Pharmaceutical Research最新文献

{"title":"Computational Design of a Trivalent Multi-Epitope mRNA Vaccine Candidate Against Western, Eastern, and Venezuelan Equine Encephalitis Viruses.","authors":"Rongliu Qin, Yuying Luo, Ziyou Zhou, Yizhong Xu, Xu Wu, Yanqun Hou, Jie Chen, Fei Zhu, Pinhua Pan","doi":"10.1007/s11095-026-04192-3","DOIUrl":"https://doi.org/10.1007/s11095-026-04192-3","url":null,"abstract":"<p><strong>Purpose: </strong>Western equine encephalitis virus (WEEV), Eastern equine encephalitis virus (EEEV), and Venezuelan equine encephalitis virus (VEEV) are mosquito-borne neurotropic alphaviruses that can cause severe encephalitis in humans and equids, yet no licensed vaccines are currently available for routine human prevention. This study aimed to computationally design a trivalent multi-epitope mRNA vaccine targeting WEEV, EEEV, and VEEV.</p><p><strong>Methods: </strong>Immunoinformatics and reverse vaccinology approaches were used to identify conserved cytotoxic T-lymphocyte, helper T-lymphocyte, and linear B-cell epitopes from the three viruses. Fifteen candidate constructs incorporating different immunomodulatory strategies were evaluated for predicted antigenicity, safety, stability, and solubility, and the construct with the most balanced overall profile was selected for further analysis. Secondary- and tertiary-structure prediction, molecular docking, molecular dynamics (MD) simulations, binding free-energy analysis, and immune simulation were subsequently performed.</p><p><strong>Results: </strong>WEV showed a favorable overall physicochemical and immunological profile, supporting its further structural and immunological characterization. Molecular docking demonstrated favorable interactions between WEV and TLR2, TLR3, and TLR4, with the strongest predicted HADDOCK score observed for TLR4. In contrast, molecular dynamics simulations and MM-PBSA analysis indicated greater dynamic stability and a more favorable estimated binding free energy for the WEV-TLR2 complex. In silico immune simulation predicted enhanced IgM and IgG production, B- and T-cell responses, memory-cell formation, and increased IFN-γ and IL-2 levels.</p><p><strong>Conclusions: </strong>WEV represents a computationally designed trivalent multi-epitope mRNA vaccine candidate against WEEV, EEEV, and VEEV. The present study provides a sequence-defined framework for the rational development of multivalent vaccines, and further in vitro and in vivo studies are warranted to evaluate antigen expression, immunogenicity, protective efficacy, and safety.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Predictive Performance of Machine Learning and Population Pharmacokinetic Models for Valproic Acid Clearance and Trough Concentrations: An In-silico Simulation Study in Epilepsy Scenarios.","authors":"Janthima Methaneethorn, Supavadee Aramvith, Khanita Duangchaemkarn, Brad Reisfeld","doi":"10.1007/s11095-026-04206-0","DOIUrl":"https://doi.org/10.1007/s11095-026-04206-0","url":null,"abstract":"<p><strong>Purpose: </strong>While population pharmacokinetic (PopPK) models traditionally guide valproic acid (VPA) dosing, machine learning (ML) may better capture complex, nonlinear relationships. A direct comparison of their predictive performances remains poorly defined. This study compared the predictive performance of ML and PopPK models for VPA clearance and trough concentrations.</p><p><strong>Methods: </strong>PopPK and ML models were developed and validated using two independent simulated datasets. Trough concentration and clearance were each evaluated under a priori and a posteriori conditions and were compared against matched PopPK references.</p><p><strong>Results: </strong>For trough concentration, most ML models significantly outperformed PopPK population prediction (PRED) under a priori condition, while individual prediction (IPRED) significantly outperformed all ML models under a posteriori condition. For clearance, the best-performing ML model (kNN) significantly outperformed a population-typical prediction (CL PRED) under a priori condition, whereas the best-performing ML model (CatBoost) showed a small but statistically significant advantage over the empirical Bayes estimate for clearance (CL EBE) under a posteriori condition.</p><p><strong>Conclusions: </strong>Relative performance depended on the prediction target and available data. Under a priori condition, ML outperformed PopPK for both endpoints. Under a posteriori condition, PopPK remained superior for trough concentration, while ML performed comparably for clearance. Further real-world validation is needed.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights into Poloxamer 188-Mediated Stabilization of AAV8 Capsids Using Coarse-Grained Molecular Dynamics.","authors":"Leila Sharifi, Jahanbakhsh Ghasemi, Leo Santisi, Shivangi Naik, Willow DiLuzio, Arani Chanda, Bodhisattwa Chaudhuri","doi":"10.1007/s11095-026-04187-0","DOIUrl":"https://doi.org/10.1007/s11095-026-04187-0","url":null,"abstract":"<p><strong>Purpose: </strong>Aggregation of adeno-associated virus (AAV) during manufacturing and storage remains a challenge in gene therapy formulation. This study evaluates how varying Poloxamer188 (P188) concentrations affect the structural stability and aggregation behavior of two full AAV8 capsids.</p><p><strong>Methods: </strong>Coarse-grained molecular dynamics simulations of AAV8 capsids with P188 were performed for 4000 ns at 300 K. Center-of-mass (COM) separation, residue-level contacts, surface coverage, van der Waals interactions, radius of gyration (Rg), relative shape anisotropy (k²), and simulation snapshots were analyzed.</p><p><strong>Results: </strong>Persistent capsid association was not observed in systems containing 10 or 24 P188 molecules (0.15% and 0.35% w/v), whereas systems containing 2 or 5 P188 molecules (0.03% and 0.07% w/v) showed delayed association relative to the surfactant-free system. Capsid surface coverage increased with P188 loading. Polyethylene oxide (EO) segments associated with the capsid surface early and persistently, followed by gradual polypropylene oxide (PO) engagement, indicating a preferential/sequential interaction mechanism. Higher P188 loadings showed negligible van der Waals attraction, consistent with steric shielding. Chain-resolved Rg and k² profiles indicated initial conformational rearrangement followed by stabilization of distinct surface-associated P188 conformations, with varying spatial extension and shape anisotropy.</p><p><strong>Conclusions: </strong>These findings provide mechanistic insight into the stabilizing effect of P188 on AAV via concentration-dependent surface coverage and steric hindrance that minimize capsid-capsid interactions associated with aggregation. The reported concentrations are nominal finite-box values defined by discrete P188 molecule counts and represent comparative simulation conditions rather than experimentally derived formulation thresholds. These findings provide a molecular basis for understanding P188-mediated AAV stabilization and for guiding formulation optimization.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Sustained Release Chitosan/β-Glycerol Phosphate-Based Injectable Thermo-Gels Containing Naproxen Sodium: In-Vitro and In-Vivo Evaluation.","authors":"Hassan Ahmad, Sadia Jafar Rana, Tahir Ali Chohan, Haashim Iqbal, Rawdha Benziane, Manoochehr Rasekh, Saman Zafar, Muhammad Sohail Arshad, Zeeshan Ahmad","doi":"10.1007/s11095-026-04197-y","DOIUrl":"https://doi.org/10.1007/s11095-026-04197-y","url":null,"abstract":"<p><strong>Purpose: </strong>To develop in-situ chitosan/β-glycerol phosphate (β-GP) thermogels loaded with naproxen sodium for sustained drug delivery, to circumvent issues related with prolonged oral administration of naproxen (e.g. ulceration, abdominal discomfort, diarrhoea, bloating, etc.). To overcome these complications, in-situ gel formulations are developed as a promising strategy for long-term management of chronic inflammatory disorders such as arthritis. Furthermore, this system is evaluated with an earlier naproxen formulation prepared using sodium alginate.</p><p><strong>Methods: </strong>Thermogels containing varying chitosan concentrations were prepared at pH 7.4 and 37°C, followed by drug loading. Key physicochemical properties, including injectability, gelation time, and sol-gel fraction, were evaluated. In-vitro release studies were conducted using a dialysis membrane with a USP dissolution basket apparatus-I. Anti-inflammatory efficacy was assessed in Sprague-Dawley rats with carrageenan-induced hind ankle inflammation.</p><p><strong>Results: </strong>Results indicated that formulations with higher polymer content exhibited shorter gelation times and increased gel fractions. In-vitro release from F6CGP demonstrated sustained naproxen sodium delivery, following the Korsmeyer-Peppas model with Fickian diffusion kinetics (n ≤ 0.45). In-vivo, the swelling of the inflamed hind ankle joint decreased progressively over 72 h (≈ -2.6 ± 0.73 mm), confirming effective anti-inflammatory action; relatively better as compared to the previous sodium alginate system.</p><p><strong>Conclusions: </strong>In-situ chitosan/β-glycerol gel-forming injectable formulation F6CGP provides sustained naproxen sodium release and shows potential as a therapeutic strategy for chronic inflammatory conditions such as arthritis. The results also indicate that this polymeric system can play a key role in modulating critical formulation parameters i.e. gelation time, gel fraction, injectability, drug release etc.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liposomal Formulation of a Tetravalent Oxaliplatin Prodrug: Preparation and Antitumor Efficacy.","authors":"Shiyuan Wang, Junqiang Wei, Guohua Wang, Dawei Chen, Ming Zhao, Haiyang Hu","doi":"10.1007/s11095-026-04188-z","DOIUrl":"https://doi.org/10.1007/s11095-026-04188-z","url":null,"abstract":"<p><strong>Objective: </strong>To overcome the limitations of oxaliplatin (OXA) in triple-negative breast cancer (TNBC) therapy-including glutathione (GSH)-induced resistance, poor lipophilicity, low cellular uptake, and significant off-target toxicity.</p><p><strong>Methods: </strong>Based on the \"like dissolves like\" concept, two amphiphilic tetravalent oxaliplatin (OXA(IV)) prodrugs modified with double long alkyl chains were synthesized. Through formulation screening and optimization, liposomes loaded with OXA(IV) prodrugs containing octane (OXA(IV)-C8LIP) and dodecane (OXA(IV)-C12LIP) alkyl chains were effectively prepared using microfluidic technology, achieving good encapsulation efficiency and drug loading.</p><p><strong>Results: </strong>Compared with free OXA, the liposomal formulations exhibited higher cellular uptake, improved cytotoxicity against TNBC cells, and dramatically enhanced tumor accumulation via the enhanced permeability and retention (EPR) effect. In vivo, they substantially extended plasma half-life, demonstrated excellent antitumor efficacy, and showed low systemic toxicity. According to the well-established mechanism of Pt(IV) prodrugs, the reductive activation of these compounds is expected to deplete intracellular glutathione (GSH) and elevate reactive oxygen species (ROS), potentially contributing to the reversal of drug resistance and enhanced cytotoxicity.</p><p><strong>Conclusion: </strong>These OXA(IV) liposomes represent a promising nanomedicine for TNBC therapy. Moreover, the simple prodrug encapsulation strategy may be extended to other antitumor drugs with poor stability and short half-life.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insight Into the Role of Release Kinetics of Chemical Penetration Enhancer on Drug Diffusion in Drug-in-adhesive Patch.","authors":"Yucheng Xiang, Haoyuan Song, Dongjun Li, Jingxian Li, Jiuheng Ruan","doi":"10.1007/s11095-026-04199-w","DOIUrl":"https://doi.org/10.1007/s11095-026-04199-w","url":null,"abstract":"<p><strong>Purpose: </strong>As a key excipient in drug-in-adhesive patches, the diffusion behavior of chemical penetration enhancers (CPE) directly affects the diffusion behavior of drugs and thus determines whether the drug can achieve effective skin penetration. Therefore, the study of the release kinetics (RK) of CPE is pivotal.</p><p><strong>Methods: </strong>RK of five CPEs (Span 80 (Span), Isopropyl palmitate (IPP); Dipropylene Glycol (DPG); Menthol (MEN) and N-methyl-2-pyrrolidone (NMP)) and its effect on drug diffusion were researched by in vitro release study, in vitro skin penetration study, molecular dynamic simulation and Raman imaging. And the molecular mechanisms were characterized using modulated-temperature differential scanning calorimetry, rheology study, Fourier transform infrared spectroscopy and ¹³C nuclear magnetic resonance spectroscopy.</p><p><strong>Results: </strong>The various RK behaviors of CPE enhanced the dynamic change in release rate (k) of drug at different degrees, and their RK parameters (k_a-CPEs and T_lag-CPEs) had a multilinear correlation (R² = 0.96) with the increment in k (Δk) over the whole diffusion process. Moreover, the physicochemical properties of CPE determined their k_a-CPEs and T_lag-CPEs, k_a-CPEs were related to polarizability (P) and dielectric constant (ε') and T_lag-CPEs had linear relationship (R² = 0.98) with LogP_o/w.</p><p><strong>Conclusions: </strong>The miscibility between CPE and the matrix (assessed by LogP_o/w and ε') as well as the interaction strength between CPE and the matrix or drug (assessed by P) determined the RK behaviors, thereby enhancing their overall effect on drug diffusion. The proposed mathematical model enabled prediction of CPE's regulatory effect on drug diffusion based on CPE's inherent properties.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Siliconization Techniques, Headspace, Mechanical and Thermal Stress on Particle Generation in an Antibody Formulation.","authors":"Alexandra Lucas, Deepak Kumar Tripathi, Angelina Bespalova, Chiara Callegari, Vaibhav Upadhyay, Myles Chetcuti, Odra Pinato, Andrew A Monte, David L Bain, Anthony Vico, Krishna M G Mallela","doi":"10.1007/s11095-026-04168-3","DOIUrl":"10.1007/s11095-026-04168-3","url":null,"abstract":"<p><strong>Objective: </strong>Pre-filled syringes (PFSs) have become a preferred delivery system for biotherapeutics due to their convenience, accuracy, and cost-effectiveness. Silicone oil (SO) is commonly used as a lubricant in PFSs; however, its leaching can trigger immunogenicity and raise clinical and regulatory concerns. This study evaluates the impact of syringe design and handling parameters on particle formation and aggregation of a model therapeutic antibody in SO-lubricated PFSs.</p><p><strong>Methods: </strong>The study systematically evaluated multiple factors influencing protein stability in prefilled syringes, including siliconization technique (standard sprayed-on [Stdr] vs. cross-linked [Alba®]), headspace volume (low vs. high), and applied stress conditions (slow freeze-thaw cycles and end-over-end agitation). The antibody formulation stability was assessed to determine the combined effects of these parameters on subvisible particle generation and aggregation. Comprehensive analytical characterization was performed using light obscuration (LO), micro flow imaging, size-exclusion chromatography (SEC), and analytical ultracentrifugation (AUC).</p><p><strong>Result: </strong>Syringes with standard sprayed-on siliconization and larger headspace volumes exhibited substantially higher subvisible particle concentrations and aggregate formation, especially under slow freeze-thaw and high-temperature end-over-end stress conditions. In contrast, syringes with cross-linked siliconization (Alba®) showed markedly reduced silicone oil particle shedding and improved protein stability across all tested stress environments. Collectively, these findings highlight that the siliconization method, headspace volume, and stress conditions act synergistically to influence aggregate formation and silicone oil particle release following fill-finish operations.</p><p><strong>Conclusion: </strong>Optimizing syringe design and handling parameters can significantly reduce silicone oil induced particle formation and protein aggregation, thereby improving formulation stability.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Microenvironment-Responsive Intelligent Hydrogel Co-Delivery System Enhances Ferroptosis for Triple-Negative Breast Cancer Therapy.","authors":"Yong Chen, Mingxin Xu, An Liu","doi":"10.1007/s11095-026-04189-y","DOIUrl":"https://doi.org/10.1007/s11095-026-04189-y","url":null,"abstract":"<p><strong>Purpose: </strong>Triple-negative breast cancer (TNBC) lacks effective therapeutic targets. Aurisin A (AA), a natural sesterterpenoid, shows anti-TNBC potential but is limited by poor water solubility. This study aimed to develop a tumor microenvironment (TME)-responsive co-delivery hydrogel to enhance AA efficacy.</p><p><strong>Methods: </strong>AA was complexed with hydroxypropyl-β-cyclodextrin (HP-β-CD) to form AA@HP-β-CD, which was co-loaded with acetazolamide (ACZ) into a triple-responsive injectable hydrogel (PCG). The anti-TNBC mechanism was investigated using HCC1937 cells, focusing on ferroptosis induction. In vivo antitumor efficacy and safety were evaluated in a xenograft nude mouse model.</p><p><strong>Results: </strong>AA@HP-β-CD significantly improved AA solubility and stability. Mechanistically, AA induced ferroptosis in TNBC cells by upregulating HSP90 and promoting GPX4 degradation, leading to glutathione depletion, iron accumulation, and lipid peroxidation. ACZ disrupted intracellular pH homeostasis, further sensitizing cells to AA-induced ferroptosis. The PCG hydrogel enabled sustained, TME-triggered drug release. In the xenograft model, intratumoral injection of PCG/ACZ/AA@HP-β-CD achieved a 76.3% tumor inhibition rate with no observable toxicity to major organs.</p><p><strong>Conclusions: </strong>The TME-responsive PCG/ACZ/AA@HP-β-CD hydrogel integrates drug solubilization, intelligent delivery, and dual-mechanism enhancement. The combination of AA-induced ferroptosis via the HSP90/GPX4 axis and ACZ-mediated pH disruption represents a promising strategy for TNBC therapy with good biosafety.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Copula-Based Framework for Modeling Dependency Structures in PBPK Virtual Populations: A Chinese Adult Case Study.","authors":"Tingyu Xiao, Jia Geng, Meizhen Li, Yehua Xie, Feifan Xie","doi":"10.1007/s11095-026-04205-1","DOIUrl":"https://doi.org/10.1007/s11095-026-04205-1","url":null,"abstract":"<p><strong>Purpose: </strong>Physiologically based pharmacokinetic (PBPK) models require virtual populations that preserve dependencies between organ physiological parameters and demographic covariates. We developed a copula-based framework to model organ-demographic dependencies and benchmarked it against PK-Sim using Chinese adults.</p><p><strong>Methods: </strong>Demographic data for Chinese adults aged 18-65 years from public databases and literature-derived organ/tissue weights were used. Marginal distributions were estimated using kernel density estimation, and dependencies were modeled with vine copulas. Virtual individuals were generated by conditional sampling and inverse marginal transformation, conserving whole-body mass by scaling muscle and adipose tissue weights. A range-matched PK-Sim population served as the comparator.</p><p><strong>Results: </strong>The analysis included 45,154 demographic records and 11 organs/tissues. Fitted copula models reproduced the observed marginal distributions and dependencies. In the generated virtual population, P5-P95 intervals of organ/tissue weights encompassed Chinese reference means. Compared with PK-Sim, 83.6% of organ/tissue-pair comparisons exhibited higher Kendall's τ values, whereas PK-Sim generally produced weak or near-zero correlations. Organ-demographic relationships were more consistent with published data for most organs, although discrepancies remained for the pancreas and muscle.</p><p><strong>Conclusion: </strong>Explicit modeling of dependency structures, in addition to marginal distributions, generated PBPK virtual populations with more physiologically plausible relationships among organ parameters and demographic covariates.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically Based Pharmacokinetic Modeling of Inhaled Polymyxin B: From Rabbit Optimization to Human Predictions.","authors":"Ramya Mahadevan, Shekhar Yeshwante, Rajnikant Sharma, Quentin Valle, ChunFu Cheng, Rani S Sellers, Maria Soledad Ramirez, Jian Li, Qi Tony Zhou, David Z D'Argenio, Gauri G Rao","doi":"10.1007/s11095-026-04194-1","DOIUrl":"https://doi.org/10.1007/s11095-026-04194-1","url":null,"abstract":"<p><strong>Objectives: </strong>Despite the potential of aerosolized polymyxin B (PMB) to enhance local lung exposure while minimizing nephrotoxicity in multidrug-resistant pneumonia, clinical adoption remains limited by insufficient inhaled pharmacokinetic (PK) data. This study developed a physiologically based pharmacokinetic (PBPK) modeling framework to translate preclinical PK data from rabbits to humans and coupled it with a mechanism-based pharmacodynamic model to define optimal inhaled PMB regimens.</p><p><strong>Methods: </strong>A whole-body PBPK model was developed using plasma and tissue concentration data following subcutaneous and intratracheal PMB administration (2 mg/kg) in rabbits, extrapolated to humans using allometric scaling, and validated against clinical plasma and epithelial lining fluid (ELF) data. Monte Carlo simulations evaluated the probability of PK/PD target attainment (PTA) and probability of toxicity attainment (PToXA).</p><p><strong>Results: </strong>Intratracheal administration achieved ~ 10.4-fold higher lung exposure relative to subcutaneous dosing while reducing kidney exposure by 27.7%. A plasma exposure threshold of 92.9 mg·h/L and a kidney tissue exposure threshold of 157 mg·h/L were identified as indicators of higher risk of AKI. Inhaled PMB monotherapy achieved favorable ELF PTA with 0% PToXA and predicted substantial bacterial load reduction (≥ 4 log₁₀ CFU/mL at 24 h), whereas IV monotherapy failed to achieve ELF PTA, with several regimens exceeding 40% PToXA and minimal bactericidal activity.</p><p><strong>Conclusion: </strong>Inhaled PMB provides superior site-specific exposure with minimal predicted nephrotoxicity. Our PBPK-mechanism-based modeling framework suggests that nebulized PMB rapidly clears bacteria while avoiding dose-limiting nephrotoxicity associated with intravenous therapy. These findings support advancing aerosolized PMB toward clinical implementation as a precision-dosing strategy for MDR pulmonary infections.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}