Pharmaceutical Research最新文献

{"title":"MR Molecular Image Guided Treatment of Pancreatic Cancer with Targeted ECO/miR-200c Nanoparticles in Immunocompetent Mouse Tumor Models.","authors":"Victoria Laney, Ryan Hall, Xueer Yuan, Emma Hampson, Augusta Halle, Grace Yeung, Kristen-Weber Bonk, Suneel Apte, Jordan Winter, Ruth Keri, Zheng-Rong Lu","doi":"10.1007/s11095-024-03762-7","DOIUrl":"10.1007/s11095-024-03762-7","url":null,"abstract":"<p><strong>Objective: </strong>Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplasia due to increased deposition of extracellular matrix (ECM) proteins. This work investigates the efficacy of targeted ECO/miR-200c nanoparticles (ELNP) on ECM remodeling in PDAC and tumor proliferation with MR molecular imaging (MRMI) with MT218 in immunocompetent mouse models.</p><p><strong>Methods: </strong>The miR-200c mediated regulation of EMT markers was measured in PDAC cells in vitro. Wild-type mice bearing mutated KRAS-driven KPC subcutaneous or orthotopic tumors were dosed weekly with RGD-ELNP/miR-200c at 1 mg-RNA/kg for a total of 4 doses. We utilized MT218-MRMI to non-invasively monitor the alteration of tumor ECM EDN-FN levels by miR-200c and tumor response to the treatment. The changes were also validated by posthumous histopathology.</p><p><strong>Results: </strong>Transfection of PDAC cells with ELNP/miR-200c downregulated the expression of FN1 and EDB-FN and some mesenchymal markers, inhibiting 3D spheroid formation and migration of KPC PDAC cells. RGD-ELNP/miR-200c treatment resulted in significant signal reduction in the MT218 enhanced MRMI images of both subcutaneous and orthotopic KPC tumors compared to those prior to treatment and treated with a non-specific control. MT218-MRMI results were suggestive of EDB-FN downregulation in tumors, which was later confirmed by immunohistochemistry. Tumor growth in subcutaneous tumors was significantly attenuated with RGD-ELNP/miR-200c and was an observed trend in orthotopic tumors. Substantial necrosis and remodeling were observed in both models treated with RGD-ELNP/miR-200c based on H&E staining.</p><p><strong>Conclusion: </strong>These results demonstrate the feasibility of RGD-ELNP/miR-200c in modulating PDAC ECM and restraining tumor growth and the utility of MT218-MRMI for non-invasively monitoring miR-200c efficacy.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1811-1825"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11436418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142093677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Approaches to Design Space Development and Regulatory Applications for Drug Products: Findings from the IQ Utilization of Design Space for Filings Working Group Survey.","authors":"James E Miesle, Frederick Osei-Yeboah, Anette Pauli-Bruns, Bei Chen, Slobodanka Manceva, Jonathan B Wade, Shawn Yin, Divyakant Desai, Olivier Dirat, Chandan Bhugra, Fanny Stauffer","doi":"10.1007/s11095-024-03765-4","DOIUrl":"10.1007/s11095-024-03765-4","url":null,"abstract":"<p><strong>Purpose: </strong>The concept of a Design Space (DSp) was introduced in ICH Q8 as a tool within the quality-by-design (QbD) approach to pharmaceutical development with the intent of being globally applicable. However, there appears to be variance in the regulatory agency expectations in pharmaceutical product filing and implementation of DSp. This paper presents some of the current industry perspective on design space.</p><p><strong>Methods: </strong>The Utilization of Design Space for Filings (UDSpF) Working Group in the Innovation and Quality (IQ) Consortium conducted a survey to establish a baseline for the current understanding of DSp among IQ member companies and assess the similarities and/or differences in strategies when filing a DSp. The survey focused on how IQ member companies approach DSp development, the primary drivers for the DSp, the presentation of the DSp in the filing, DSp verification and the benefits and flexibility anticipated and/or realized.</p><p><strong>Results: </strong>A total of 14 responses were received and analyzed representing a small sample size but a large proportion of the innovator industry/large pharmaceutical companies. The survey results revealed that DSp is not yet a commonplace for small molecule drug products and may not even be utilized as much in large molecule drug products. The benefits of DSp, with respect to enhanced process understanding, are well understood by the sponsors; however, the benefits of filed DSp with respect to manufacturing flexibility are not fully realized in the commercial lifecycle of the product. There are also challenges in gaining consistent buy-in/value proposition for DSp among cross-functional teams within organizations.</p><p><strong>Conclusions: </strong>There are still gaps in design space implementation for its full benefit in the pharmaceutical industry. The WG has presented a unified view from member companies on the approach to DSp considering when/where the DSp experiments are conducted and on the extent of the DSp development proposed in a dossier.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1775-1786"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133451","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":"Current Insights into CAR T-Cell-Based Therapies for Myelodysplastic Syndrome.","authors":"Manav Gandhi, Bhirisha Sharma, Sujit Nair, Ashok D B Vaidya","doi":"10.1007/s11095-024-03761-8","DOIUrl":"10.1007/s11095-024-03761-8","url":null,"abstract":"<p><p>Myelodysplastic syndromes (MDS) are due to defective hematopoiesis in bone marrow characterized by cytopenia and dysplasia of blood cells, with a varying degree of risk of acute myeloid leukemia (AML). Currently, the only potentially curative strategy is hematopoietic stem cell transplantation (HSCT). Many patients are ineligible for HSCT, due to late diagnosis, presence of co-morbidities, old age and complications likely due to graft-versus-host disease (GvHD). As a consequence, patients with MDS are often treated conservatively with blood transfusions, chemotherapy, immunotherapy etc. based on the grade and manifestations of MDS. The development of chimeric antigen receptor (CAR)-T cell therapy has revolutionized immunotherapy for hematological malignancies, as evidenced by a large body of literature. However, resistance and toxicity associated with it are also a challenge. Hence, there is an urgent need to develop new strategies for immunological and hematopoetic management of MDS. Herein, we discuss current limitations of CAR T-cell therapy and summarize novel approaches to mitigate this. Further, we discuss the in vivo activation of tumor-specific T cells, immune check inhibitors (ICI) and other approaches to normalize the bone marrow milieu for the management of MDS.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1757-1773"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073535","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 a New Dry Powder Aerosol Synthetic Lung Surfactant Product for Neonatal Respiratory Distress Syndrome (RDS) - Part II: In vivo Efficacy Testing in a Rabbit Surfactant Washout Model.","authors":"Robert M DiBlasi, Hattie KenKnight, Niko Kontoudios, Dale Farkas, Mohammad A M Momin, Felicia Hall, Michael Hindle, Worth Longest","doi":"10.1007/s11095-024-03754-7","DOIUrl":"10.1007/s11095-024-03754-7","url":null,"abstract":"<p><strong>Purpose: </strong>Surfactant therapy incorporates liquid bolus instillation via endotracheal tube catheter and a mechanical ventilator in preterm neonates with respiratory distress syndrome (RDS). Aerosolized surfactants have generated interest and conflicting data on the efficacy of phospholipid (PL) dose requirements. We developed and characterized a synthetic lung surfactant excipient enhanced growth (SLS-EEG) dry powder aerosol product. In this study, we compare the in vivo performance of the new aerosol product with standard-of-care liquid instillation.</p><p><strong>Methods: </strong>Juvenile rabbits were sedated, anesthetized, intubated, and ventilated. Endogenous surfactant was depleted via whole lung lavage. Animals received either a standard dose of liquid Curosurf (200 mg PL/kg) instilled via a tracheal catheter, SLS-EEG powder aerosol (60 mg device loaded dose; equivalent to 24 mg PL/kg), or sham control. Gas exchange, lung compliance, and indices of disease severity were recorded every 30 min for 3.5 h and macro- and microscopy images were acquired at necropsy.</p><p><strong>Results: </strong>While aerosol was administered at an approximately tenfold lower PL dose, both liquid-instilled and aerosol groups had similar, nearly complete recoveries of arterial oxygenation (PaO₂; 96-100% recovery) and oxygenation index, and the aerosol group had superior recovery of compliance (P < 0.05). The SLS-EEG aerosol group showed less lung tissue injury, greater uniformity in lung aeration, and more homogenous surfactant distribution at the alveolar surfaces compared with liquid Curosurf.</p><p><strong>Conclusions: </strong>The new dry powder aerosol SLS product (which includes the delivery strategy, formulation, and delivery system) has the potential to be a safe, effective, and economical alternative to the current clinical standard of liquid bolus surfactant instillation.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1827-1842"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11436456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acceleration of Final Residual Solvent Extraction From Poly(lactide-co-glycolide) Microparticles.","authors":"Florian Kias, Roland Bodmeier","doi":"10.1007/s11095-024-03744-9","DOIUrl":"10.1007/s11095-024-03744-9","url":null,"abstract":"<p><strong>Purpose: </strong>The removal of the residual solvent dichloromethane from biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles was investigated by aqueous or alcoholic wet extraction or vacuum-drying.</p><p><strong>Methods: </strong>Microparticles were prepared by the O/W solvent extraction/evaporation method. The solidified microparticles were separated by filtration and the effect of subsequent drying and wet extraction methods were investigated. The residual solvent content was analysed with gas chromatography (organic solvents) and Karl Fischer titration (water). The effect of extraction conditions on microparticle aggregation, surface morphology and encapsulation of the drugs dexamethasone and risperidone was investigated.</p><p><strong>Results: </strong>Residual dichloromethane was reduced to 2.43% (w/w) (20 °C) or 0.03% (w/w) (35 °C) by aqueous wet extraction. With vacuum-drying, residual dichloromethane only decreased from about 5% (w/w) to 4.34% (w/w) (20 °C) or 3.20% (w/w) (35 °C) due to the lack of the plasticizing effect of water. Redispersion of filtered, wet microparticles in alcoholic media significantly improved the extraction due to an increased PLGA plasticization. The potential of different extractants was explained with the Gordon-Taylor equation and Hansen solubility parameters. Extraction in methanol: or ethanol:water mixtures reduced residual dichloromethane from 4 - 7% (w/w) to 0.5 - 2.3% (w/w) within 1 h and 0.08 - 0.18% (w/w) within 6 h. Higher alcohol contents and higher temperature resulted in aggregation of microparticles and lower drug loadings.</p><p><strong>Conclusion: </strong>The final removal of residual dichloromethane was more efficient with alcoholic wet extraction followed by aqueous wet extraction at elevated temperature and vacuum drying of the microparticles.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1869-1879"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11436459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid Synthesis and Evaluation of Resveratrol-Piperazine Cocrystals by Ultrasound and Microwave Methods.","authors":"Simona Ioniţă, Mariana Pătrașcu, Elena Mirabela Soare, Daniel Lincu, Irina Atkinson, Adriana Rusu, Mihaela Maria Pop, Coca Iordache, Cătălina-Diana Ușurelu, Andreea Simona Baltac, Raul-Augustin Mitran, Jeanina Pandele-Cuşu, Victor Fruth","doi":"10.1007/s11095-024-03758-3","DOIUrl":"10.1007/s11095-024-03758-3","url":null,"abstract":"<p><strong>Objective: </strong>Resveratrol-piperazine cocrystals have been obtained by ultrasound (US) and microwave-assisted (MW) techniques, using the solution and slurry-based methods, to study the influence of the synthesis method on the resulting cocrystal properties, and scalability of the processes. The potential of these cocrystals is represented by the unique properties of their components, resveratrol, and piperazine, which could be also used in veterinary practice. Resveratrol has antimicrobial, antiviral and anticarcinogenic properties, while piperazine can be used in the treatment of parasitic infections.</p><p><strong>Methods: </strong>The influence of ultrasound and microwave-assisted treatment was studied by varying synthesis parameters such as reaction time, temperature, and US or MW power. The main advantage of using these methods is represented by shorter synthesis time compared to conventional methods, resulting in the direct formation of the cocrystals.</p><p><strong>Results: </strong>All samples were obtained in high purity, above 97%. Cocrystal yield correlated positively with ultrasound reaction time, while temperature was not found to influence the microwave synthesis yield up to 50°C, in the case of solution-based methods. MW and US-assisted solution-based methods lead to yields between 52.9 and 68.1%. In the case of the slurry-based method, a minimum reaction time of 5 min leads to the formation of cocrystals with high purity. The resveratrol-piperazine cocrystal's solubility and in vitro antibacterial activity were also evaluated, showing promising results.</p><p><strong>Conclusions: </strong>Ultrasound and microwave-assisted techniques offer a viable alternative for synthesizing resveratrol-piperazine cocrystals with short reaction times, high yield, and purity, suitable for scalable resveratrol-piperazine cocrystals.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1843-1853"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902604","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":"Generic Enrichment Method for Liquid Chromatography-Multiple Reaction Monitoring-Mass Spectrometry Assay for Quantitative Measurement of Biological Therapeutics in Serum.","authors":"Sisi Zhang, Hui Xiao, Ning Li","doi":"10.1007/s11095-024-03759-2","DOIUrl":"10.1007/s11095-024-03759-2","url":null,"abstract":"<p><strong>Purpose: </strong>The study aims to leverage the capabilities of Liquid Chromatography-Multiple Reaction Monitoring Mass Spectrometry (LC-MRM), a key technique in quantifying therapeutic proteins in pharmacokinetic studies. The focus is on demonstrating an enrichment method using ProteoMiner beads, which can be integrated with LC-MRM to detect low-abundance biotherapeutics in serum, such as monoclonal antibodies and gene therapy products.</p><p><strong>Methods: </strong>The ProteoMiner enrichment method was employed and integrated with LC-MRM. The lower limit of quantification of serum drug substance concentrations was compared with that achievable with immuno-enrichment. The method used commercially available reagents, eliminating the need for assay-specific antibodies and reducing potential bias and development time.</p><p><strong>Results: </strong>The ProteoMiner enrichment method showed comparable performance to immuno-enrichment, meeting traditional assay requirements in terms of precision, accuracy, and specificity.</p><p><strong>Conclusions: </strong>The ProteoMiner enrichment method, when combined with LC-MRM, offers a reliable and efficient alternative to immuno-enrichment for detecting and quantifying low-abundance biotherapeutics in serum. This approach, which uses commercially available reagents, can eliminate the bias and time associated with the development of assay-specific antibodies. It holds significant potential for accelerating pharmacokinetic analysis in both early and late stages of pharmaceutical development.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1881-1892"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036572","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 Novel Size Exclusion Chromatography Method for the Analysis of Monoclonal Antibodies and Antibody-drug Conjugates by Using Sodium Iodide in the Mobile Phase.","authors":"Jian-Zhong Liu, Lei Li, Wei-Jie Fang","doi":"10.1007/s11095-024-03763-6","DOIUrl":"10.1007/s11095-024-03763-6","url":null,"abstract":"<p><strong>Purposes: </strong>Size exclusion chromatography (SEC) is widely used to characterize molecular size variants of antibody drugs. However, SEC analysis is hindered by secondary interactions (or nonspecific interactions) between proteins and stationary phase packing, which result in poor column efficiency. Previous studies have reported that chaotropic salt can inhibit these interactions, but the corresponding applications of this aspect are relatively rare. Therefore, this study introduces a novel approach using sodium iodide (NaI) as a mobile-phase component in SEC and investigates the influence of the mobile-phase composition on secondary interactions.</p><p><strong>Methods: </strong>SEC analysis was performed on one antibody-drug conjugate and four monoclonal antibodies (mAbs) using three different mobile-phase systems (i.e., sodium chloride/L-arginine hydrochloride/NaI mobile phases system) to compare the column efficiency. Subsequently, mAb-1 was used as a model to investigate the effects of these factors on secondary interactions by adjusting the ionic strength (salt concentration) and pH of the NaI mobile-phase system.</p><p><strong>Results: </strong>NaI exhibits superior column efficiency performance in the SEC analysis of most products. The ionic strength will affect nonideal electrostatic and hydrophobic interaction. An appropriate ionic strength can inhibit electrostatic interactions, while an excessive ionic strength increases hydrophobic interactions. pH primarily influences electrostatic interactions. Determining the appropriate pH necessitates consideration of the isoelectric point of the protein and the pH tolerance of the column.</p><p><strong>Conclusions: </strong>In SEC analysis, using NaI as the salt component in the mobile phase reduces secondary interactions and improves column efficiency. This approach is advantageous for samples with intense secondary interactions and is a suitable alternative.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1893-1901"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133450","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":"Correction: Development of a New Dry Powder Aerosol Synthetic Lung Surfactant Product for Neonatal Respiratory Distress Syndrome (RDS) - Part I: In Vitro Testing and Characterization.","authors":"Mohammad A M Momin, Dale Farkas, Michael Hindle, Felicia Hall, Robert M DiBlasi, Worth Longest","doi":"10.1007/s11095-024-03760-9","DOIUrl":"10.1007/s11095-024-03760-9","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1903"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11436437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formulation and Validation of an Extended Sigmoid Emax Model in Pharmacodynamics.","authors":"Jong Hyuk Byun","doi":"10.1007/s11095-024-03752-9","DOIUrl":"10.1007/s11095-024-03752-9","url":null,"abstract":"<p><strong>Purpose or objective: </strong>Drug concentration-response curves (DRCs) are crucial in pharmacology for assessing the drug effects on biological systems. The widely used sigmoid Emax model, which accounts for response saturation, relies heavily on the effective drug concentration ( <math><mrow><mi>E</mi> <msub><mi>D</mi> <mn>50</mn></msub> </mrow> </math> ). This reliance can lead to validation errors and inaccuracies in model fitting. The Emax model cannot generate multiple DRCs, raising concerns about whether the dataset is fully utilized.</p><p><strong>Methods: </strong>This study formulates an extended Emax (eEmax) model designed to overcome these limitations. The eEmax model generates multiple DRCs from a single dataset by using various estimated <math> <mrow> <msup><mrow><mi>α</mi></mrow> <mo>'</mo></msup> <mtext>s</mtext> <mo>∈</mo> <mfenced><mtext>0,100</mtext></mfenced> </mrow> </math> , while keeping <math><mrow><mi>E</mi> <msub><mi>D</mi> <mi>α</mi></msub> </mrow> </math> fixed, rather than estimating an <math><mrow><mi>E</mi> <msub><mi>D</mi> <mn>50</mn></msub> </mrow> </math> value as in the Emax model.</p><p><strong>Results: </strong>This model effectively captures a broader range of concentration-response behavior, including non-sigmoidal patterns, thus providing greater flexibility and accuracy compared to the Emax model. Validation using various drug-response data and PKPD frameworks demonstrates the eEmax model's improved accuracy and versatility in handling concentration-response data.</p><p><strong>Conclusions: </strong>The eEmax model provides a robust and flexible method for drug concentration-response analysis, facilitating the generation of multiple DRCs from a single dataset and reducing the possibility of validation errors. This model is particularly valuable for its ease of use and its capability to fully utilize datasets, providing its potential in PKPD modeling and drug discovery.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1787-1795"},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982981","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}