Pharmaceutical Research最新文献_第4页

Pharmacokinetic Assessment of Drug Efflux from Erythrocytes Loaded with Corticosteroid Esters. 满载皮质类固醇酯的红细胞外排药物的药动学评估。

IF 4.3 3区医学

Pharmaceutical Research Pub Date : 2025-08-01 Epub Date: 2025-08-15 DOI: 10.1007/s11095-025-03913-4

William J Jusko, Ruihong Yu

{"title":"Pharmacokinetic Assessment of Drug Efflux from Erythrocytes Loaded with Corticosteroid Esters.","authors":"William J Jusko, Ruihong Yu","doi":"10.1007/s11095-025-03913-4","DOIUrl":"10.1007/s11095-025-03913-4","url":null,"abstract":"Purpose: Drugs can be found in erythrocytes (RBC) in accordance with their physicochemical and specific binding properties, but particularly high concentrations can be attained using an ex vivo hypotonic pre-swelling method. Pharmacokinetic (PK) methodology and characterization of in vivo data for RBC-loaded corticosteroid prodrugs was sought.Methods: Three studies providing in vitro and in vivo assessments of the pharmacokinetics of steroid ester prodrugs loaded into RBC were found. A PK model involving three fractional input rates and two-compartment disposition was applied.Results: After their sodium phosphate ester pro-drugs were loaded into RBC and dosed intravenously, dexamethasone (DEX) and betamethasone (BET) plasma concentrations were markedly prolonged with three phases in humans and animals. For DEX in humans, a PK model accounted for the typical biexponential disposition of the active steroid and for input of a large fraction (0.72) released within 1 h, a small fraction (0.27) released over several hours (t1/2 = 5.5 h), and a very small fraction (0.008) released extremely slowly (t1/2 = 109 h). The DEX RBC concentrations were expected to remain far higher than plasma concentrations for this prolonged time. The PK model was also applied to DEX in rabbits and BET in rats with generally similar results and indicating full bioavailability.Conclusions: The proposed PK methodology well characterized the input properties of RBC-loaded controlled-release formulations of corticosteroids in animal and humans in context of the flip-flop kinetics of the released drug. The model may be relevant to other types of RBC-loaded therapeutic agents.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1299-1306"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855973","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}

引用次数: 0

Dissolution Profile of Tosufloxacin Tosylate in Biorelevant Bicarbonate Buffer Containing Sodium Chloride: Precipitation of Hemi-hydrochloride Salt at the Particle Surface. tosuflo沙星tosy酸酯在含氯化钠的生物相关碳酸氢盐缓冲液中的溶解谱：半盐酸盐在颗粒表面的沉淀。

IF 4.3 3区医学

Pharmaceutical Research Pub Date : 2025-08-01 Epub Date: 2025-08-11 DOI: 10.1007/s11095-025-03905-4

Nanami Okamoto, Hibiki Yamamoto, Kiyohiko Sugano

{"title":"Dissolution Profile of Tosufloxacin Tosylate in Biorelevant Bicarbonate Buffer Containing Sodium Chloride: Precipitation of Hemi-hydrochloride Salt at the Particle Surface.","authors":"Nanami Okamoto, Hibiki Yamamoto, Kiyohiko Sugano","doi":"10.1007/s11095-025-03905-4","DOIUrl":"10.1007/s11095-025-03905-4","url":null,"abstract":"Purpose: The purpose of the present study was to investigate the dissolution profile of tosufloxacin tosylate monohydrate (TFLX TS) in biorelevant bicarbonate buffer (BCB). TFLX is a zwitterionic drug (pKa: 5.8 and 8.7), formulated as tosylate salt to enhance its dissolution.Methods: The dissolution profiles were measured in BCB or phosphate buffer (PPB) at pH 6.5 with buffer capacity (β) = 0.88 or 4.4 mM/pH, containing NaCl or Na2SO4 (I = 0.14 M). The residual particles were analyzed by powder X-ray diffraction. In a separate study, the particle surface of TFLX TS after contact with BCB was observed by scanning electron microscopy and real-time polarized light microscopy. The pH solubility profile of TFLX was measured using HCl and TS solutions.Results: TFLX TS dissolved less in the NaCl media than in the Na2SO4 media. It also dissolved less in PPB than in BCB (at β = 4.4 mM/pH), and less at β = 4.4 mM/pH than at 0.88 mM/pH. The analysis of residual particles indicated that the hemi-hydrochloride salt (TFLX 1/2HCl) precipitated on the particle surface of TFLX TS in the NaCl media. In contrast, the free form of TFLX precipitated in the Na2SO4 media. The pH solubility profile matched the hemi-hydrochloride stoichiometry (Ksp = [TFLX∙H+][TFLX][Cl-]).Conclusion: The dissolution of TFLX TS in the NaCl media was suppressed by the precipitation of TFLX 1/2HCl on the particle surface. This is an important case showing that NaCl can suppress the dissolution profile of a non-HCl drug salt at a neutral pH.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1363-1372"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822265","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}

引用次数: 0

Influence of Milling Parameters on Crystal Morphology, Thermal Behavior, and Dissolution of Mesalamine Nanocrystals. 铣削参数对美沙拉胺纳米晶形貌、热行为和溶解的影响。

IF 4.3 3区医学

Pharmaceutical Research Pub Date : 2025-08-01 Epub Date: 2025-07-23 DOI: 10.1007/s11095-025-03891-7

Sakshi Kunjir, Prajakta Pathare, Sonam Sharma, Jyoti Deoriya, Subramanian Natesan, Rajkumar Malayandi

{"title":"Influence of Milling Parameters on Crystal Morphology, Thermal Behavior, and Dissolution of Mesalamine Nanocrystals.","authors":"Sakshi Kunjir, Prajakta Pathare, Sonam Sharma, Jyoti Deoriya, Subramanian Natesan, Rajkumar Malayandi","doi":"10.1007/s11095-025-03891-7","DOIUrl":"10.1007/s11095-025-03891-7","url":null,"abstract":"Purpose: The low aqueous solubility limits the therapeutic potential of both new and existing drug molecules. Mesalamine (MES), a primary therapeutic agent for inflammatory bowel diseases, has low aqueous solubility and incomplete dissolution in the colon; hence, it requires a high administered dose (maximum daily dose of 4.8 g/day). This study attempts to improve the dissolution velocity and solubility by designing MES nanocrystals.Methods: MES nanocrystals were prepared using the dry ball milling (BM) process. MES nanocrystals (NCs) were prepared using Soluplus as stabilizer, and milling parameters were optimized to obtain the desirable particle size and other pharmaceutical attributes.Results: The prepared MES NCs were characterized to understand the influence of key milling parameters like time, speed, and stabilizer concentration. Variations in these parameters resulted in diverse morphologies, including rectangular bars, elongated hexagons, spheroids, and plates. Batch 29 (40/1/400) exhibited a plate-like crystal habit with a particle size of 435 nm and a PDI of 0.39, demonstrating an improved dissolution efficacy (84% in 60 min). Spectroscopic, microscopic, and thermal analyses confirmed the influence of ball milling on solubility, dissolution rate, particle size, and crystal habits.Conclusion: The study outcomes could be useful for the successful scale-up and commercialization of drug products based on the dry BM platform technology.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1409-1427"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699199","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}

引用次数: 0

Investigation of the Binding Characteristics of Agonists and Various Antagonists Targeting Histamine 1 Receptor. 针对组胺1受体的激动剂和各种拮抗剂结合特性的研究。

IF 4.3 3区医学

Pharmaceutical Research Pub Date : 2025-08-01 Epub Date: 2025-08-04 DOI: 10.1007/s11095-025-03899-z

Panpan Lei, Yuxiu Zhang, Xiaoyu Ma, Sifan Xie, Jiapan Gao, Bingxi Ren, Yuanji Wang, Weina Ma

{"title":"Investigation of the Binding Characteristics of Agonists and Various Antagonists Targeting Histamine 1 Receptor.","authors":"Panpan Lei, Yuxiu Zhang, Xiaoyu Ma, Sifan Xie, Jiapan Gao, Bingxi Ren, Yuanji Wang, Weina Ma","doi":"10.1007/s11095-025-03899-z","DOIUrl":"10.1007/s11095-025-03899-z","url":null,"abstract":"Objective: The histamine H1 receptor (H1R) plays a central role in mediating allergic responses, making it a critical target for therapeutic intervention. However, the molecular mechanisms underlying drug binding to H1R remain incompletely elucidated.Methods: We employed an integrated approach combining site-directed mutagenesis, cell membrane chromatography (CMC) and pharmacological activity assays to systematically characterize the binding mechanisms of H1R agonists and antagonists. We constructed various H1R/CMC systems using high-expression H1R cells (wild type, TM3, TM5, TM6, and ECL2 mutants) and evaluated the binding affinities of three agonists (histamine, HTMT, betahistine) and three classes of antagonists (ethylenediamine/propanamine, tricyclic, piperidine derivatives).Results: Our findings reveal distinct agonist binding preferences: histamine primarily targets TM3, HTMT interacts with TM5, and betahistine shows a strong preference for TM6. Among antagonists, ethylenediamine/propanamine and piperidine classes predominantly block TM3 and TM6 regions, while tricyclic antagonists additionally depend on TM5 region for their inhibitory effects. Pharmacological validation through phospholipase C (PLC) activity assays corroborated these results, demonstrating that mutations in specific transmembrane domains significantly alter agonist-induced signaling and antagonist-mediated efficacy.Conclusion: These mechanistic insights into H1R ligand binding provide a structural foundation for the rational design of targeted therapies with improved selectivity and efficacy against allergic disorders.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1315-1329"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144785007","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}

引用次数: 0

Utilizing Octanoic Acid to Quantitatively Assess the Oxidation Status of PS80. 利用辛酸定量评价PS80氧化状态。

IF 4.3 3区医学

Pharmaceutical Research Pub Date : 2025-08-01 Epub Date: 2025-08-11 DOI: 10.1007/s11095-025-03908-1

Yue Guo, Sisi Zhang, Jamie Ash, Stacey Helming, Rachel Mullen, Xuening Hu, Qingyan Hu, Jing Wang, Tse-Hong Chen, Shao-Chun Wang, Douglas Kamen, Biao Shen, Hui Xiao, Ning Li

{"title":"Utilizing Octanoic Acid to Quantitatively Assess the Oxidation Status of PS80.","authors":"Yue Guo, Sisi Zhang, Jamie Ash, Stacey Helming, Rachel Mullen, Xuening Hu, Qingyan Hu, Jing Wang, Tse-Hong Chen, Shao-Chun Wang, Douglas Kamen, Biao Shen, Hui Xiao, Ning Li","doi":"10.1007/s11095-025-03908-1","DOIUrl":"10.1007/s11095-025-03908-1","url":null,"abstract":"Purpose: The study aims to address the gap in research concerning the stability of polysorbate (PS) in placebo samples, as opposed to drug products. While PS is a critical excipient in protein drug formulations, its stability in placebo samples has been less explored. Notably, PS in placebo samples is more susceptible to oxidation rather than hydrolysis, even at low temperatures like 5℃. The study seeks to provide a quantitative measure for PS oxidation, which has traditionally been described in vague terms.Method: The research identified octanoic acid as an oxidative product of PS80, which can serve as a reliable marker for PS80 oxidation. This marker enables the detection of early signs of oxidation and facilitates a quantitative description of the oxidation status, regardless of the stress conditions and incubation times. The method's accuracy and precision were validated to be within 15%, aligning with industry standards.Results: The use of octanoic acid as a marker successfully indicates the oxidation status of PS80, offering a quantitative approach to assess PS80 stability. This method provides a clearer understanding of the shelf-life of placebo products concerning PS80 stability.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1397-1407"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822266","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}

引用次数: 0

Effect of Colour and Surface Properties of Solid Pharmaceutical Dosage Forms on Light Reflection in Solar Spectral Range. 固体药物剂型的颜色和表面性质对太阳光谱反射的影响。

IF 4.3 3区医学

Pharmaceutical Research Pub Date : 2025-08-01 Epub Date: 2025-07-28 DOI: 10.1007/s11095-025-03896-2

Elżbieta Mickoś, Anna Banyś, Magdalena Hartman-Petrycka, Żaneta Gortat-Stanisławska, Sławomir Wilczyński

{"title":"Effect of Colour and Surface Properties of Solid Pharmaceutical Dosage Forms on Light Reflection in Solar Spectral Range.","authors":"Elżbieta Mickoś, Anna Banyś, Magdalena Hartman-Petrycka, Żaneta Gortat-Stanisławska, Sławomir Wilczyński","doi":"10.1007/s11095-025-03896-2","DOIUrl":"10.1007/s11095-025-03896-2","url":null,"abstract":"Objective: The objective of the present study was to undertake a comparative analysis of the effect of colour, score line, embossing or printing on the surface of selected solid oral pharmaceutical dosage forms on the reflectance properties in the range of ultraviolet A, visible and near infrared radiation from 335 to 2500 nm. This analysis was carried out using the value of directional hemispherical reflectance as a parameter indicating the resistance of the pharmaceutical dosage form to solar radiation through reflection mechanism. Reflected radiation has no physical or chemical effects.Methods: Directional hemispherical reflectance (DHR) was used in analysis. Quantitative assessment of the reflected radiation by the sample allows the determination of how much radiation is absorbed or transmitted by the tested object, thus allowing the assessment of the interaction strength of specific spectral ranges.Results: External parameters of the pharmaceutical dosage form, such as colour, score lines, embossing, or imprints, can determine interactions of medicinal product with electromagnetic radiation.Conclusions: These findings have practical implications for pharmaceutical formulation. The results suggest that colour and surface texture should be considered when developing photostable pharmaceutical products.Highlights: • Electromagnetic radiation affect on stability of medicinal product. • Reflected radiation does not cause physical and chemical effects. • Colour and structural elements of solid pharmaceutical dosage form determine reflective properties. • Directional hemispherical reflectance (reflectance) as a measurer of exposure to radiation.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1429-1441"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732748","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}

引用次数: 0

Cyclodextrin-mediated Enhancement of Haloperidol Solubility: Physicochemical Studies and In Vivo Investigation Using Planaria Worms. 环糊精介导的氟哌啶醇溶解度增强：物理化学研究和涡虫体内研究。

IF 4.3 3区医学

Pharmaceutical Research Pub Date : 2025-08-01 Epub Date: 2025-08-15 DOI: 10.1007/s11095-025-03909-0

Yuehuai Xiong, Kenneth Shankland, Vitaliy V Khutoryanskiy

{"title":"Cyclodextrin-mediated Enhancement of Haloperidol Solubility: Physicochemical Studies and In Vivo Investigation Using Planaria Worms.","authors":"Yuehuai Xiong, Kenneth Shankland, Vitaliy V Khutoryanskiy","doi":"10.1007/s11095-025-03909-0","DOIUrl":"10.1007/s11095-025-03909-0","url":null,"abstract":"Purpose: This study aims to evaluate the ability of various cyclodextrins (CDs) to enhance the aqueous solubility of haloperidol (HAL), through the formation of inclusion complexes. It also investigates the pharmacological activity of CD/HAL complexes using a planaria model.Methods: Inclusion complexes were prepared using α-CD, β-CD, methyl-β-CD, hydroxypropyl-β-CD and γ-CD. The solubility of HAL in the presence of CDs was assessed, and the stoichiometry of the complexes was determined using Job's method. Physicochemical interactions between HAL and CDs were characterized by nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). The in vivo pharmacological activity was tested in planaria worms following exposure to HAL in the presence or absence of CDs.Results: HAL's aqueous solubility was significantly enhanced in the presence of α-CD, methyl-β-CD, and hydroxypropyl-β-CD, while γ-CD showed no effect. Only modest solubility improvements were observed with increasing β-CD concentrations up to 8 mg/mL. Stoichiometric analysis confirmed a 1:1 ratio of HAL to CD in the inclusion complexes. In vivo studies demonstrated that HAL reduced planaria mobility, mimicking cataleptic effects seen in mammals, whereas the presence of CDs reduced this pharmacological effect.Conclusion: Cyclodextrins, particularly α-CD, methyl-β-CD, and hydroxypropyl-β-CD, effectively enhance the solubility of haloperidol by forming 1:1 inclusion complexes. The reduction in haloperidol-induced behavioral changes in planaria by CDs suggests a potential impact on drug bioavailability and supports the use of planaria as a simple in vivo model for screening neuroactive compounds and formulations.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1373-1383"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855971","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}

引用次数: 0

Effects of Liver Surgery on Drug Transporters in the Liver and Remote Organs. 肝脏手术对肝脏及远端器官药物转运体的影响。

IF 4.3 3区医学

Pharmaceutical Research Pub Date : 2025-08-01 Epub Date: 2025-07-30 DOI: 10.1007/s11095-025-03901-8

Reza Mehvar

{"title":"Effects of Liver Surgery on Drug Transporters in the Liver and Remote Organs.","authors":"Reza Mehvar","doi":"10.1007/s11095-025-03901-8","DOIUrl":"10.1007/s11095-025-03901-8","url":null,"abstract":"Alterations in drug transporters in acute liver failure and chronic liver diseases, such as cirrhosis, have been reviewed before. However, there is a lack of comprehensive reviews on how liver surgery, including transplantation and partial hepatectomy, affects drug transporters. Because ischemia-reperfusion (IR) injury is a hallmark of liver transplantation and most other surgical procedures of the liver, this review focuses on the effects of IR injury, in addition to liver resection, on the expression and function of transporters in the liver and remote organs. Most of the reported studies in this area are carried out in animal models of liver surgeries, with relatively limited data in humans. The results indicate that the effects of IR injury and partial hepatectomy on drug transporters are complex and depend on many variables, such as the species, length and type of ischemia, reperfusion time, and the extent of liver resection. However, for a few major transporters, clear trends have emerged based on both animal and human studies. A major trend is that warm (normothermic) hepatic IR injury or liver transplantation causes overexpression of P-glycoprotein in the liver and remote organs, affecting the pharmacokinetics of substrate drugs. Another observed trend is the relocalization of the liver MRP2/Mrp2 from the canalicular membranes to the cytoplasmic area, reducing the function of the transporter even in the absence of a change in its protein. Alterations in transporter function, such as P-glycoprotein, may significantly impact the pharmacokinetics and pharmacodynamics of drugs in patients undergoing liver surgeries.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1231-1249"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754029","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}

引用次数: 0

IVPT Data Challenges in the Real World: Outliers, Anomalous and Aberrant Data: Examples. 现实世界中的IVPT数据挑战：异常值，异常和异常数据：示例。

IF 4.3 3区医学

Pharmaceutical Research Pub Date : 2025-07-01 Epub Date: 2025-07-16 DOI: 10.1007/s11095-025-03893-5

Paul A Lehman

{"title":"IVPT Data Challenges in the Real World: Outliers, Anomalous and Aberrant Data: Examples.","authors":"Paul A Lehman","doi":"10.1007/s11095-025-03893-5","DOIUrl":"10.1007/s11095-025-03893-5","url":null,"abstract":"Background: The in vitro permeation test (IVPT) is a sensitive and robust model system that has been vital in elucidating the fundamental parameters surrounding the absorption of both therapeutic agents and industrial chemicals through skin. Unlike most clinical bioequivalence study designs, the IVPT method allows for the evaluation of multiple replicates (skin sections) from the same donor (\"subject\") at the same time. Though this should provide an advantage for a better characterization of the topical permeation kinetics within a donor, it also comes with the likelihood that any given skin replicate within the same donor, may demonstrate an unusual or anomalous absorption profile. These are often described as 'outliers', those sections demonstrating a substantial difference in percutaneous absorption kinetics to the other replicates.Methods: A retrospective analysis of data from the authors' archives has been screened with the objective of finding and addressing a number of questions regarding skin section and donor data outliers, anomalous data, missing data and the establishment of a representative Jmax.Conclusion: When the IVPT method has been properly designed and performed, outliers reflect anomalies in the donor's skin and donor population rather than as an artifact of the IVPT method. Identification and statistical confirmation approaches help to differentiate anomalous data from the core data set. In addition, missing data, and determining a representative Jmax, confound the accurate determination of BE for topical formulations.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1089-1099"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144650121","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}

引用次数: 0

First-in-Class Clinically Investigated Oral Factor D Inhibitors for the Treatment of Complement-Mediated Diseases. 口服因子D抑制剂治疗补体介导性疾病的临床研究

IF 4.3 3区医学

Pharmaceutical Research Pub Date : 2025-07-01 Epub Date: 2025-06-25 DOI: 10.1007/s11095-025-03882-8

Venkat R Gadhachanda, Jason A Wiles, Steven D Podos, David Boyer, Jane Thanassi, Dhara Patel, Yongsen Zhao, Lijuan Wang, Mingjun Huang

{"title":"First-in-Class Clinically Investigated Oral Factor D Inhibitors for the Treatment of Complement-Mediated Diseases.","authors":"Venkat R Gadhachanda, Jason A Wiles, Steven D Podos, David Boyer, Jane Thanassi, Dhara Patel, Yongsen Zhao, Lijuan Wang, Mingjun Huang","doi":"10.1007/s11095-025-03882-8","DOIUrl":"10.1007/s11095-025-03882-8","url":null,"abstract":"Objective: The goal of the study was to discover small molecular inhibitors of complement factor D (FD), an essential protease for activation of the alternative pathway (AP) of complement, that possess the characteristics for clinical investigation in complement-mediated diseases such as paroxysmal nocturnal hemoglobinuria (PNH).Methods: Compounds were synthesized and tested in vitro for potency, selectivity, and metabolic stability. The optimized compounds were subjected further to a panel of in vitro tests for primary and secondary pharmacology including inhibitory effects on FD, different complement pathways and disease models, as well as to pharmacokinetic and pharmacodynamic evaluations in animals.Results: Following multiple rounds of optimization, danicopan and later vermicopan were chosen as candidates for clinical investigation. Both compounds demonstrated potent and selective inhibitory effects on FD and AP, suitable pharmacokinetic characteristics for oral dosing, and efficacy in PNH in vitro disease models. In addition to enhanced in vitro potency, vemircopan exhibited lower clearance and higher bioavailability in animal studies compared with danicopan.Conclusion: Preclinical evaluations of danicopan and vermicopan provided rationales to conduct clinical studies in complement-mediated diseases. Recently, danicopan was approved as an add-on therapy to the C5 inhibitors ravulizumab or eculizumab for the treatment of extravascular hemolysis in patients with PNH.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"1119-1131"},"PeriodicalIF":4.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497664","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}

引用次数: 0