Pharmaceutics最新文献

{"title":"From Platform Development to Scale-Up: Stable Producer Cell Line-Based Lentiviral Vector Manufacturing.","authors":"Ane Arrasate, Igone Bravo, Haizea Fernandez, Carolina Amagliani, Carlos Salgado, Maria Garcia, Carolina Guiance, Maite Azcarate, Tania Arias, Carlos Lopez-Robles, Maria Carazo-Hidalgo, Lorea Blazquez, Cristina Garcia, Maria Echeverria, Andrés Lamsfus-Calle, Marie J Fertin","doi":"10.3390/pharmaceutics18101265","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101265","url":null,"abstract":"<p><p><b>Background</b>: The development of stable producer cell lines (SCLs) represents a promising alternative for lentiviral vector (LVV) manufacturing, offering improved reproducibility and reduced manufacturing costs. In previous work, our group established an SCL generation platform based on a well-characterized packaging cell line (PCL), demonstrating successful vector production at laboratory scale. However, translation of this platform to larger scales remains necessary for industrial applications. <b>Objective</b>: In this study, we aimed to evaluate the scalability of the existing platform and identify key parameters that influence the production performance (e.g., cell density, harvest timing or pH). Moreover, the platform was enhanced through extensive genetic characterization and improved integration methods. <b>Results</b>: Our findings suggest that mildly acidic culture conditions and extended harvest periods contribute to increased LVV titers. Furthermore, we conducted a comparative analysis of transgene integration strategies to determine the most suitable method for SCL generation. The results demonstrate that transposase-mediated integration provides a precise and stable approach, minimizing concatemer formation and tandem rearrangements. <b>Conclusions</b>: Collectively, these findings provide evidence that our stable producer cell line constitutes a scalable, genetically characterized and consistent LVV production platform, supporting its potential for large-scale LVV manufacturing.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271864","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":"Evaluation of Drug-Associated Phototoxicity Under 980 nm Near-Infrared Laser Irradiation in Human Dermal Fibroblasts.","authors":"Wiktoria Odrzywołek, Zuzanna Rzepka, Małgorzata Bożek, Artur Beberok, Dorota Wrześniok, Sławomir Wilczyński","doi":"10.3390/pharmaceutics18101259","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101259","url":null,"abstract":"<p><p><b>Background:</b> Many widely used drugs-including non-steroidal anti-inflammatory drugs, tetracyclines and thiazide diuretics-are labelled as photosensitising, yet their phototoxicity has been defined almost entirely by ultraviolet A (UVA) exposure. Whether this risk extends to the near-infrared (NIR) wavelengths of lasers commonly used in aesthetic medicine is unclear, and a history of such medication is often treated as a relative contraindication to laser procedures. <b>Methods:</b> A bibliometric analysis of 391 Scopus-indexed publications using VOSviewer was performed to quantitatively map the thematic structure of the retrieved literature. The bibliometric mapping was complemented by sequential refinement of the Scopus corpus and a focused assessment of the final records to determine whether studies directly addressing the predefined experimental question could be identified. We assessed whether 980 nm diode-laser irradiation of normal human dermal fibroblasts (HDFs) induces phototoxicity in the presence of seven photosensitisers (ketoprofen, meloxicam, hydrochlorothiazide, doxycycline and diclofenac, with chlorpromazine and 8-methoxypsoralen as reference photosensitizers). Cells were irradiated through the closed culture-plate lid at two fluences (62.3 and 34.4 mJ/cm and viability was measured 0.5, 1 and 24 h later. Data were analysed by two-way ANOVA (compound × laser), pairwise Welch tests with Benjamini-Hochberg correction, and equivalence testing against an ISO 10993-5-based margin. <b>Results:</b> Viability remained between 82.7% and 109.6% of control under all conditions and never fell below the 70% cytotoxicity threshold. The compound × laser interaction was non-significant at every time point (<i>p</i> = 0.25-0.69), indicating no drug-specific phototoxicity, and no pairwise comparison remained significant after correction. A small, drug- and fluence-independent reduction of about six percentage points was observed but stayed well within the non-cytotoxic range and was equally present in drug-free controls. <b>Conclusions:</b> Under the specific 980 nm irradiation conditions tested, the photosensitising drugs did not increase phototoxicity in normal human dermal fibroblasts. These findings support a wavelength-specific view of drug photosafety: rigorous UVA-directed photoprotection remains essential, whereas the tested drugs did not increase phototoxicity under the specific in vitro 980 nm irradiation conditions evaluated in this study.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271875","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":"Spray-Dried Chitosan-Clay Nanocomposite Gels as Binders: Enhanced Compressibility and Micromeritic Properties of Lactose-Based Granules for Poorly Compressible Drug Tablets.","authors":"Rapee Jarungsirawat, Peera Tabboon, Napaphak Jaipakdee, Duangkamon Sakloetsakun, Thaned Pongjanyakul","doi":"10.3390/pharmaceutics18101263","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101263","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Nanocomposites of chitosan (CH) and magnesium aluminum silicate (MAS) clay can be produced by spray drying. This study aimed to characterize and evaluate spray-dried chitosan (SDCH) and SDCH-MAS nanocomposites, which were prepared using CH with MWs of 400 kDa (4M) and 800 kDa (8M), as binders of lactose granules containing propranolol HCl (PPN) and crude powder from <i>Andrographis paniculata</i> (ADP) intended for tablet formulation. <b>Methods:</b> Lactose granules were produced using SDCH and SDCH-MAS composites via wet granulation, and the granule properties were compared with those obtained using polyvinylpyrrolidone (PVP K30). The lactose granules incorporating PPN and ADP crude powder were also prepared and compressed into tablets. The physical properties of both granules and tablets were evaluated. <b>Results:</b> SDCH-MAS composites formed intercalated or exfoliated nanocomposites, as proved by PXRD, and rapidly hydrated in water to form gels that functioned as binders. Lactose granules prepared with SDCH and SDCH-MAS composites exhibited fair to good flowability and demonstrated lower yield pressure and yield strength during plastic deformation than those prepared with PVP K30. Moreover, granules loaded with PPN offered acceptable flowability and could be compressed into tablets. Increasing MAS content reduced the disintegration time of tablets in 0.1 N HCl. The use of SD4MCH in tablets could retard PPN release, while the addition of MAS accelerated drug release. For ADP crude tablets with a 75:25 ADP-to-lactose ratio, acceptable hardness and friability were achieved when SD4MCH-MAS 1:0.6 composites and PVP K30 were used, and 75% of andrographolide dissolved within 30 min. <b>Conclusions:</b> SDCH-MAS nanocomposite gels are effective binders for lactose granules in wet-granulated tablets.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271905","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 ROS-Responsive Polymer-Micelle Delivery System Designed for the Treatment of Drug-Induced Myocarditis.","authors":"Zhikun Lai, Ziyang Wang, Yunzhe Lang, Binghua Chang, Mingyu Mao, Wenqi Lu, Jiahao Weng, Yan Shen, Qimao Feng, Xiaozhen Hu","doi":"10.3390/pharmaceutics18101261","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101261","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Drug-induced myocarditis lacks targeted therapies. Current glucocorticoid and immunosuppressant treatments suffer from poor lesion accumulation and systemic toxicity. We aimed to develop a ROS-responsive self-assembled nanocarrier (GSP) for the controlled release of glycyrrhetinic acid (GA) to inflamed myocardial tissue. <b>Methods:</b> GSP was synthesized by conjugating GA and PEG via a thioketal linker. Micelles were characterized by NMR, DLS, and TEM. ROS-triggered drug release, cytotoxicity, cellular uptake, anti-inflammatory (TNF-α) and ROS-scavenging effects were evaluated in DOX-activated H9C2 cells. In vivo, biodistribution, echocardiography, inflammatory cytokines, and histopathology were assessed in an isoproterenol-induced mouse myocarditis model. <b>Results:</b> GSP exhibited ROS-dependent release (>80% GA within 48 h under 100 mM H₂O₂ vs. <20% without). In vitro, GSP significantly reduced TNF-α and intracellular ROS in activated cardiomyocytes compared to free GA or non-responsive controls. In vivo, GSP showed enhanced cardiac accumulation via the EPR effect and markedly improved left ventricular ejection fraction and fractional shortening, reduced serum TNF-α, IL-1β, and IL-6, and decreased collagen deposition, with good biocompatibility. <b>Conclusions:</b> The ROS-responsive GSP nanocarrier enables on-demand drug release in the inflamed myocardial microenvironment, effectively attenuating inflammation and improving cardiac function, representing a promising targeted strategy for drug-induced myocarditis.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271829","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":"Impact of Process Parameters on the Quality Attributes of High-Dose Metformin Hydrochloride Film-Coated Tablets.","authors":"Nguyen Tan Duc, Dang-Khoa Nguyen, Huynh Thanh Liet, Nguyen Huynh Thiet, Phan Nguyen Truong Thang, Phu Loc Lu, Ngoc Hanh Ly, Duyen Thi My Huynh","doi":"10.3390/pharmaceutics18101264","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101264","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Formulating high-dose metformin hydrochloride film-coated tablets is challenging due to the poor flowability and compressibility inherent to high drug loading. To ensure process robustness and consistent product quality, understanding the impact of manufacturing variables is crucial. This study evaluated the effects of key process parameters on the quality attributes of 1000 mg metformin hydrochloride tablets to establish optimal processing conditions for reliable production. <b>Methods</b>: The manufacturing process, comprising wet granulation, compression, and film coating, was investigated to evaluate the influence of key process parameters on tablet quality attributes. Granules were characterized for bulk density, tapped density, and compressibility index. Core tablets were evaluated for physical appearance, weight variation, hardness, and dissolution at a 45 min sampling point across various compression forces and tableting speeds. Film-coating efficiency was assessed based on coating quality, dissolution behavior, and stability. Favorable manufacturing conditions were empirically identified through single-variable optimization and statistical analysis. <b>Results</b>: Wet granulation conducted at a chopper speed of 1400 rpm for 7 min yielded granules with the lowest compressibility index (11.88%), demonstrating significantly improved flowability. Compression at a force of 10 kN and a speed of 40 rpm produced core tablets with acceptable appearance, robust hardness (7.06-7.37 kP), and complete drug release (100%). Tablet hardness was governed by a strong interaction between compression force and tableting speed (partial η² = 0.929, <i>p</i> < 0.001) rather than by either factor alone: at 20 kN, hardness collapsed sharply once tableting speed reached 30 rpm, coincident with mild capping, identifying this force-speed combination as a process-failure condition. For the coating process, maintaining a tablet bed surface temperature of 40 °C ensured optimal coating uniformity without compromising product quality. Dissolution profile comparison against a coated reference product in the primary dissolution medium (pH 6.8) yielded f2 similarity values above 50 for all eight core tablet conditions, and stability testing under accelerated/thermal-stress conditions (up to 65 °C) confirmed maintained dissolution, assay, and related-substance (1-cyanoguanidine) compliance for both the test and reference products. The optimized manufacturing conditions successfully produced film-coated tablets that conformed to all predetermined quality specifications. <b>Conclusions</b>: Manufacturing process parameters significantly influenced the quality attributes of high-dose metformin hydrochloride film-coated tablets. Proper selection and control of these processing conditions ensured consistent granule properties, optimal tablet quality, and enhanced manufacturing robustness.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271810","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":"Saccharin-Enabled Oral Formulation, Biopharmaceutics and Early Genotoxicity Assessment of the PPARγ Antagonist T0070907.","authors":"Charlotte Devant, François Xavier Legrand, Maria Eugenia Marques Da Costa, Lilia Sehad, Nathalie Gaspar, Antonin Marchais, Maxime Annereau, Bernard Do","doi":"10.3390/pharmaceutics18101258","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101258","url":null,"abstract":"<p><p><b>Background/Objectives:</b> T0070907 is a potent PPARγ antagonist with emerging antitumour activity in osteosarcoma; however, its very low aqueous solubility, uncertain systemic exposure, and nitroaromatic structure raise significant developability concerns. This work aimed to convert T0070907 into a pharmaceutically tractable oral entity and generate an integrated early developability and genotoxicity snapshot. <b>Methods:</b> The physicochemical properties of T0070907 were characterised, solubility-enhancing strategies were evaluated, and saccharin was identified as a supramolecular excipient enabling high-dose oral delivery. A 20 mg/mL oral liquid formulation was developed and monitored using a validated, stability-indicating UHPLC/LC-MS method. In vivo systemic and tissue exposure was assessed in rats using LC-MS/MS; hepatic metabolism was explored in human liver microsomes; and genotoxicity risk was evaluated both in silico (ICH M7) and in a GLP-compliant Ames test. <b>Results:</b> Saccharin markedly enhanced solubility and enabled a 20 mg/mL oral formulation that remained stable for 90 days, with pyridin-4-amine identified as the dominant degradation product. In rats, T0070907 was below the limit of quantification in plasma after oral dosing at 5, 10 and 100 mg/kg, including in a solubilising vehicle. In contrast, T0070907 was clearly mutagenic in the Ames test. <b>Conclusions:</b> These findings support saccharin-based supramolecular formulations as a practical strategy for poorly soluble nitrobenzamides, while positioning T0070907 primarily as a pharmacological tool.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271865","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":"Dose Optimization of Cefazolin for Pediatric Patients with Renal Impairment Using Physiologically Based Pharmacokinetic Modeling (PBPK) in GastroPlus.","authors":"Abdelrahman Abdeen, Yousef A Bin Jardan, Najia Rahim, Ruqaia Alshami, Raimar Löbenberg, Muhammad Sarfraz","doi":"10.3390/pharmaceutics18101260","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101260","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Cefazolin is a first-generation cephalosporin antibiotic widely used for the treatment and prophylaxis of bacterial infections in both adult and pediatric populations. It is predominantly eliminated unchanged by the kidneys. Impaired renal function can reduce its clearance and increase systemic exposure. This study aimed to develop and validate a PBPK model of cefazolin using GastroPlus™ 9.9 to optimize dosing in pediatric patients with renal impairment. <b>Methods</b>: A cefazolin PBPK model incorporating renal transport processes was developed using clinical data from healthy adults, subsequently evaluated in adults with renal impairment, and scaled to healthy pediatrics following validation in these populations. The model was extrapolated to pediatric patients with varying degrees of renal impairment. Dose optimization was performed based on predicted exposure, followed by pharmacodynamic evaluation using unbound fractions and a selected MIC of 4 µg/mL. <b>Results</b>: The model demonstrated good agreement between observed and predicted pharmacokinetic parameters including C_max and AUC_0-∞ across the evaluated populations. Dose reductions of approximately 43%, 80%, and 90% relative to the standard pediatric dose were identified in moderate RI, severe RI, and ESRD, respectively, together with interval extension. Predicted %fT > MIC was 55.5%, 58%, 83%, and 81% for mild RI, moderate RI, severe RI, and ESRD, respectively. For surgical prophylaxis, unbound cefazolin concentrations remained above the MIC for 4.5-38.8 h across the RI groups, supporting maintenance above the MIC during a simulated 4 h surgical period. <b>Conclusions</b>: The PBPK model adequately describes cefazolin pharmacokinetic in healthy adults, adults with CKD, and healthy pediatric subjects and provides a model-informed basis for dose and interval adjustment in pediatric RI. The proposed regimens are model-based extrapolations requiring clinical confirmation, especially because the pediatric RI model was not independently validated against observed pediatric RI data.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271822","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":"Biogenic Selenium Nanoparticle-Based Nanocomposite Hydrogel for Dual Delivery of Curcumin and Simvastatin for Topical Wound Healing Applications.","authors":"Nahla A Kasem, Hatem A Sarhan, Mahmoud Mostafa, Heba A Hofny, Deiaa E Elsayed Abouzed, Mahmoud M A Elsayed, Mahmoud Elkot Mostafa","doi":"10.3390/pharmaceutics18101257","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101257","url":null,"abstract":"<p><p><b>Background:</b> Chronic and ischemic wounds are dysregulated, causing inflammation, oxidative stress, and bacterial colonization. This work developed a bionanocomposite hydrogel using biogenic selenium nanoparticles (SeNPs) to encapsulate and topically distribute two weakly water-soluble medicines, curcumin (Curc) and simvastatin (SMV), to improve wound healing. <b>Methods:</b> Green production of biogenic SeNPs utilizing Psidium guajava (guava) leaf extract. Based on entrapment efficiency (%EE; E1) and cumulative drug release after 2 and 8 h (E2) and (E3), a two-factor, three-level Box-Behnken design selected the SeNP-to-drug weight ratio (C₁) and ethanol concentration (C₂). The selected nanoconstruct was integrated into a 2% <i>w</i>/<i>v</i> Carbopol 934 hydrogel and characterized by UV-vis, FTIR, SEM, and DLS. In a 14-day full-thickness excisional wound model in Wistar rats, wound contraction, tissue remodeling, inflammatory responses, and healing kinetics were examined to determine its therapeutic efficiency. <b>Results:</b> Formulation F9 had the highest overall attractiveness (0.998) and %EE values of 94.71% for SMV and 93.92% for Curc. DLS showed a hydrodynamic particle size of 177.7 nm and PDI of 0.41. Both medications were successfully incorporated without chemical incompatibility based on FTIR analysis. The selected nanogel maintained a skin-friendly pH of 6.2 ± 0.1 and sustained biphasic drug release. In vivo, the half-dose nanogel showed an enhanced wound-healing response, accelerating wound contraction and achieving complete epithelialization in 14 ± 1.06 days (<i>p</i> < 0.05) compared to 22 ± 2.5 days for the sham control, corresponding to a 36% reduction in healing time. Histopathology showed epidermal thickness restoration and well-organized collagen deposition. In addition, therapy dramatically decreased the proinflammatory biomarkers IL-1β, MMP-9, and COX-2 and increased IL-10 levels without causing tissue discomfort. <b>Conclusions:</b> The biogenic SeNP-based nanogel delivers Curc and SMV locally with prolonged drug release and anti-inflammatory and tissue-remodeling effects. The half-dose combination accelerated wound healing while retaining tissue compatibility, suggesting this green nanocomposite hydrogel could be a promising topical method for advanced cutaneous wound therapy.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271859","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 Constrained Deep Learning in Physiologically Based Pharmacokinetic Modeling: Virtual Patient Generation, Machine-Learned Scaling Laws, and Pediatric Precision Dosing.","authors":"Lei Zhang, Yichao Xu","doi":"10.3390/pharmaceutics18101256","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101256","url":null,"abstract":"<p><p>Physiologically based pharmacokinetic (PBPK) modeling is now central to pediatric dose selection, because clinical sampling in children is ethically constrained and simple weight-based scaling is unreliable while organ function and enzyme activity are still maturing. Three bottlenecks limit classical PBPK in this setting, namely building physiologically coherent virtual patient populations, extrapolating drug disposition across species and age, and estimating many mechanism-linked parameters from sparse data. Over the past five years, deep learning has begun to address each. Generative models constrained by physiological knowledge create virtual patients that preserve realistic correlations and whole-body coherence. Graph networks and neural ordinary differential equations learn continuous scaling and maturation relationships instead of relying on fixed exponents. Physics-informed networks and surrogate emulators estimate mechanistic parameters and quantify uncertainty in data-poor pediatric settings. This review surveys these developments, organizes them by the PBPK workflow they serve, and links them to precision dosing of three antiepileptic drugs, lacosamide, lamotrigine, and oxcarbazepine. Unlike earlier surveys focused on concentration prediction and therapeutic drug monitoring, we keep the mechanistic model in the foreground, treating the virtual patient as the unit of simulation. We also discuss open problems, including validation standards for generated populations, the regulatory qualification of learning-enhanced PBPK, uncertainty reporting, and the prospect of foundation models of pharmacokinetics. Throughout, we distinguish methodological maturity from demonstrated clinical benefit.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271853","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":"Integrating PBPK Simulation and In Vitro Pharmacodynamics to Model Efavirenz-Associated Hepatic Oxidative Stress in Pregnancy.","authors":"Bárbara Costa, Maria João Gouveia, Nuno Vale","doi":"10.3390/pharmaceutics18101253","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101253","url":null,"abstract":"<p><p><b>Background</b>: Certain antiretroviral drugs, including efavirenz, have been associated with mitochondrial and oxidative effects in hepatic cells, but quantitative translation from nominal in vitro concentrations to an in vivo effect-site concentration remains uncertain. <b>Methods</b>: A hypothesis-generating physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) framework integrated simulated EFV concentration-time profiles for six pregnancy/CYP2B6 scenarios with published Hep3B MitoSOX concentration-response data fitted with the Hill-Emax model. Translational exposure was evaluated as total hepatic EFV concentration relative to the nominal in vitro concentration range and as unbound hepatic concentration approximated from total plasma concentration and fraction unbound. <b>Results</b>: Simulations predicted lower total plasma exposure during pregnancy in the reference normal-metaboliser scenario (C_p,total Cmax: decreasing from 9.94 to 7.15 µM). Under the free-drug scenario (f_u,p = 0.22%), the estimated Cmax,u decreased from 0.0219 to 0.0157 µM, remaining far below the lowest non-zero nominal in vitro concentration (10 µM). Benchmarked against the fu,vitro-corrected in vitro EC₅₀ (0.324 μM via Kalvass-Maurer protein-binding correction), this margin narrowed to approximately 15- to 21-fold at the reference f_u,p and to approximately 2-fold at the highest literature-reported value of f_u,p (1.5%). <b>Conclusions</b>: Pregnancy and CYP2B6 phenotype altered simulated EFV exposure, whereas quantitative translation to the Hep3B oxidative stress response depended strongly on the concentration metric used. Because unbound EFV was not reported in the in vitro system and intracellular hepatic EFV was unavailable, neither comparison establishes a definitive effect-site match. This framework supports an exploratory QIVIVE interpretation and identifies the exposure measurements required for quantitative validation.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271801","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}