Pharmaceutical Research最新文献

{"title":"Chemical Distribution Uniformity Assessment of \"Intra-Tablet\" by Hyperspectral Raman Imaging Analysis.","authors":"Ningyun Sun, Jing Zhang, Mingtao Guo, Yibin Mao, Wei Wu, Yi Lu","doi":"10.1007/s11095-024-03778-z","DOIUrl":"https://doi.org/10.1007/s11095-024-03778-z","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to develop a new index, Distribution Uniformity Index (DUI), to assess the \"intra-tablet\" homogeneity.</p><p><strong>Methods: </strong>High-resolution hyperspectral Raman imaging was adopted to scan a tablet to get the components' distribution. The heuristic algorithm was applied to generate a Raman heatmap with RGB colors quantitatively correlated with the concentrations of each component. DUI is defined as the ratio of the area under the uniformity curve of the sample image to that of the randomized image. The accuracy and applicability of DUI were verified by constructing model images with controlled uniformity and random regions. The effects of \"intra-tablet\" homogeneity on the disintegration and dissolution of spironolactone tablets were investigated.</p><p><strong>Results: </strong>DUI value was directly obtained from heuristic visual analysis of macro-pixel from hyperspectral Raman images. A good linear relationship and good repeatability were confirmed between DUI and the uniformity of model images. The size of CaSO₄·2H₂O affected the \"intra-tablet\" homogeneity of spironolactone tablets, which was detected by the DUI value. The better \"intra-tablet\" homogeneity led to a higher disintegration and dissolution of spironolactone tablets.</p><p><strong>Conclusions: </strong>DUI represents a novel index to evaluate the \"intra-tablet\" homogeneity and is beneficial for formulation research and development.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591128","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":"The Current State of Biotransformation Science - Industry Survey of In Vitro and In Vivo Practices, Clinical Translation, and Future Trends.","authors":"John P Savaryn, Kevin Coe, Matthew A Cerny, Kevin Colizza, Patricia Moliner, Lloyd King, Bin Ma, Jim Atherton, Adam Auclair, Mark T Cancilla, Marsha Eno, Ulrik Jurva, Qin Yue, Sean Xiaochun Zhu, Elyse Freiberger, Guo Zhong, Ben Barlock, Jonny Nachtigall, Laurent Laboureur, Sandeepraj Pusalkar, Runcong Guo, Michael Niehues, Simon Hauri, Ester Tor Carreras, Christine Maurer, Chandra Prakash, Gary J Jenkins","doi":"10.1007/s11095-024-03787-y","DOIUrl":"https://doi.org/10.1007/s11095-024-03787-y","url":null,"abstract":"<p><p>Embedded within the field of drug metabolism and pharmacokinetics (DMPK), biotransformation is a discipline that studies the origins, disposition, and structural identity of metabolites to provide a comprehensive safety assessment, including the assessment of exposure coverage in toxicological species. Spanning discovery and development, metabolite identification (metID) scientists employ various strategies and tools to address stage-specific questions aimed at guiding the maturation of early chemical matter into drug candidates. During this process, the identity of major (and minor) circulating human metabolites is ascertained to comply with the regulatory requirements such as the Metabolites in Safety Testing (MIST) guidance. Through the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), the \"Translatability of MetID In Vitro Systems Working Group\" was created within the Translational and ADME Sciences Leadership Group. The remit of this group was to objectively determine how accurate commonly employed in vitro systems have been with respect to prediction of circulating human metabolites, both qualitatively and quantitatively. A survey composed of 34 questions was conducted across 26 pharmaceutical companies to obtain a foundational understanding of current metID practices, preclinically and clinically, as well as to provide perspective on how successful these practices have been at predicting circulating human metabolites. The results of this survey are presented as an initial snapshot of current industry-based metID practices, including our perspective on how a harmonized framework for the conduct of in vitro metID studies could be established. Future perspectives from current practices to emerging advances with greater translational capability are also provided.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576500","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":"Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps.","authors":"Alper Karagöl, Taner Karagöl, Mengke Li, Shuguang Zhang","doi":"10.1007/s11095-024-03786-z","DOIUrl":"https://doi.org/10.1007/s11095-024-03786-z","url":null,"abstract":"<p><strong>Objective: </strong>Glutamate transporters play a key role in central nervous system physiology by maintaining excitatory neurotransmitter homeostasis. Biological assemblies of the transporters, consisting of cyclic homotrimers, emerge as a crucial aspect of glutamate transporter modulation. Hence targeting heteromerization promises an effective approach for modulator design. On the other hand, the dynamic nature of transcription allows for the generation of transporter isoforms in structurally distinct manners.</p><p><strong>Methods: </strong>The potential isoforms were identified through the analysis of computationally generated gene-centric isoform maps. The conserved features of isoform sequences were revealed by computational chemistry methods and subsequent structural analysis of AlphaFold2 predictions. Truncated isoforms were further subjected to a wide range of docking analyses, 50ns molecular dynamics simulations, and evolutionary coupling analyses.</p><p><strong>Results: </strong>Energetic landscapes of isoform-canonical transporter complexes suggested an inhibitory potential of truncated isoforms on glutamate transporter bio-assembly. Moreover, isoforms that mimic the trimerization domain (in particular, TM2 helices) exhibited stronger interactions with canonical transporters, underscoring the role of transmembrane helices in isoform interactions. Additionally, self-assembly dynamics observed in truncated isoforms mimicking canonical TM5 helices indicate a potential protective role against unwanted interactions with canonical transporters.</p><p><strong>Conclusion: </strong>Our computational studies on glutamate transporters offer insights into the roles of alternative splicing on protein interactions and identifies potential drug targets for physiological or pathological processes.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564650","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 3D-Printed Two-Compartment Capsular Devices for Pulsatile Release of Peptide and Permeation Enhancer.","authors":"Pengchong Xu, Hanh Thuy Nguyen, Siyuan Huang, Huyen Tran","doi":"10.1007/s11095-024-03785-0","DOIUrl":"https://doi.org/10.1007/s11095-024-03785-0","url":null,"abstract":"<p><strong>Objective: </strong>The oral absorption of a peptide is driven by a high local concentration of a permeation enhancer (PE) in the gastrointestinal tract. We hypothesized that a controlled release of both PE and peptide from a solid formulation, capable of maintaining an effective co-localized concentration of PE and peptide could enhance oral peptide absorption. In this study, we aimed to develop a 3D-printed two-compartment capsular device with controlled pulsatile release of peptide and sodium caprate (C10).</p><p><strong>Methods: </strong>3D-printed two-compartment capsular device was fabricated using a fused deposition modeling method. This device was then filled with LY peptide and C10. The release profile was modulated by changing the thickness and polymer type of the capsular device. USP apparatus II dissolution test was used to evaluate the impacts of device thickness and polymer selection on release profile in vitro. An optimal device was then enteric coated with HPMCAS.</p><p><strong>Results: </strong>A strong linear relationship between the thickness of capsular devices and the delay in the release onset time was observed. An increase in the device thickness or the use of PLA decreased the release rate. The capsular device with compartment 1, compartment 2 and fence thickness of 0.4; 0.95 and 0.5 mm, respectively, and the use of PVA achieved desired pulsatile release profiles of both peptide and C10. Furthermore, enteric-coated capsular devices with HPMCAS had similar pulsatile release profiles compared to non-enteric coated devices.</p><p><strong>Conclusion: </strong>These findings suggest potential application of 3D-printing techniques in the formulation development for complex modified drug release products.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564647","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":"An Update on Recent Drug Delivery Systems Targeting Brain Diseases via the Transnasal Pathway.","authors":"Huiying Zeng, Huangjie Lu, Jie Yang, Ping Hu","doi":"10.1007/s11095-024-03790-3","DOIUrl":"https://doi.org/10.1007/s11095-024-03790-3","url":null,"abstract":"<p><strong>Objective: </strong>To explore the potential of transnasal drug delivery systems (DDS) as an effective means of bypassing the bloodbrain barrier (BBB) for enhanced central nervous system (CNS) targeting, aiming to improve therapeutic outcomes for CNS disorders while reducing systemic side effects.</p><p><strong>Methods: </strong>A review of current and emerging DDS technologies, including polymer nanoparticles, liposomes, and micelles, was conducted to assess their suitability for precision-targeted delivery to the brain through the transnasal route.</p><p><strong>Results: </strong>The investigated DDS demonstrate promising capabilities for CNS targeting via the nasal pathway, effectively preserving both the nasal mucosa and CNS integrity. These systems enhance drug precision within neural tissues, potentially improving therapeutic outcomes without harming adjacent tissues.</p><p><strong>Conclusions: </strong>Transnasal DDS offer a promising alternative to traditional delivery methods, with significant potential to advance the treatment of cerebrovascular diseases, neurodegenerative disorders, brain tumors, and psychiatric conditions. This approach represents an evolving frontier in neurotherapeutics, with the potential to transform CNS drug delivery practices.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546708","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":"The Research Progress of Metformin Regulation of Metabolic Reprogramming in Malignant Tumors.","authors":"Qihai Sui, Huiqiang Yang, Zhengyang Hu, Xing Jin, Zhencong Chen, Wei Jiang, Fenghao Sun","doi":"10.1007/s11095-024-03783-2","DOIUrl":"https://doi.org/10.1007/s11095-024-03783-2","url":null,"abstract":"<p><strong>Background: </strong>Metabolism reprogramming is a crucial hallmark of malignant tumors. Tumor cells demonstrate enhanced metabolic efficiency, converting nutrient inputs into glucose, amino acids, and lipids essential for their malignant proliferation and progression. Metformin, a commonly prescribed medication for type 2 diabetes mellitus, has garnered attention for its potential anticancer effects beyond its established hypoglycemic benefits.</p><p><strong>Methods: </strong>This review adopts a comprehensive approach to delineate the mechanisms underlying metabolite abnormalities within the primary metabolic processes of malignant tumors.</p><p><strong>Results: </strong>This review examines the abnormal activation of G protein-coupled receptors (GPCRs) in these metabolic pathways, encompassing aerobic glycolysis with increased lactate production in glucose metabolism, heightened lipid synthesis and cholesterol accumulation in lipid metabolism, and glutamine activation alongside abnormal protein post-translational modifications in amino acid and protein metabolism. Furthermore, the intricate metabolic pathways and molecular mechanisms through which metformin exerts its anticancer effects are synthesized and analyzed, particularly its impacts on AMP-activated protein kinase activation and the mTOR pathway. The analysis reveals a multifaceted understanding of how metformin can modulate tumor metabolism, targeting key nodes in metabolic reprogramming essential for tumor growth and progression. The review compiles evidence that supports metformin's potential as an adjuvant therapy for malignant tumors, highlighting its capacity to interfere with critical metabolic pathways.</p><p><strong>Conclusion: </strong>In conclusion, this review offers a comprehensive overview of the plausible mechanisms mediating metformin's influence on tumor metabolism, fostering a deeper comprehension of its anticancer mechanisms. By expanding the clinical horizons of metformin and providing insight into metabolism-targeted tumor therapies, this review lays the groundwork for future research endeavors aimed at refining and advancing metabolic intervention strategies for cancer treatment.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505806","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":"Identification of Patients Who Require Two-Point Blood Sampling for the Peak and Trough Values Rather Than One-Point Blood Sampling for the Trough Value for the Evaluation of AUC of Vancomycin Using Bayesian Estimation.","authors":"Ayako Suzuki, Masaru Samura, Tomoyuki Ishigo, Satoshi Fujii, Yuta Ibe, Hiroaki Yoshida, Hiroaki Tanaka, Fumiya Ebihara, Takumi Maruyama, Yukihiro Hamada, Hisato Fujihara, Fumihiro Yamaguchi, Fumio Nagumo, Toshiaki Komatsu, Atsushi Tomizawa, Akitoshi Takuma, Hiroaki Chiba, Yoshifumi Nishi, Yuki Enoki, Kazuaki Taguchi, Kazuaki Matsumoto","doi":"10.1007/s11095-024-03781-4","DOIUrl":"https://doi.org/10.1007/s11095-024-03781-4","url":null,"abstract":"<p><strong>Objectives: </strong>It is recommended to adjust the dose of vancomycin (VCM) with a target area under the concentration-time curve (AUC) of 400-600 μg·h/mL. Factors that affect the deviation between AUCs are estimated from the trough value alone and the trough and peak values using practical AUC-guided therapeutic drug monitoring (PAT) for vancomycin. In this study, factors that affect AUC were evaluated.</p><p><strong>Methods: </strong>AUCs were estimated from a single trough value and trough and peak values, and the patients were classified into those who showed a 10% or greater deviation (deviation group) and those in whom the deviation was less than 10% (no-deviation group). Risk factors related to ≥ 10% deviation of AUC were identified by univariate and multivariate analysis.</p><p><strong>Results: </strong>As a result of univariate and multivariate analysis of 30 patients in the deviation group and 344 patients in the no-deviation group, a creatinine clearance (CLcr) of ≥ 110 mL/min (odds ratio (OR) = 3.697, 95% confidence interval (CI) = 1.616-8.457, p = 0.002), heart failure with a brain natriuretic peptide (BNP) of ≥ 300 pg/mL (OR = 4.854, 95%CI = 1.199-19.656, p = 0.027), and the concomitant use of angiotensin converting enzyme inhibitor or angiotensin II receptor blocker (ACE-I/ARB) (OR = 2.544, 95%CI = 1.074-6.024, p = 0.034) were identified as risk factors of ≥ 10% deviation of AUC.</p><p><strong>Conclusions: </strong>Estimation of AUC by two-point blood sampling for the trough and peak values rather than one-point blood sampling for the trough value is suggested to improve the prediction accuracy in patients with enhanced renal function, severe heart failure, and patients using ACE-I/ARB.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472346","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 Mathematical Function Control-Based 3D Printed Tablets and Effect on Drug Release.","authors":"Honghe Wang, Indrajeet Karnik, Prateek Uttreja, Peilun Zhang, Sateesh Kumar Vemula, Michael A Repka","doi":"10.1007/s11095-024-03780-5","DOIUrl":"https://doi.org/10.1007/s11095-024-03780-5","url":null,"abstract":"<p><strong>Purpose: </strong>The application of 3D printing technology in drug delivery is often limited by the challenges of achieving precise control over drug release profiles. The goal of this study was to apply surface equations to construct 3D printed tablet models, adjust the functional parameters to obtain multiple tablet models and to correlate the model parameters with the in vitro drug release behavior.</p><p><strong>Methods: </strong>This study reports the development of 3D-printed tablets using surface geometries controlled by mathematical functions to modulate drug release. Utilizing fused deposition modeling (FDM) coupled with hot-melt extrusion (HME) technology, personalized drug delivery systems were produced using thermoplastic polymers. Different tablet shapes (T1-T5) were produced by varying the depth of the parabolic surface (b = 4, 2, 0, -2, -4 mm) to assess the impact of surface curvature on drug dissolution.</p><p><strong>Results: </strong>The T5 formulation, with the greatest surface curvature, demonstrated the fastest drug release, achieving complete release within 4 h. In contrast, T1 and T2 tablets exhibited a slower release over approximately 6 h. The correlation between surface area and drug release rate was confirmed, supporting the predictions of the Noyes-Whitney equation. Differential Scanning Calorimetry (DSC) and Scanning Electron Microscope (SEM) analyses verified the uniform dispersion of acetaminophen and the consistency of the internal structures, respectively.</p><p><strong>Conclusions: </strong>The precise control of tablet surface geometry effectively tailored drug release profiles, enhancing patient compliance and treatment efficacy. This novel approach offers significant advancements in personalized medicine by providing a highly reproducible and adaptable platform for optimizing drug delivery.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472344","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":"Ground Salicornia herbacea Powder Suppresses AOM/DSS-induced Colon Cancer by Inhibiting Wnt/β-catenin Signaling and Nrf2.","authors":"Yeonoh Cho, Ji Hyeon Cha, Yujin Hwang, Hee-Taik Kang, Jong Hun Lee","doi":"10.1007/s11095-024-03784-1","DOIUrl":"https://doi.org/10.1007/s11095-024-03784-1","url":null,"abstract":"<p><strong>Purpose: </strong>This study aims to evaluate the effects of prebiotics and probiotics on colorectal cancer (CRC) progression in an AOM/DSS-induced mouse model.</p><p><strong>Methods: </strong>In AOM/DSS-induced mouse model, treatment groups received either S. herbacea as a prebiotic (PRE) or in combination with Lactobacillus plantarum as a probiotic (PRO). PCNA, Ki-67, β-catenin, c-Myc, and Nrf2 were evaluated using immunohistochemistry (IHC). The impact on polyp formation and progression was assessed by categorizing polyps according to their size.</p><p><strong>Results: </strong>Both PRE and PRO treatments resulted in a significant reduction in large polyp formation when compared to AOM/DSS induced control group. IHC analyses demonstrated reduced biomarker expression for cell proliferation in PRE and PRO groups, specifically showing decreased staining for PCNA, Ki-67, β-catenin, and c-Myc, indicating downregulation of Wnt signaling and suppressed cell proliferation. Reduced Nrf2 expression highlights the impact of treatments interfering with cancer cell defenses. Notably, there were no significant differences in the outcomes between PRE and PRO groups, suggesting that prebiotics show anticancer effects.</p><p><strong>Conclusion: </strong>The study suggests that S. herbacea, a prebiotic, effectively suppresses CRC progression, with limited additional benefits from combining with probiotics. These findings underscore the therapeutic potential of prebiotics in CRC.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472345","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 Preclinical Pharmacokinetics and Disposition of Favipiravir Following Pulmonary and Oral Administration as Potential Adjunct Therapy Against Airborne RNA Viruses.","authors":"Venkata Siva Reddy Devireddy, Hasham Shafi, Sonia Verma, Sanjay Singh, J V U S Chakradhar, Naresh Kothuri, Himanshu Bansode, Sunil Kumar Raman, Deepak Sharma, Lubna Azmi, Rahul Kumar Verma, Amit Misra","doi":"10.1007/s11095-024-03782-3","DOIUrl":"https://doi.org/10.1007/s11095-024-03782-3","url":null,"abstract":"<p><strong>Background: </strong>Favipiravir is administered orally, even against airborne RNA viruses, in a loading-dose/maintenance dose regimen. We investigated whether-(a) pulmonary delivery of favipiravir would generate high concentrations in the luminal side of the respiratory tract; and (b) avoiding first-pass metabolism by the liver by inhaled drug would generate comparable pharmacokinetics (PK) with doses significantly smaller than the oral maintenance dose.</p><p><strong>Methods: </strong>A dry powder inhalation (DPI) of favipiravir formulated by mixing with Inhalac 400® was prepared and characterized. Inhalations of ~ 120 µg dose strength, with or without a prior oral loading dose were administered to mice. Comparator mice received human-equivalent oral doses (3 mg). Three mice per sampling time point were sacrificed and favipiravir concentrations in the blood plasma, bronchio-alveolar lavage fluid (BALF) and lung tissue homogenate determined by HPLC.</p><p><strong>Results: </strong>One-compartment PK modeling of concentration-time data indicated that the area under the curve (AUC_0-24 h) generated in the BALF recovered from mice receiving inhalations of ~ 1/25th of the oral dose subsequent to an oral loading dose was 86.72 ± 4.48 µg⋅mL^-1⋅h. This was consistently higher than the AUC observed in the BALF of orally-dosed mice (56.71 ± 53.89 µg mL^-1⋅h). In blood serum, the respective values of AUC were 321.55 ± 124.91 and 354.71 ± 99.60 µg⋅mL^-1⋅h.</p><p><strong>Conclusion: </strong>Pulmonary delivery of significantly smaller doses of favipiravir generates meaningful drug disposition and pharmacokinetics at the site of respiratory viral infections. We provide the rationale for designing a self-administered, non-invasive, low-cost, targeted drug delivery system against airborne RNA virus infection.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472343","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}