Pharmaceutics最新文献

{"title":"A Preliminary Study on the Accuracy of MRI-Guided Thalamic Infusion of AAV2-GFP and Biodistribution Analysis Using Cryo-Fluorescence Tomography in Nonhuman Primates.","authors":"Ernesto A Salegio, Reinier Espinosa, Geary R Smith, David Shoshan, Matthew Silva, Eli White, Jacob McDonald","doi":"10.3390/pharmaceutics17091167","DOIUrl":"10.3390/pharmaceutics17091167","url":null,"abstract":"<p><p><b>Background:</b> Adeno-associated viral (AAV) vectors are the leading platform for gene therapy, but common delivery routes show limited spread to distal cortical structures, hence the utility of direct, intrathalamic infusions for broader transgene distribution. In this preliminary study, we recapitulate previous studies targeting the thalamus as a conduit to achieve cortical transgene spread and showcase novel data evaluating biodistribution of a green fluorescent protein (GFP) using cryo-fluorescence tomography (CFT). For the first time in nonhuman primates (NHPs) and coupled with magnetic resonance imaging (MRI)-guidance, we demonstrated the application of CFT as a powerful tool to map out vector distribution in the NHP brain. <b>Methods:</b> Briefly, a single thalamic infusion was performed in African green monkeys using ClearPoint's navigational platform to deliver an AAV serotype 2 vector containing a GFP payload. Transgene biodistribution was assessed in the left and right hemispheres using CFT and histological analysis, respectively. <b>Results:</b> Infusions were successfully performed with sub-millimetric target accuracy and with minimal error, achieving ~86% thalamic coverage with the largest infusion volume. Histology confirmed the presence of the GFP transgene, with the strongest signal in the cerebral gray/white matter and internal capsule, while CFT allowed for the three-dimensional detection of the transgene starting at the site of infusion and spreading to multiple cortical regions. <b>Conclusions:</b> These findings suggest that by combining MRI-guided technology with CFT imaging, it is feasible to map whole-brain gene biodistribution in NHPs. This proof-of-concept study bridges the gap between cellular microscopy and MRI-guidance to provide a complete picture of disease and treatment with clinical applicability.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12473227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategic and Chemical Advances in Antibody-Drug Conjugates.","authors":"Ibrahim A Alradwan, Meshal K Alnefaie, Nojoud Al Fayez, Alhassan H Aodah, Majed A Majrashi, Meshael Alturki, Mohannad M Fallatah, Fahad A Almughem, Essam A Tawfik, Abdullah A Alshehri","doi":"10.3390/pharmaceutics17091164","DOIUrl":"10.3390/pharmaceutics17091164","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) are a rapidly advancing class of targeted cancer therapeutics that couple the antigen specificity of monoclonal antibodies (mAbs) with the potent cytotoxicity of small-molecule drugs. In their core design, a tumor-targeting antibody is covalently linked to a cytotoxic payload via a chemical linker, enabling the selective delivery of highly potent agents to malignant cells while sparing normal tissues, thereby improving the therapeutic index. Humanized and fully human immunoglobulin G1(IgG1) antibodies are the most common ADC backbones due to their stability in systemic circulation, robust Fcγ receptor engagement for immune effector functions, and reduced immunogenicity. Antibody selection requires balancing tumor specificity, internalization rate, and binding affinity to avoid barriers to tissue penetration, such as the binding-site barrier effect, while emerging designs exploit tumor-specific antigen variants or unique post-translational modifications to further enhance selectivity. Advances in antibody engineering, linker chemistry, and payload innovation have reinforced the clinical success of ADCs, with more than a dozen agents FDA approved for hematologic malignancies and solid tumors and over 200 in active clinical trials. This review critically examines established and emerging conjugation strategies, including lysine- and cysteine-based chemistries, enzymatic tagging, glycan remodeling, non-canonical amino acid incorporation, and affinity peptide-mediated methods, and discusses how conjugation site, drug-to-antibody ratio (DAR) control, and linker stability influence pharmacokinetics, efficacy, and safety. Innovations in site-specific conjugation have improved ADC homogeneity, stability, and clinical predictability, though challenges in large-scale manufacturing and regulatory harmonization remain. Furthermore, novel ADC architectures such as bispecific ADCs, conditionally active (probody) ADCs, immune-stimulating ADCs, protein-degrader ADCs, and dual-payload designs are being developed to address tumor heterogeneity, drug resistance, and off-target toxicity. By integrating mechanistic insights, preclinical and clinical data, and recent technological advances, this work highlights current progress and future directions for next-generation ADCs aimed at achieving superior efficacy, safety, and patient outcomes, especially in treating refractory cancers.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12473541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: El-Tanani et al. Revolutionizing Drug Delivery: The Impact of Advanced Materials Science and Technology on Precision Medicine. <i>Pharmaceutics</i> 2025, <i>17</i>, 375.","authors":"Mohamed El-Tanani, Shakta Mani Satyam, Syed Arman Rabbani, Yahia El-Tanani, Alaa A A Aljabali, Ibrahim Al Faouri, Abdul Rehman","doi":"10.3390/pharmaceutics17091165","DOIUrl":"10.3390/pharmaceutics17091165","url":null,"abstract":"<p><p>After the publication of the review article [...].</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12473828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioavailability Enhancement of Curcumin by PEG-Based Gastroretentive System: Development and In Vitro Evaluation.","authors":"Orsolya Csendes, Gábor Vasvári, Ádám Haimhoffer, László Horváth, Monika Béresová, Attila Bényei, Ildikó Bácskay, Pálma Fehér, Zoltán Ujhelyi, Dániel Nemes","doi":"10.3390/pharmaceutics17091166","DOIUrl":"10.3390/pharmaceutics17091166","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Increasing the bioavailability of poorly absorbed drugs is a continuous challenge in modern pharmaceutical technology. This is due to the problematic nature of BCS class IV active pharmaceutical ingredients: these drugs possess poor solubility and membrane permeability. Moreover, many undergo immediate efflux and/or rapid systemic metabolism after absorption. This project aimed to improve the bioavailability of BCS class IV drugs by formulating gastroretentive self-emulsifying systems using curcumin as a model drug. <b>Methods:</b> The base of the systems was created by melting emulsifying agents, dissolution retardants, and PEGs together. Curcumin was added after the mixture was cooled slightly. Aqueous dispersions of several compositions were characterized by dynamic light scattering. After screening these results, the viscosities of the selected formulations were evaluated. Dissolution retardants were selected and added to the most superior samples, and their dissolution profiles were compared. Gastroretention of the final formulation was achieved by dispersing air in the molten system through melt foaming; internal structure was assessed by microCT, and physicochemical properties by PXRD and DSC. Cytotoxicity was measured in Caco-2 cells using MTT and Neutral Red assays, and transcellular transport was also studied. <b>Results:</b> Based on these results, a homogeneous gastric floating system was developed. We observed an advantageous cytotoxic profile and increased bioavailability. <b>Conclusions:</b> Overall, we were able to create a self-emulsifying gastroretentive formulation displaying extended release and gastric retention with a low amount of cost-efficient excipients.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12473007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of the Effect of the Combination of Sodium Valproate and Sodium Dichloroacetate on the Expression of <i>SLC12A2</i>, <i>SLC12A5</i>, <i>CDH1</i>, <i>CDH2</i>, <i>EZH2</i>, and <i>GFAP</i> in Primary Female Glioblastoma Cells with That of Temozolomide.","authors":"Dovydas Gečys, Laimis Akramas, Aidanas Preikšaitis, Ingrida Balnytė, Arūnas Vaitkevičius, Julija Šimienė, Donatas Stakišaitis","doi":"10.3390/pharmaceutics17091161","DOIUrl":"10.3390/pharmaceutics17091161","url":null,"abstract":"<p><p>The search for an effective treatment for adult high-grade glioblastoma (GBM) remains urgent. <b>Background/Objectives</b>: The study aimed to determine the expression of carcinogenesis-related genes, such as <i>SLC12A2</i>, <i>SLC12A5</i>, <i>CDH1</i>, <i>CDH2</i>, <i>EZH2</i>, and <i>GFAP</i>, in primary glioblastoma (WHO Grade IV; IDH-wild-type) cells from three adult women: GBM5-1, GBM5-2F, and GBM5-3F. <b>Methods</b>: The impact of the combination of sodium valproate and sodium dichloroacetate (2 mM NaVPA-3 mM NaDCA) on the expression of these genes was determined and compared with the effects of 50 µM temozolomide after 24 h of treatment. <b>Results</b>: 2 mM NaVPA-3 mM NaDCA, as well as temozolomide, had individual impacts on the <i>SLC12A2</i>, <i>SLC12A5</i>, <i>CDH1</i>, <i>CDH2</i>, <i>EZH2</i>, and <i>GFAP</i> expressions of tested GBM5-1, GBM5-2F, and GBM5-3F primary cells of female GBM patients. <b>Conclusions</b>: The combination of 2 mM NaVPA-3 mM NaDCA may have an advantage in antitumor activity and may be more effective than TMZ; however, the effect is individual.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12473538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox-Responsive π-Conjugated Prodrug Nanoassemblies for Cancer Chemotherapy.","authors":"Shuwei Liu, Liuhui Chen, Hongyuan Zhang, Yuequan Wang, Cong Luo","doi":"10.3390/pharmaceutics17091162","DOIUrl":"10.3390/pharmaceutics17091162","url":null,"abstract":"<p><p><b>Background</b>: Redox-responsive prodrug nanoassemblies (NAs) have been extensively utilized in precise cancer therapy. But there is no research shedding light on the impacts of the π-π stacking interactions on the self-assembly capacity of redox-responsive prodrugs and the in vivo delivery fate of NAs. <b>Methods</b>: Three structurally engineered doxorubicin (DOX) prodrugs (FAD, FBD, and FGD) were developed through α-, β-, and γ-positioned disulfide linkages with π-conjugated Fmoc moieties. The NAs were comprehensively characterized for their self-assembly kinetics, redox-responsive drug release profiles, and physicochemical stability. Biological evaluations included cellular uptake efficiency, in vivo pharmacokinetics, and antitumor efficacy in tumor-bearing mouse models. <b>Results</b>: Systematic characterization revealed that π-conjugated disulfide bond positioning dictates prodrug self-assembly and inversely regulates reductive drug release relative to carbon spacer length. The FBD NAs demonstrated optimal redox-responsive release kinetics while maintaining minimal systemic toxicity, achieving 101.7-fold greater tumor accumulation (AUC) than DiR Sol controls. In 4T1 tumor-bearing models, FBD NAs displayed potent antitumor efficacy, yielding a final mean tumor volume of 518.06 ± 54.76 mm³ that was statistically significantly smaller than all comparator groups (<i>p</i> < 0.001 by ANOVA at a 99% confidence interval). <b>Conclusion</b>: These findings demonstrate that strategic incorporation of redox-sensitive disulfide bonds with different π-π stacking interactions in the prodrug structure effectively optimizes the delivery-release balance of DOX in vivo, ensuring both potent antitumor efficacy and reduced systemic toxicity.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12473931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances in the Development of Pro-PROTAC for Selective Protein Degradation.","authors":"Fady Hakem, Ahmad Abdelwaly, Reem Alshaman, Abdullah Alattar, Fawaz E Alanazi, Sawsan A Zaitone, Mohamed A Helal","doi":"10.3390/pharmaceutics17091160","DOIUrl":"10.3390/pharmaceutics17091160","url":null,"abstract":"<p><p>PROTACs are trimeric small molecules consisting of a specific modulator of the target protein connected to a ligase-recruiting ligand via a suitably flexible linker. Ligase-recruiting ligands deliver ubiquitin ligases like E3 ligase to the Protein of Interest (POI). The vicinity of the POI-PROTAC-E3 ternary complex enables the E3 ligase to ubiquitinate the surface lysine residues of the POI. The Ubiquitin-Proteasome System (UPS) then degrades the POI. However, despite the considerable advances in the design of PROTACs targeting several types of enzymes and receptors, this strategy is still facing the challenges of precision target delivery and duration of action. In this review, we highlight the recent approaches for the development of PROTAC prodrugs or pro-PROTAC to control the delivery of PROTACs and achieve the required on-target exposure. This strategy may facilitate the application of the PROTAC technology and expand its clinical benefits.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12473374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of Fenbendazole Solubility Using Particle Size Reduction Methods in the Presence of Soluplus^®.","authors":"Amirhossein Karimi, Pedro Barea, Óscar Benito-Román, Beatriz Blanco, María Teresa Sanz, Clement L Higginbotham, John G Lyons","doi":"10.3390/pharmaceutics17091163","DOIUrl":"10.3390/pharmaceutics17091163","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Fenbendazole is a potential cancer treatment and a proven antiparasitic in veterinary applications. However, its poor water solubility limits its application. In this study, potential fenbendazole solubility enhancement was investigated through size reduction methods. The effect of the presence of Soluplus^® on solubility was investigated as well. <b>Methods</b>: Solubility enhancement was explored using microfluidization and ultrasonication techniques. These techniques were applied to fenbendazole alone and in combination with Soluplus^®. UV-Vis spectroscopy was used to determine solubility. Possible chemical reactions were checked using Fourier transform infrared spectroscopy (FT-IR). Differential scanning calorimetry (DSC) was conducted to analyze the physical structure and crystallinity of the samples. Scanning electron microscopy (SEM) was also utilized for characterization of the effect of the treated formulations and the size reduction method on morphology. The elements present in samples were identified with energy-dispersive X-ray spectroscopy (EDX) combined with SEM. A comparison of crystalline structure between the products was performed via X-ray powder diffraction (XRPD). Dynamic light scattering (DLS) was also used to measure the samples' average particle size at different stages. <b>Results</b>: Both ultrasonication and microfluidization led to marginal increases in the solubility of neat fenbendazole. In contrast, formulations processed in the presence of Soluplus^® demonstrated a greater enhancement in solubility. However, solubility improvement was not retained in the dried samples. The post-drying samples, irrespective of the presence of Soluplus^®, showed nearly the same solubility as neat fenbendazole. <b>Conclusions</b>: Size-reduction methods, particularly when combined with Soluplus^®, improved the solubility of fenbendazole. However, drying appeared to reverse these gains, regardless of the method used.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12473244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategies for Assessing Physical Compatibility of Calcium Folinate with Bicarbonate During Methotrexate Rescue Therapy in Pediatric Patients with Acute Lymphoblastic Leukemia.","authors":"Kaveh Teimori, Bjarke Strøm Larsen, Mathias Buaas Austli, Niklas Nilsson, Ingunn Tho, Katerina Nezvalova-Henriksen","doi":"10.3390/pharmaceutics17091155","DOIUrl":"10.3390/pharmaceutics17091155","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer requiring cytotoxic methotrexate treatment. This always necessitates intravenous administration of rescue therapy consisting of calcium folinate and bicarbonate. Current recommendations advise against mixing these two drugs due to concerns regarding precipitate formation of calcium carbonate (CaCO₃) that could result in catheter and capillary obstruction. These recommendations are based on drug concentrations not clinically relevant in pediatric ALL settings. Our study investigated the effect of clinically relevant calcium folinate-bicarbonate concentrations on the risk of CaCO₃ precipitation. <b>Methods</b>: A theoretical prediction model provided estimates of final mixing concentrations in five scenarios: three simulated pediatric patient models (approx. 1, 9, and 14 years), an undiluted drug mix, and a high-risk control outlier case. Physical compatibility tests were conducted using validated methods for particle detection, complemented by Raman spectroscopy for particle identification. <b>Results</b>: Theoretical predictions suggested CaCO₃ precipitation with elevated bicarbonate concentrations and pH levels. Our simulated patient models and high-risk control outlier case showed that CaCO₃ precipitation may be avoided below certain serum methotrexate concentrations and thereby calcium folinate and bicarbonate concentrations. Physical testing demonstrated particle formation only in the undiluted mix with Raman spectroscopy confirming the finding. <b>Conclusions</b>: Mixing calcium folinate and bicarbonate appears safe under specific methotrexate-directed pediatric ALL treatment conditions. While high bicarbonate concentrations pose precipitation risks, protocol-based dosing regimens mitigate this. Switching to disodium folinate or using in-line filters could further enhance co-administration safety if bicarbonate concentrations exceed the safety limit suggested by our results.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-Body Physiologically Based Pharmacokinetic-Pharmacodynamic Modeling for Interspecies Translation and Mechanistic Characterization of Plasma and Tissue Disposition of GalNAc-siRNAs.","authors":"Emilie Langeskov Salim, Kim Kristensen, Girish Chopda, Erik Sjögren","doi":"10.3390/pharmaceutics17091154","DOIUrl":"10.3390/pharmaceutics17091154","url":null,"abstract":"<p><p><b>Introduction/aim:</b> N-acetylgalactoseamine-conjugated small interfering RNAs (GalNAc-siRNAs) are an emerging class of drugs possessing an extensive clinical potential because of their high target specificity to the asialoglycoprotein receptor (ASGPR) in hepatocytes. Overall, GalNAc-sRNAs are well-tolerated across species but differences in pharmacokinetic (PK) and pharmacodynamic (PD) properties have been observed. Furthermore, despite GalNAc-siRNA's high liver specificity, distribution into off-target organs does occur. Through whole-body physiologically based pharmacokinetic (PBPK) modeling, this study seeks to mechanistically address species differences, establish clinical PK-PD relationships, and characterize off-target organ accumulation, ultimately expediting the preclinical-to-clinical translation of GalNAc-sRNAs in drug development. <b>Materials/Methods:</b> For model development, validation, and establishment of species' translations, three in-house GalNAc-siRNAs with PK data from different biospecimens, as well as downstream effects on mRNA and target proteins in mouse, monkey, and human, were leveraged. A WB-PBPK-PD legacy model, developed as an extension to the generic model for large molecules in the platform Open Systems Pharmacology Suite, was further validated and applied to address the specific aims of this study. <b>Results:</b> The model successfully quantified the PK-PD relationships across species and characterized accumulation in off-target organs. The model further sheds light on species-specific differences, such as liver permeability, subcutaneous absorption rate, as well as PD-related mechanisms. Moreover, the model confirmed previously established compound-specific pharmacokinetic differences and similarities. <b>Conclusions</b>: This PBPK-PD can serve as a framework for future investigations of novel GalNAc-siRNAs across species.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}