process from the epidural fat compartment.</p><p><strong>Conclusions: </strong>This study mechanistically describes the flip-flop pharmacokinetics of sufentanil and allows for more precise dosing of epidural sufentanil (NCT06069219).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526694","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":"Maternal-Fetal Physiologically Based Population Pharmacokinetics Model Development of Lopinavir/Ritonavir in HIV/HBV Co-infected Pregnant Women to Quantitatively Describe the Gestational PK Characteristics and Predict the Potential Disease-Drug-Drug Interaction (DDDI).","authors":"Ling Song, Xuan Guo, Wei Yang, Jie Song, Dongyang Liu","doi":"10.1007/s40262-025-01493-5","DOIUrl":"10.1007/s40262-025-01493-5","url":null,"abstract":"<p><strong>Background and objective: </strong>Lopinavir/ritonavir (LPV/r) has been widely used in HIV/HBV co-infected pregnant-women. We aim to characterize the maternal-fetal (m-f) pharmacokinetic (PK) of LPV/r and support the dose optimization and potential drug-drug interaction (DDI) evaluation in this population.</p><p><strong>Methods: </strong>Lopinavir PK characteristics in human immunodeficiency virus/hepatitis B virus (HIV/HBV) co-infected pregnant women (n = 35) and fetus were calculated using non-compartmental analysis followed by quantification of maternal PK characteristics using population PK (PopPK) analysis. A maternal-fetal lopinavir physiologically based pharmacokinetic (PBPK) model was developed by incorporating trans-placental transfer, disease- and pregnancy-related physiological changes. This final population PBPK model was applied to simulate different dose regimens of LPV/r and potential DDI risks under different drug combination scenarios.</p><p><strong>Results: </strong>(AUC_last) of lopinavir in co-infected pregnancy was first reported to be 34.1 and 31.0 mg/L/h for the 2nd and 3rd trimesters. The PBPK-simulated PK parameters were within 0.75 to ~ 1.16-fold of the observations at different stages of pregnancy. The m-f PBPK model-simulated umbilical vein:maternal plasma (UV:MP) ratio of lopinavir was around 0.16 at late trimester, which is consistent with the PopPK model-simulated individual value of 0.116. Simulated results indicated that a standard dose of LPV/r (400/100 mg Q12 h) might not target the effective therapeutic concentration. Model-simulated DDI results suggested that lopinavir increased dose or shortened dosing interval when co-administered with rifampicin in HIV/HBV co-infected pregnancy.</p><p><strong>Conclusions: </strong>This work successfully applied model-informed approaches to quantitatively assess lopinavir m-f PK and also provided a novel strategy for DDI risk evaluation and dosing optimization for other P-gp substrates in HIV/HBV co-infected pregnant women.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"885-898"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Lung Deposition After Administration of Inhaled Mosliciguat (BAY 1237592): Results from Randomized Phase I Studies in Healthy Men.","authors":"Soundos Saleh, Tobias Mundry, Johannes Nagelschmitz, Ulf Buetehorn, Stephan Holzschuh, Sylvia M Nikkho","doi":"10.1007/s40262-025-01503-6","DOIUrl":"10.1007/s40262-025-01503-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Mosliciguat is the first soluble guanylate cyclase activator designed for dry powder inhalation. It is currently under development for the treatment of pulmonary hypertension; the inhaled route of administration delivers the drug to the pulmonary vasculature with the aim of improving pulmonary hemodynamics. We conducted three phase I trials in healthy male volunteers to characterize the pharmacokinetic profile of mosliciguat, focusing on lung deposition after inhalation with a low-resistance device in a lactose carrier-based dry powder formulation.</p><p><strong>Methods: </strong>Study 1 was a randomized, open-label, four-way crossover study (Part 2) comparing the pharmacokinetics of mosliciguat by inhalation (1000 μg), inhalation (1000 μg) with charcoal block, in oral solution (1000 μg), and intravenously (100 μg). (The oral and intravenous doses were selected in Part 1 of the study.) Study 2 was an 8-day, randomized, single-blind, placebo-controlled, multiple-dose escalation study of once-daily inhaled mosliciguat (480, 1000, and 2000 μg). Study 3 was a 2-week, multiple-dose, randomized, placebo-controlled, single-blind study of once-daily inhaled mosliciguat 1000 μg.</p><p><strong>Results: </strong>In Study 1 (Part 2) the absolute bioavailability of inhaled mosliciguat was 18.8% without charcoal block and 16.3% with charcoal block. The absolute bioavailability of oral mosliciguat was 23.1%. Pharmacokinetic parameters showed low-to-moderate inter-subject variability. Time to maximum plasma concentration (t_max) was 2.0 h after inhalation and 1.0 h after oral administration; half-life was 15.1 and 4.4 h, respectively. Based on accumulation ratios in Study 2, the area under the concentration-time curve (AUC) and maximum plasma concentration (C_max) increased by 45-51% and 15-21%, respectively, across doses at day 8. In Study 2 the half-life of inhaled mosliciguat with multiple dosing was 57.4 and 42.3 h at doses of 1000 and 2000 µg, respectively. Data showed moderate variability in AUC and C_max (geometric coefficients of variation, 26.6% and 24.7%, respectively, in study 3 on day 1). Trough levels showed accumulation ratios of 1.7-2.1 in Study 2 (day 8) and 2.5 in Study 3 (day 14). In all three studies, mosliciguat was well tolerated, without major systemic effects on heart rate or blood pressure.</p><p><strong>Conclusions: </strong>Inhaled mosliciguat had a longer t_max and half-life than oral mosliciguat. Accumulation data suggest formation of a mosliciguat depot in the lungs and continuous transfer to the systemic circulation, with an indication of an increase in accumulation ratio with longer duration of treatment.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"909-924"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12158843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119087","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":"Integrated Two-Analyte Population Pharmacokinetics Model of Patritumab Deruxtecan (HER3-DXd) Monotherapy in Patients with Solid Tumors.","authors":"Yuan Xu, Mark Lee, Rujuta Joshi, Xiaoning Wang, Hillary Husband, Rena Byrne, Tim Waterhouse, Malaz Abutarif, Pavan Vaddady, Tushar Garimella, Li Li","doi":"10.1007/s40262-025-01521-4","DOIUrl":"10.1007/s40262-025-01521-4","url":null,"abstract":"<p><strong>Background and objective: </strong>Patritumab deruxtecan (HER3-DXd, also known as MK-1022) is an antibody-drug conjugate comprising a fully human monoclonal antibody against human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload, deruxtecan (DXd), via a tetrapeptide-based cleavable linker. We developed a population pharmacokinetic (PK) model for anti-HER3-ac-DXd (anti-HER3 antibody conjugated DXd) and DXd to characterize their PKs and investigate the impact of preselected covariates.</p><p><strong>Methods: </strong>Data were pooled from four phase I/II studies including patients with breast, lung, and colorectal cancer (N = 733) treated with HER3-DXd monotherapy (1.6-8.0 mg/kg intravenously every 3 weeks). An integrated population PK model, established using stepwise methodology, simultaneously described both anti-HER3-ac-DXd and DXd disposition.</p><p><strong>Results: </strong>Anti-HER3-ac-DXd PK was described by a two-compartment model with three elimination pathways: linear transient clearance, nonspecific time-dependent clearance, and nonlinear Michaelis-Menten clearance. DXd PK was described by a one-compartment model with two clearance pathways: linear and nonlinear Michaelis-Menten clearance. The formation of DXd was rate limited by all three clearance pathways of anti-HER3-ac-DXd. Moderate hepatic impairment was a significant covariate on DXd but not anti-HER3-ac-DXd exposure. Other prespecified covariates did not have a clinically important impact on exposure to anti-HER3-ac-DXd or DXd.</p><p><strong>Conclusions: </strong>The final integrated population PK model characterized the PK of both anti-HER3-ac-DXd and DXd in patients with solid tumors treated with HER3-DXd and supported the selected 5.6 mg/kg Q3W dosing regimen. Consistent with current data, dose adjustment based on the covariates investigated is not warranted.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"943-957"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics of 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}