Pharmaceutics最新文献

{"title":"Drug Loss at Arterial Bends Can Dominate Off-Target Drug Delivery by Paclitaxel-Coated Balloons.","authors":"Linnea Tscheuschner, Efstathios Stratakos, Marios Kostakis, Miltiadis Gravanis, Michalis Katsimpoulas, Giancarlo Pennati, Fragiska Sigala, Abraham R Tzafriri","doi":"10.3390/pharmaceutics17020197","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020197","url":null,"abstract":"<p><p><b>Background/Objective</b>: Paclitaxel-coated balloons (PCBs) can deliver efficacious drug concentrations to treated arterial segments but are known to exhibit high tracking losses. We aimed to define the governing factors impacting tracking loss and to contrast its drug distribution consequences with those of PCB inflation at the treatment site. <b>Methods</b>: Four naïve and four in-stent restenosis (ISR) porcine superficial femoral arteries (SFA) were treated with PCBs, and plasma samples were collected post-tracking and post-inflation. Animals were sacrificed <1 h post-intervention, and local, upstream, and downstream tissues were collected for paclitaxel quantification. Computationally driven quantitative benchtop-tracking and frictional PCB-sliding experiments modeled paclitaxel loss and delivery to upstream tissue. <b>Results</b>: Paclitaxel concentrations in plasma peaked pre-inflation and declined 30-fold immediately post-inflation. Correspondingly, losses of 30% and 1% of nominal PCB load were measured in vitro during, respectively, tracking over single bend and during device insertion. Mean paclitaxel concentrations were equally high at ISR and naïve SFA treatment sites (56,984 vs. 79,837 ng/g, <i>p</i> > 0.99) and ranged from 9 to 89 ng/g in tissues downstream of these treatment sites. Sampling of non-target upstream iliac artery tissues revealed paclitaxel concentration of 4351 ± 4084 ng/g. Benchtop sliding of PCB samples onto ex vivo porcine artery samples exhibited efficient, pressure independent frictional paclitaxel transfer (124 µg at 0.05 atm vs 126 µg at 0.1 atm, <i>p</i> > 0.99). <b>Conclusions</b>: PCB interactions at porcine vessel bends led to premature tracking loss, resulting in peak plasma concentrations exceeding post-inflation concentrations, and delivery to upstream tissue that is plausibly explained as arising from efficient friction-mediated coating transfer.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503245","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":"Influence of Ethanol as a Preservative in Topical Formulation on the Dermal Penetration Efficacy of Active Compounds in Healthy and Barrier-Disrupted Skin.","authors":"Christian Raab, Tien Trung Do, Cornelia M Keck","doi":"10.3390/pharmaceutics17020196","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020196","url":null,"abstract":"<p><p>(1) Background: Ethanol is a multifunctional excipient often used as a preservative in topical formulations. Due to its known ability to impair skin barrier function, this study investigated the effect of ethanol (EtOH) as a preservative in creams on the dermal penetration of active compounds. (2) Methods: A hydrophilic and a lipophilic fluorescent dye were used as active ingredient surrogates that were incorporated into creams with and without ethanol. The dermal penetration efficacy was assessed by epifluorescence microscopy on an ex vivo porcine ear model with intact and irritated skin. (3) Results: Ethanol reduced the dermal penetration by about 40% for the hydrophilic and about 20% for the lipophilic surrogates on intact skin, but had minimal impact on irritated skin. The bio-physical skin properties were also altered by the addition of ethanol to the cream. On intact skin, it increased transepidermal water loss (TEWL) and decreased skin hydration, whereas on irritated skin, it decreased TEWL and increased skin hydration. The results indicate that skin impairment can be considered to have different stages, while in an early stage of skin impairment, the formation of a \"Pudding skin\" is proposed. A \"Pudding skin\" is the formation of a thin layer of dried skin on top of the skin that \"seals\" the lower parts of the skin and reduces dermal penetration and water loss from inside the skin and reduces the dermal penetration of chemical compounds from outside the skin. (4) Conclusions: Overall, the findings emphasize the need to carefully consider the use of ethanol in formulations, balancing its preservative benefits with its potential to impair the efficacy of active ingredients, particularly in varying skin conditions.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503297","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":"Study on Lyophilised Orodispersible Tablets from Plant-Based Drinks as Bulking Agents.","authors":"Adrienn Katalin Demeter, Dóra Farkas, Márton Király, Zoltán Kovács, Krisztina Ludányi, István Antal, Nikolett Kállai-Szabó","doi":"10.3390/pharmaceutics17020195","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020195","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Oral administration of active pharmaceutical ingredients (APIs) is the most commonly used route of administration. As dysphagia is a prevalent problem, the size of the swallowed dosage form could negatively influence patient adherence. Orally disintegrating tablets (ODTs) are beneficial dosage forms because they disintegrate within a few seconds in the oral cavity without water. Lactose is one of the most commonly used excipients in the pharmaceutical industry; it served as the central concept of a recent publication on the formulation of milk-based ODTs despite lactose malabsorption being widespread worldwide. Consequently, the plant-based alternative market has grown exponentially and has become a prevailing food trend, with various alternatives to choose from. For this reason, the development of a nonsteroidal anti-inflammatory drug (NSAID)-containing ODT with plant-based drinks (PBDs) was assessed for its innovative potential. <b>Methods:</b> Different PBDs were investigated and compared to traditional and lactose-free milk. The liquids' viscosity, pH, and particle size were determined, and an electronic tongue was used for the sensory evaluation. The various ODTs were prepared with the freeze-drying method, and then the qualitative characteristics of the dosage form were investigated. <b>Results:</b> Our different measurements show that different plant beverages differ from each other and that these differences have an impact on the technological processing. According to the HPLC-DAD measurements, all values were in the required range. <b>Conclusions:</b> These measurements suggest that the soya drink is the most similar to traditional cow milk and would be the most appropriate choice among the investigated plant-based drinks to be used as a carrier system for an ibuprofen-containing ODT.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503341","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 and Characterization of Silibinin-Loaded Nanoemulsions: A Promising Mucoadhesive Platform for Enhanced Mucosal Drug Delivery.","authors":"Ana Paula Santos Tartari, Joslaine Jacumazo, Ariane Krause Padilha Lorenzett, Rilton Alves de Freitas, Rubiana Mara Mainardes","doi":"10.3390/pharmaceutics17020192","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020192","url":null,"abstract":"<p><p><b>Background:</b> Silibinin (SLB), a flavonoid derived from milk thistle, exhibits promising therapeutic properties but faces significant clinical limitations due to poor solubility and bioavailability. <b>Objectives:</b> This study focuses on the development and characterization of SLB-loaded nanoemulsions designed for mucosal delivery. <b>Methods:</b> Nanoemulsions were prepared using the spontaneous emulsification method, guided by pseudoternary phase diagrams to determine selected component ratios. Comprehensive characterization included particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency, rheological properties, and surface tension. Mucoadhesive properties were evaluated using quartz crystal microbalance with dissipation (QCM-D) to quantify interactions with mucin layers. <b>Results:</b> The combination of Capryol 90, Tween 80, and Transcutol in selected proportions yielded nanoemulsions with excellent stability and solubilization capacity, enhancing the solubility of silibinin by 625 times compared to its intrinsic solubility in water. The ternary phase diagram indicated that achieving nanoemulsions with particle sizes between 100 and 300 nm required higher concentrations of surfactants (60%), relative to oil (20%) and water (20%), with formulations predominantly composed of Smix (surfactant and cosurfactant mixture in a 1:1 ratio). Rheological analysis revealed Newtonian behavior, characterized by constant viscosity across varying shear rates and a linear torque response, ensuring ease of application and mechanical stability. QCM-D analysis confirmed strong mucoadhesive interactions, with significant frequency and dissipation shifts, indicative of prolonged retention and enhanced mucosal drug delivery. Furthermore, contact angle measurements showed a marked reduction in surface tension upon interaction with mucin, with the SLB-loaded nanoemulsion demonstrating superior wettability and strong mucoadhesive potential. <b>Conclusions:</b> These findings underscore the suitability of SLB-loaded nanoemulsions as a robust platform for effective mucosal drug delivery, addressing solubility and bioavailability challenges while enabling prolonged retention and controlled therapeutic release.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503170","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":"PEGylated Nanoliposomes Encapsulated with Anticancer Drugs for Breast and Prostate Cancer Therapy: An Update.","authors":"Sijongesonke Peter, Vuyolwethu Khwaza, Sibusiso Alven, Tobeka Naki, Blessing Atim Aderibigbe","doi":"10.3390/pharmaceutics17020190","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020190","url":null,"abstract":"<p><p>There are different types of cancer treatments, including surgery, radiotherapy, and chemotherapy. However, the complexity of cancer has resulted in treatment challenges to medicinal scientists and a socio-economic burden to the public health system globally. The pharmacological limitations associated with the current conventional anticancer drugs include lack of specificity, poor bioavailability, toxicity, drug resistance, and poor delivery mechanisms, which make cancer treatment challenging. Thus, the number of cancer cases is escalating rapidly, especially breast and prostate cancer in women and men, respectively. The application of nanoformulations is gaining momentum for treating different cancer types. However, they also exhibit challenges that must be addressed for effective cancer treatment. Nanoliposomes are nanoformulations that are widely explored for cancer treatment with interesting therapeutic outcomes. They have been functionalized with PEG to further improve their therapeutic outcomes. Hence, this review provides an update on PEGylated nanoliposomes loaded with anticancer drugs for the treatment of breast and prostate cancer, focusing on pre-clinical studies published in the last decade (2015 to 2024) to reflect the recent advancements made in the design of PEGylation nanoliposomes. Highlights of the clinically and commercially available PEGylation nanoliposomes are also presented in this review.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503207","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":"Exploratory Study on Nanoparticle Co-Delivery of Temozolomide and Ligustilide for Enhanced Brain Tumor Therapy.","authors":"Gang Ke, Mingxia Zhang, Pengyi Hu, Jing Zhang, Abid Naeem, Lianfang Wang, Huixin Xu, Yu Liu, Ming Cao, Qin Zheng","doi":"10.3390/pharmaceutics17020191","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020191","url":null,"abstract":"<p><p><b>Background:</b> Temozolomide (TMZ) is the first-line therapy for glioblastoma (GBM), but its clinical efficacy is limited by its short half-life, poor brain targeting, adverse side effects, and the development of drug resistance. Ligustilide (LIG) has been shown to enhance blood-brain barrier permeability and reduce P-glycoprotein activity, thereby potentiating the synergistic effect of TMZ against GBM. <b>Methods:</b> The dual-drug-loaded nanoparticles encapsulating both TMZ and LIG (TMZ/LIG-NPs) were prepared using Poly (d,l-lactic-co-glycolide)-monomethoxy poly (ethylene glycol) (PLGA-mPEG). The physicochemical properties of the NPs, including particle size and zeta potential, were characterized. Cellular uptake of NPs was evaluated using flow cytometry and fluorescence staining. The pharmacokinetic profile and cytotoxicity of TMZ/LIG-NPs were compared to those of free TMZ and a mixture of TMZ and LIG in rat and glioma cells, respectively. <b>Results:</b> The mean particle size of TMZ/LIG-NPs was 117.6 ± 0.7 nm, with a zeta potential of -26.5 ± 0.4 mV. Cellular uptake of NPs was significantly higher than that of free drug in U251 cells. Encapsulation of TMZ in NPs significantly increased its half-life by 1.62-fold compared to free TMZ and significantly improved its pharmacokinetic profile. Moreover, the storage stability of the TMZ/LIG-NPs solution was extended to one month. The toxicity of TMZ/LIG-NPs to glioma cells C6 and U251 was markedly enhanced compared to the mixture of TMZ and LIG. <b>Conclusions:</b> The development of TMZ/LIG-NPs using PLGA-mPEG effectively enhanced the stability and efficacy of both TMZ and LIG. This dual drug-loaded nanoparticle system represents a promising strategy for glioblastoma therapy.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502147","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":"LB-100 Enhances Drugs Efficacy Through Inhibition of P-Glycoprotein Expression in Multidrug-Resistant Glioblastoma and Non-Small Cell Lung Carcinoma Cellular Models.","authors":"Ana Podolski-Renić, Margarita Chigriai, Sofija Jovanović Stojanov, Marija Grozdanić, Ema Lupšić, Igor Nikolić, Miodrag Dragoj, Jelena Dinić, Milica Pešić","doi":"10.3390/pharmaceutics17020189","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020189","url":null,"abstract":"<p><p><b>Background/Objectives</b>: This study explores the potential of LB-100 (a protein phosphatase 2A-PP2A inhibitor) combined with adavosertib (a WEE1 kinase inhibitor) and doxorubicin (DOX), to overcome multidrug resistance (MDR) in cancer cells and enhance treatment efficacy. <b>Methods</b>: We evaluated LB-100 combinations with adavosertib and DOX in patient-derived glioblastoma and non-small cell lung carcinoma cells (NSCLCs) using a real-time cell analyzer. Effectiveness was also assessed through immunofluorescence assay, and interactions were analyzed via SynergyFinder+. We also examined P-glycoprotein (P-gp) expression and drug resistance genes' expression in MDR glioblastoma and NSCLCs after LB-100 treatment, as well as LB-100 sensitizing effect on DOX and DOX accumulation. <b>Results</b>: LB-100 significantly boosts the effectiveness of adavosertib and DOX after multiple applications. It also enhances these drugs' cytotoxicity in a single application without acting synergistically. Additionally, LB-100 reduces P-gp expression in MDR glioblastoma and NSCLCs, sensitizing them to DOX and increasing its accumulation. <b>Conclusions</b>: LB-100 enhances the effectiveness of drugs against MDR cancer cells, presenting a promising strategy to overcome drug resistance in glioblastoma and NSCLCs through P-gp modulation.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503318","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":"Intranasal Mucoadhesive In Situ Gel of Glibenclamide-Loaded Bilosomes for Enhanced Therapeutic Drug Delivery to the Brain.","authors":"Meenakshi Tripathi, Laxmi Gharti, Amit Bansal, Hemlata Kaurav, Sandeep Sheth","doi":"10.3390/pharmaceutics17020193","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020193","url":null,"abstract":"<p><strong>Background: </strong>The neuroprotective efficacy of glibenclamide (GLIB) has been demonstrated in multiple rodent models of ischemia, hemorrhagic stroke, traumatic brain damage, spinal cord injury, and metastatic brain tumors. Due to its poor solubility, GLIB has low oral bioavailability, limiting its transportation to the brain via the oral route.</p><p><strong>Objectives: </strong>Here, we attempted to develop and optimize an intranasal mucoadhesive in situ gel of GLIB-loaded bilosomes using a 3² Box-Behnken design for brain drug delivery.</p><p><strong>Methods: </strong>To facilitate a longer residence time of the administered dose within the nasal cavity, the prepared bilosomes were loaded into a mucoadhesive in situ gel providing resistance to rapid mucociliary clearance. The amounts of sodium deoxycholate, the cholesterol/Span 40 mixture, and the molar ratio between the mixture's components were chosen as independent variables, while the entrapment efficiency and in vitro drug release were selected as dependent variables.</p><p><strong>Results and conclusions: </strong>The optimal formulation was analyzed for particle size and entrapment efficiency, which were found to be 270.6 nm and 68.39%, respectively. In vitro drug release from optimal formulation after 12 h was 87.29 ± 1.98% as compared to 52.01 ± 2.04% of plain in situ gel of drug. An in vivo brain drug delivery study performed on Swiss albino mice showed that the brain concentration of drug through intranasal administration from mucoadhesive in situ gel of GLIB-bilosomes after 12 h was 2.12 ± 0.16 µg/mL as compared to 0.68 ± 0.04 µg/mL from plain in situ gel of drug. Conclusively, the developed bilosomal formulation offers a favorable intranasal substitute with enhanced therapeutic drug delivery to the brain.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503307","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":"AI-Driven Innovation in Skin Kinetics for Transdermal Drug Delivery: Overcoming Barriers and Enhancing Precision.","authors":"Nubul Albayati, Sesha Rajeswari Talluri, Nirali Dholaria, Bozena Michniak-Kohn","doi":"10.3390/pharmaceutics17020188","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020188","url":null,"abstract":"<p><p>Transdermal drug delivery systems (TDDS) offer an alternative to conventional oral and injectable drug administration by bypassing the gastrointestinal tract and liver metabolism, improving bioavailability, and minimizing systemic side effects. However, widespread adoption of TDDS is limited by challenges such as the skin's permeability barrier, particularly the stratum corneum, and the need for optimized formulations. Factors like skin type, hydration levels, and age further complicate the development of universally effective solutions. Advances in artificial intelligence (AI) address these challenges through predictive modeling and personalized medicine approaches. Machine learning models trained on extensive molecular datasets predict skin permeability and accelerate the selection of suitable drug candidates. AI-driven algorithms optimize formulations, including penetration enhancers and advanced delivery technologies like microneedles and liposomes, while ensuring safety and efficacy. Personalized TDDS design tailors drug delivery to individual patient profiles, enhancing therapeutic precision. Innovative systems, such as sensor-integrated patches, dynamically adjust drug release based on real-time feedback, ensuring optimal outcomes. AI also streamlines the pharmaceutical process, from disease diagnosis to the prediction of drug distribution in skin layers, enabling efficient formulation development. This review highlights AI's transformative role in TDDS, including applications of models such as Deep Neural Networks (DNN), Artificial Neural Networks (ANN), BioSIM, COMSOL, K-Nearest Neighbors (KNN), and Set Covering Machine (SVM). These technologies revolutionize TDDS for both skin and non-skin diseases, demonstrating AI's potential to overcome existing barriers and improve patient care through innovative drug delivery solutions.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503289","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":"Ustekinumab Drug Clearance Is Better Associated with Disease Control than Serum Trough Concentrations in a Prospective Cohort of Inflammatory Bowel Disease.","authors":"Andres J Yarur, Thierry Dervieux, Ryan Ungaro, Elizabeth A Spencer, Alexandra Bruss, Lizbeth Nunez, Brandon Berens, Séverine Vermeire, Zhigang Wang, John C Panetta, Erwin Dreesen, Marla C Dubinsky","doi":"10.3390/pharmaceutics17020187","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020187","url":null,"abstract":"<p><p><b>Background/Objectives</b>: This study aimed to compare the association of ustekinumab (UST) drug clearance (CL) and trough drug concentrations with disease activity in patients with inflammatory bowel diseases (IBDs). <b>Methods</b>: A prospective cohort of 83 patients with IBD receiving maintenance therapy with 90 mg subcutaneous UST was analyzed using Bayesian PK modeling. UST concentrations and antibodies to UST (ATU) were collected at the trough and measured using a drug-tolerant homogenous mobility shift assay (HMSA). CL was estimated using Bayesian estimation methods with priors from a previous population pharmacokinetic study specifically reparametrized using HMSA. Outcomes were combined clinical and biochemical remission and endoscopic healing index (EHI) score, a validated marker of endoscopic active disease in IBD. Statistical analysis consisted of linear and nonlinear mixed effect models for repeated time-to-event analysis. <b>Results</b>: A total of 83 patients with IBD were enrolled (median age 42 years, 52% female) and evaluated across 312 dose cycles (median follow-up: 279 days, median of 3 cycles/patient). Median concentrations and CL were 5.0 µg/mL and 0.157 L/day, respectively. Most patients (89%) were exposed to other biologics before starting UST, which was associated with lower rates of clinical and biochemical remission (<i>p</i> = 0.01). Longitudinal changes in concentrations were not associated with remission (<i>p</i> = 0.53). Conversely, higher CL was associated with a lower likelihood of remission (<i>p</i> < 0.01). EHI > 50 points (endoscopic active disease, <i>n</i> = 303 cycles) was associated with higher UST CL (<i>p</i> < 0.01). <b>Conclusions</b>: UST CL was more strongly associated with clinical and biochemical outcomes than trough concentrations, highlighting its potential role in therapy optimization.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503215","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}