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Publisher: Springer-Verlag (Total: 2355 journals)

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Showing 1 - 200 of 2355 Journals sorted alphabetically
3D Research     Hybrid Journal   (Followers: 19, SJR: 0.214, h-index: 10)
4OR: A Quarterly J. of Operations Research     Hybrid Journal   (Followers: 10, SJR: 1.073, h-index: 25)
AAPS J.     Hybrid Journal   (Followers: 21, SJR: 1.192, h-index: 74)
AAPS PharmSciTech     Hybrid Journal   (Followers: 6, SJR: 0.718, h-index: 54)
Abdominal Imaging     Hybrid Journal   (Followers: 14, SJR: 0.723, h-index: 60)
Abhandlungen aus dem Mathematischen Seminar der Universitat Hamburg     Hybrid Journal   (Followers: 3, SJR: 0.447, h-index: 12)
Academic Psychiatry     Full-text available via subscription   (Followers: 23, SJR: 0.492, h-index: 32)
Academic Questions     Hybrid Journal   (Followers: 8, SJR: 0.135, h-index: 6)
Accreditation and Quality Assurance: J. for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26, SJR: 0.378, h-index: 30)
Acoustical Physics     Hybrid Journal   (Followers: 11, SJR: 0.355, h-index: 20)
Acoustics Australia     Hybrid Journal  
Acta Analytica     Hybrid Journal   (Followers: 7, SJR: 0.387, h-index: 6)
Acta Applicandae Mathematicae     Hybrid Journal   (Followers: 1, SJR: 0.624, h-index: 34)
Acta Biotheoretica     Hybrid Journal   (Followers: 5, SJR: 0.419, h-index: 25)
Acta Diabetologica     Hybrid Journal   (Followers: 13, SJR: 1.318, h-index: 46)
Acta Endoscopica     Hybrid Journal   (Followers: 1, SJR: 0.113, h-index: 8)
acta ethologica     Hybrid Journal   (Followers: 4, SJR: 0.465, h-index: 23)
Acta Geochimica     Hybrid Journal   (Followers: 6)
Acta Geodaetica et Geophysica     Hybrid Journal   (Followers: 2, SJR: 0.294, h-index: 13)
Acta Geotechnica     Hybrid Journal   (Followers: 7, SJR: 1.818, h-index: 22)
Acta Informatica     Hybrid Journal   (Followers: 5, SJR: 0.524, h-index: 32)
Acta Mathematica     Hybrid Journal   (Followers: 11, SJR: 8.021, h-index: 47)
Acta Mathematica Hungarica     Hybrid Journal   (Followers: 2, SJR: 0.53, h-index: 29)
Acta Mathematica Sinica, English Series     Hybrid Journal   (Followers: 6, SJR: 0.406, h-index: 30)
Acta Mathematica Vietnamica     Hybrid Journal   (SJR: 0.451, h-index: 5)
Acta Mathematicae Applicatae Sinica, English Series     Hybrid Journal   (SJR: 0.22, h-index: 20)
Acta Mechanica     Hybrid Journal   (Followers: 20, SJR: 0.898, h-index: 52)
Acta Mechanica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.426, h-index: 29)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5, SJR: 0.525, h-index: 18)
Acta Meteorologica Sinica     Hybrid Journal   (Followers: 3, SJR: 0.524, h-index: 14)
Acta Neurochirurgica     Hybrid Journal   (Followers: 6, SJR: 0.833, h-index: 73)
Acta Neurologica Belgica     Hybrid Journal   (Followers: 1, SJR: 0.348, h-index: 27)
Acta Neuropathologica     Hybrid Journal   (Followers: 5, SJR: 6.61, h-index: 117)
Acta Oceanologica Sinica     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 17)
Acta Parasitologica     Hybrid Journal   (Followers: 9, SJR: 0.581, h-index: 28)
Acta Physiologiae Plantarum     Hybrid Journal   (Followers: 2, SJR: 0.551, h-index: 39)
Acta Politica     Hybrid Journal   (Followers: 13, SJR: 0.658, h-index: 20)
Activitas Nervosa Superior     Hybrid Journal  
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5, SJR: 0.103, h-index: 4)
ADHD Attention Deficit and Hyperactivity Disorders     Hybrid Journal   (Followers: 22, SJR: 0.871, h-index: 15)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 8)
Administration and Policy in Mental Health and Mental Health Services Research     Partially Free   (Followers: 15, SJR: 0.795, h-index: 40)
Adsorption     Hybrid Journal   (Followers: 4, SJR: 0.774, h-index: 52)
Advances in Applied Clifford Algebras     Hybrid Journal   (Followers: 3, SJR: 0.319, h-index: 15)
Advances in Atmospheric Sciences     Hybrid Journal   (Followers: 34, SJR: 0.959, h-index: 44)
Advances in Computational Mathematics     Hybrid Journal   (Followers: 15, SJR: 1.255, h-index: 44)
Advances in Contraception     Hybrid Journal   (Followers: 3)
Advances in Data Analysis and Classification     Hybrid Journal   (Followers: 52, SJR: 1.113, h-index: 14)
Advances in Gerontology     Partially Free   (Followers: 8, SJR: 0.141, h-index: 3)
Advances in Health Sciences Education     Hybrid Journal   (Followers: 25, SJR: 1.397, h-index: 42)
Advances in Manufacturing     Hybrid Journal   (Followers: 3, SJR: 0.2, h-index: 4)
Advances in Polymer Science     Hybrid Journal   (Followers: 41, SJR: 0.637, h-index: 89)
Advances in Therapy     Hybrid Journal   (Followers: 5, SJR: 0.79, h-index: 44)
Aegean Review of the Law of the Sea and Maritime Law     Hybrid Journal   (Followers: 7)
Aequationes Mathematicae     Hybrid Journal   (Followers: 2, SJR: 0.882, h-index: 23)
Aerobiologia     Hybrid Journal   (Followers: 2, SJR: 0.511, h-index: 36)
Aesthetic Plastic Surgery     Hybrid Journal   (Followers: 9, SJR: 0.821, h-index: 49)
African Archaeological Review     Hybrid Journal   (Followers: 16, SJR: 0.612, h-index: 24)
Afrika Matematika     Hybrid Journal   (Followers: 1, SJR: 0.248, h-index: 6)
AGE     Hybrid Journal   (Followers: 7, SJR: 1.358, h-index: 33)
Ageing Intl.     Hybrid Journal   (Followers: 7, SJR: 0.337, h-index: 10)
Aggiornamenti CIO     Hybrid Journal   (Followers: 1)
Aging Clinical and Experimental Research     Hybrid Journal   (Followers: 3, SJR: 0.529, h-index: 55)
Agricultural Research     Hybrid Journal   (Followers: 3)
Agriculture and Human Values     Hybrid Journal   (Followers: 13, SJR: 1.197, h-index: 49)
Agroforestry Systems     Hybrid Journal   (Followers: 19, SJR: 0.64, h-index: 56)
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 10, SJR: 1.732, h-index: 59)
AI & Society     Hybrid Journal   (Followers: 6, SJR: 0.171, h-index: 19)
AIDS and Behavior     Hybrid Journal   (Followers: 13, SJR: 2.006, h-index: 71)
Air Quality, Atmosphere & Health     Hybrid Journal   (Followers: 4, SJR: 0.706, h-index: 19)
Akupunktur & Aurikulomedizin     Full-text available via subscription   (Followers: 1)
Algebra and Logic     Hybrid Journal   (Followers: 4, SJR: 0.566, h-index: 18)
Algebra Universalis     Hybrid Journal   (Followers: 2, SJR: 0.388, h-index: 22)
Algebras and Representation Theory     Hybrid Journal   (Followers: 1, SJR: 0.868, h-index: 20)
Algorithmica     Hybrid Journal   (Followers: 8, SJR: 0.898, h-index: 56)
Allergo J.     Full-text available via subscription   (Followers: 1, SJR: 0.183, h-index: 20)
Allergo J. Intl.     Hybrid Journal   (Followers: 2)
Alpine Botany     Hybrid Journal   (Followers: 5, SJR: 0.729, h-index: 20)
ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3, SJR: 1.392, h-index: 32)
AMBIO     Hybrid Journal   (Followers: 15, SJR: 1.094, h-index: 87)
American J. of Cardiovascular Drugs     Hybrid Journal   (Followers: 15, SJR: 0.864, h-index: 39)
American J. of Community Psychology     Hybrid Journal   (Followers: 25, SJR: 1.237, h-index: 83)
American J. of Criminal Justice     Hybrid Journal   (Followers: 8, SJR: 0.634, h-index: 13)
American J. of Cultural Sociology     Hybrid Journal   (Followers: 14, SJR: 0.283, h-index: 3)
American J. of Dance Therapy     Hybrid Journal   (Followers: 4, SJR: 0.175, h-index: 13)
American J. of Potato Research     Hybrid Journal   (Followers: 2, SJR: 0.558, h-index: 35)
American J. of Psychoanalysis     Hybrid Journal   (Followers: 22, SJR: 0.293, h-index: 13)
American Sociologist     Hybrid Journal   (Followers: 14, SJR: 0.18, h-index: 13)
Amino Acids     Hybrid Journal   (Followers: 8, SJR: 1.362, h-index: 83)
AMS Review     Partially Free   (Followers: 4)
Analog Integrated Circuits and Signal Processing     Hybrid Journal   (Followers: 7, SJR: 0.21, h-index: 37)
Analysis and Mathematical Physics     Hybrid Journal   (Followers: 3, SJR: 0.665, h-index: 7)
Analysis in Theory and Applications     Hybrid Journal   (Followers: 1)
Analysis of Verbal Behavior     Hybrid Journal   (Followers: 5)
Analytical and Bioanalytical Chemistry     Hybrid Journal   (Followers: 30, SJR: 1.096, h-index: 123)
Anatomical Science Intl.     Hybrid Journal   (Followers: 2, SJR: 0.301, h-index: 26)
Angewandte Schmerztherapie und Palliativmedizin     Hybrid Journal  
Angiogenesis     Hybrid Journal   (Followers: 3, SJR: 2.212, h-index: 69)
Animal Cognition     Hybrid Journal   (Followers: 16, SJR: 1.122, h-index: 55)
Annales françaises de médecine d'urgence     Hybrid Journal   (Followers: 1, SJR: 0.156, h-index: 4)
Annales Henri Poincaré     Hybrid Journal   (Followers: 3, SJR: 1.377, h-index: 32)
Annales mathématiques du Québec     Hybrid Journal   (Followers: 4)
Annali dell'Universita di Ferrara     Hybrid Journal   (SJR: 0.504, h-index: 14)
Annali di Matematica Pura ed Applicata     Hybrid Journal   (Followers: 1, SJR: 1.167, h-index: 26)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 12, SJR: 2.112, h-index: 98)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18, SJR: 1.182, h-index: 94)
Annals of Combinatorics     Hybrid Journal   (Followers: 3, SJR: 0.849, h-index: 15)
Annals of Data Science     Hybrid Journal   (Followers: 11)
Annals of Dyslexia     Hybrid Journal   (Followers: 10, SJR: 0.857, h-index: 40)
Annals of Finance     Hybrid Journal   (Followers: 28, SJR: 0.686, h-index: 14)
Annals of Forest Science     Hybrid Journal   (Followers: 6, SJR: 0.929, h-index: 57)
Annals of Global Analysis and Geometry     Hybrid Journal   (Followers: 1, SJR: 1.136, h-index: 23)
Annals of Hematology     Hybrid Journal   (Followers: 15, SJR: 1.117, h-index: 62)
Annals of Mathematics and Artificial Intelligence     Hybrid Journal   (Followers: 8, SJR: 0.593, h-index: 42)
Annals of Microbiology     Hybrid Journal   (Followers: 10, SJR: 0.402, h-index: 26)
Annals of Nuclear Medicine     Hybrid Journal   (Followers: 5, SJR: 0.68, h-index: 45)
Annals of Operations Research     Hybrid Journal   (Followers: 10, SJR: 1.186, h-index: 78)
Annals of Ophthalmology     Hybrid Journal   (Followers: 12)
Annals of Regional Science     Hybrid Journal   (Followers: 8, SJR: 0.405, h-index: 42)
Annals of Software Engineering     Hybrid Journal   (Followers: 13)
Annals of Solid and Structural Mechanics     Hybrid Journal   (Followers: 10, SJR: 0.553, h-index: 8)
Annals of Surgical Oncology     Hybrid Journal   (Followers: 14, SJR: 1.902, h-index: 127)
Annals of Telecommunications     Hybrid Journal   (Followers: 7, SJR: 0.315, h-index: 25)
Annals of the Institute of Statistical Mathematics     Hybrid Journal   (Followers: 1, SJR: 0.931, h-index: 31)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5, SJR: 0.992, h-index: 87)
Apidologie     Hybrid Journal   (Followers: 4, SJR: 1.14, h-index: 57)
APOPTOSIS     Hybrid Journal   (Followers: 8, SJR: 1.554, h-index: 87)
Applicable Algebra in Engineering, Communication and Computing     Hybrid Journal   (Followers: 2, SJR: 0.354, h-index: 27)
Applications of Mathematics     Hybrid Journal   (Followers: 1, SJR: 0.274, h-index: 20)
Applied Biochemistry and Biotechnology     Hybrid Journal   (Followers: 42, SJR: 0.575, h-index: 80)
Applied Biochemistry and Microbiology     Hybrid Journal   (Followers: 16, SJR: 0.267, h-index: 26)
Applied Cancer Research     Open Access  
Applied Categorical Structures     Hybrid Journal   (Followers: 2, SJR: 0.361, h-index: 21)
Applied Composite Materials     Hybrid Journal   (Followers: 48, SJR: 0.705, h-index: 35)
Applied Entomology and Zoology     Partially Free   (Followers: 3, SJR: 0.554, h-index: 34)
Applied Geomatics     Hybrid Journal   (Followers: 4, SJR: 0.323, h-index: 9)
Applied Geophysics     Hybrid Journal   (Followers: 8, SJR: 0.541, h-index: 13)
Applied Intelligence     Hybrid Journal   (Followers: 11, SJR: 0.777, h-index: 43)
Applied Magnetic Resonance     Hybrid Journal   (Followers: 4, SJR: 0.358, h-index: 34)
Applied Mathematics & Optimization     Hybrid Journal   (Followers: 4, SJR: 0.955, h-index: 33)
Applied Mathematics - A J. of Chinese Universities     Hybrid Journal   (SJR: 0.275, h-index: 8)
Applied Mathematics and Mechanics     Hybrid Journal   (Followers: 5, SJR: 0.37, h-index: 26)
Applied Microbiology and Biotechnology     Hybrid Journal   (Followers: 61, SJR: 1.262, h-index: 161)
Applied Physics A     Hybrid Journal   (Followers: 7, SJR: 0.535, h-index: 121)
Applied Physics B: Lasers and Optics     Hybrid Journal   (Followers: 23, SJR: 0.983, h-index: 104)
Applied Psychophysiology and Biofeedback     Hybrid Journal   (Followers: 8, SJR: 0.677, h-index: 47)
Applied Research in Quality of Life     Hybrid Journal   (Followers: 11, SJR: 0.288, h-index: 15)
Applied Solar Energy     Hybrid Journal   (Followers: 17, SJR: 0.251, h-index: 6)
Applied Spatial Analysis and Policy     Hybrid Journal   (Followers: 5, SJR: 0.351, h-index: 9)
Aquaculture Intl.     Hybrid Journal   (Followers: 22, SJR: 0.613, h-index: 40)
Aquarium Sciences and Conservation     Hybrid Journal   (Followers: 1)
Aquatic Ecology     Hybrid Journal   (Followers: 32, SJR: 0.646, h-index: 44)
Aquatic Geochemistry     Hybrid Journal   (Followers: 4, SJR: 0.764, h-index: 39)
Aquatic Sciences     Hybrid Journal   (Followers: 13, SJR: 1.172, h-index: 53)
Arabian J. for Science and Engineering     Hybrid Journal   (Followers: 5, SJR: 0.345, h-index: 20)
Arabian J. of Geosciences     Hybrid Journal   (Followers: 1, SJR: 0.417, h-index: 16)
Archaeological and Anthropological Sciences     Hybrid Journal   (Followers: 23, SJR: 1.056, h-index: 15)
Archaeologies     Hybrid Journal   (Followers: 12, SJR: 0.397, h-index: 13)
Archiv der Mathematik     Hybrid Journal   (Followers: 1, SJR: 0.597, h-index: 29)
Archival Science     Hybrid Journal   (Followers: 56, SJR: 0.804, h-index: 22)
Archive for History of Exact Sciences     Hybrid Journal   (Followers: 8, SJR: 0.28, h-index: 15)
Archive for Mathematical Logic     Hybrid Journal   (Followers: 1, SJR: 0.946, h-index: 23)
Archive for Rational Mechanics and Analysis     Hybrid Journal   (SJR: 4.091, h-index: 66)
Archive of Applied Mechanics     Hybrid Journal   (Followers: 5, SJR: 0.865, h-index: 40)
Archives and Museum Informatics     Hybrid Journal   (Followers: 131)
Archives of Computational Methods in Engineering     Hybrid Journal   (Followers: 4, SJR: 2.841, h-index: 40)
Archives of Dermatological Research     Hybrid Journal   (Followers: 7, SJR: 0.9, h-index: 65)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 12, SJR: 0.846, h-index: 84)
Archives of Gynecology and Obstetrics     Hybrid Journal   (Followers: 17, SJR: 0.695, h-index: 47)
Archives of Microbiology     Hybrid Journal   (Followers: 8, SJR: 0.702, h-index: 85)
Archives of Orthopaedic and Trauma Surgery     Hybrid Journal   (Followers: 8, SJR: 1.039, h-index: 56)
Archives of Osteoporosis     Hybrid Journal   (Followers: 2, SJR: 1.092, h-index: 13)
Archives of Sexual Behavior     Hybrid Journal   (Followers: 10, SJR: 1.198, h-index: 74)
Archives of Toxicology     Hybrid Journal   (Followers: 17, SJR: 1.595, h-index: 76)
Archives of Virology     Hybrid Journal   (Followers: 5, SJR: 1.086, h-index: 90)
Archives of Women's Mental Health     Hybrid Journal   (Followers: 14, SJR: 1.264, h-index: 50)
Archivio di Ortopedia e Reumatologia     Hybrid Journal  
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2, SJR: 1.2, h-index: 42)
ArgoSpine News & J.     Hybrid Journal   (SJR: 0.102, h-index: 3)
Argumentation     Hybrid Journal   (Followers: 5, SJR: 0.295, h-index: 18)
Arid Ecosystems     Hybrid Journal   (Followers: 3)
Arkiv för Matematik     Hybrid Journal   (Followers: 1, SJR: 0.948, h-index: 22)
Arnold Mathematical J.     Hybrid Journal   (Followers: 1)
Arthropod-Plant Interactions     Hybrid Journal   (Followers: 2, SJR: 0.797, h-index: 17)
Arthroskopie     Hybrid Journal   (Followers: 1, SJR: 0.145, h-index: 8)
Artificial Intelligence and Law     Hybrid Journal   (Followers: 11, SJR: 0.288, h-index: 25)
Artificial Intelligence Review     Hybrid Journal   (Followers: 14, SJR: 0.948, h-index: 48)
Artificial Life and Robotics     Hybrid Journal   (Followers: 8, SJR: 0.231, h-index: 14)
Asia Europe J.     Hybrid Journal   (Followers: 5, SJR: 0.247, h-index: 9)
Asia Pacific Education Review     Hybrid Journal   (Followers: 12, SJR: 0.371, h-index: 17)
Asia Pacific J. of Management     Hybrid Journal   (Followers: 16, SJR: 1.676, h-index: 50)
Asia-Pacific Education Researcher     Hybrid Journal   (Followers: 12, SJR: 0.353, h-index: 13)
Asia-Pacific Financial Markets     Hybrid Journal   (Followers: 2, SJR: 0.19, h-index: 15)
Asia-Pacific J. of Atmospheric Sciences     Hybrid Journal   (Followers: 20, SJR: 1.006, h-index: 14)
Asian Business & Management     Hybrid Journal   (Followers: 8, SJR: 0.41, h-index: 10)
Asian J. of Business Ethics     Hybrid Journal   (Followers: 7)
Asian J. of Criminology     Hybrid Journal   (Followers: 5, SJR: 0.263, h-index: 8)
AStA Advances in Statistical Analysis     Hybrid Journal   (Followers: 2, SJR: 0.681, h-index: 15)
AStA Wirtschafts- und Sozialstatistisches Archiv     Hybrid Journal   (Followers: 5, SJR: 0.195, h-index: 5)
ästhetische dermatologie & kosmetologie     Full-text available via subscription  

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Journal Cover AAPS Journal
  [SJR: 1.192]   [H-I: 74]   [21 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Online) 1550-7416
   Published by Springer-Verlag Homepage  [2355 journals]
  • Common Deficiencies of in vitro Binding Bioequivalence (BE) Studies
           Submitted in Abbreviated New Drug Applications (ANDAs)
    • Authors: Dongmei Lu; Diana Vivian; Ping Ren; Yongsheng Yang; Hongling Zhang; Xiaojian Jiang; Ethan Stier
      Abstract: Abstract There are several drug products that bind phosphate or bile acid in the gastrointestinal (GI) tract to exert their therapeutic efficacy. In vitro binding studies are used to assess bioequivalence (BE) of these products. The objective of this study is to identify the common deficiencies in Abbreviated New Drug Applications (ANDAs) for these products. Deficiencies were compiled from ANDAs containing in vitro binding BE studies. The deficiencies were classified into eight categories: Pre-Study Method Validation, During-Study Sample Analysis, Study Design, Study Procedure, Dissolution/Disintegration, Analytical Site Inspection, Data Submission, and Formulations. Within each category, additional subcategories were defined to characterize the deficiencies. A total of 712 deficiencies from 95 ANDAs for 11 drug products were identified and included in the analysis. The four categories with the most deficiencies were During-Study Sample Analysis (27.8%), Pre-Study Method Validation (17.3%), Data Submission (16.7%), and Study Design (15.7%). For the During-Study Sample Analysis category, failure to submit complete raw data or analytical runs ranked as the top deficiency (32.8%). For the Study Design category, using an unacceptable alternate study design (26.8%) was the most common deficiency. Within this category, other commonly occurring deficiencies included incorrect/insufficient number of absorbent concentrations, failure to pre-treat drug product with acid, insufficient number of replicates in study, incorrect calculation of k1 and k2 values, incorrect dosage form or pooled samples used in the study, and incorrect pH of study medium. The review and approval of these products may be accelerated if these common deficiencies are addressed in the original ANDA submissions.
      PubDate: 2018-01-11
      DOI: 10.1208/s12248-017-0182-5
      Issue No: Vol. 20, No. 2 (2018)
  • Adaptive Optimal Designs for Dose-Finding Studies with Time-to-Event
    • Authors: Yevgen Ryeznik; Oleksandr Sverdlov; Andrew C. Hooker
      Abstract: Abstract We consider optimal design problems for dose-finding studies with censored Weibull time-to-event outcomes. Locally D-optimal designs are investigated for a quadratic dose–response model for log-transformed data subject to right censoring. Two-stage adaptive D-optimal designs using maximum likelihood estimation (MLE) model updating are explored through simulation for a range of different dose–response scenarios and different amounts of censoring in the model. The adaptive optimal designs are found to be nearly as efficient as the locally D-optimal designs. A popular equal allocation design can be highly inefficient when the amount of censored data is high and when the Weibull model hazard is increasing. The issues of sample size planning/early stopping for an adaptive trial are investigated as well. The adaptive D-optimal design with early stopping can potentially reduce study size while achieving similar estimation precision as the fixed allocation design.
      PubDate: 2017-12-28
      DOI: 10.1208/s12248-017-0166-5
      Issue No: Vol. 20, No. 1 (2017)
  • Recommendations for the Development and Validation of Neutralizing
           Antibody Assays in Support of Biosimilar Assessment
    • Authors: D. Gouty; C. C. Cai; X. Y. Cai; A. Kasinath; V. Kumar; S. Alvandkouhi; J. Yang; S. Pederson; B. Babbitt; D. Peritt; A. Rudy; V. Koppenburg; A. Dasilva; M. Ullmann; S. Liu; C. Satterwhite
      Abstract: Abstract The American Association of Pharmaceutical Scientists (AAPS) biosimilar focus group on nonclinical and clinical assays has developed this manuscript to guide the industry on best practices and testing strategies when developing neutralizing antibody (NAb) assays for biosimilar programs. The immunogenicity assessment to biosimilar and originator drug products is one of the key aspects of clinical programs for biosimilars to demonstrate biosimilarity. Establishing that there are no clinically meaningful differences in immune response between a proposed product and the originator product is a key element in the demonstration of biosimilarity. It is critical to collect, evaluate, and compare the safety and immunogenicity data from the clinical pharmacology, safety, and/or efficacy studies especially when the originator drug product is known to have potential for immune-mediated toxicity. This manuscript aims to provide a comprehensive review and recommendations on assay formats, critical reagents, approaches to method development, and validation of the neutralizing antibody assays in extrapolation within the scope of biosimilar drug development programs. Even if there are multiple options on the development and validation of NAb assays for biosimilar programs, the type of drug and its MoA will help determine the assay format and technical platform for NAb assessment (e.g., cell-based or non-cell-based assay). We recommend to always perform a one-assay approach as it is better to confirm the biosimilarity using one-assay for NAb. If a one-assay approach is not feasible, then a two-assay format may be used. This manuscript will provide all the details necessary to develop NAb assays for biosimilars.
      PubDate: 2017-12-28
      DOI: 10.1208/s12248-017-0181-6
      Issue No: Vol. 20, No. 1 (2017)
  • Calibration Curves in Quantitative Ligand Binding Assays: Recommendations
           and Best Practices for Preparation, Design, and Editing of Calibration
    • Authors: Mitra Azadeh; Boris Gorovits; John Kamerud; Stephen MacMannis; Afshin Safavi; Jeffrey Sailstad; Perceval Sondag
      Abstract: Abstract The accuracy of reported sample results is contingent upon the quality of the assay calibration curve, and as such, calibration curves are critical components of ligand binding and other quantitative methods. Regulatory guidance and lead publications have defined many of the requirements for calibration curves which encompass design, acceptance criteria, and selection of a regression model. However, other important aspects such as preparation and editing guidelines have not been addressed by health authorities. The goal of this publication is to answer many of the commonly asked questions and to present a consensus and the shared views of members of the ligand binding assay (LBA) community on topics related to calibration curves with focus on providing recommendations for the preparation and editing of calibration curves.
      PubDate: 2017-12-27
      DOI: 10.1208/s12248-017-0159-4
      Issue No: Vol. 20, No. 1 (2017)
  • Demonstration of Direct Nose-to-Brain Transport of Unbound HIV-1
           Replication Inhibitor DB213 Via Intranasal Administration by
           Pharmacokinetic Modeling
    • Authors: Qianwen Wang; Yufeng Zhang; Chun-Ho Wong; H.Y. Edwin Chan; Zhong Zuo
      Abstract: Abstract Intranasal administration could be an attractive alternative route of administration for the delivery of drugs to the central nervous system (CNS). However, there are always doubts about the direct transport of therapeutics from nasal cavity to the CNS since there are only limited studies on the understanding of direct nose-to-brain transport. Therefore, this study aimed to (1) investigate the existence of nose-to-brain transport of intranasally administered HIV-1 replication inhibitor DB213 and (2) assess the direct nose-to-brain transport of unbound HIV-1 replication inhibitor DB213 quantitatively by a pharmacokinetic approach. Plasma samples were collected up to 6 h post-dosing after administration via intranasal or intravenous route at three bolus doses. In the brain-uptake study, the plasma, whole brain, and cerebrospinal fluid (CSF) were sampled between 15 min and 8 h post-dosing. All samples were analyzed with LC/MS/MS. Plasma, CSF, and brain concentration versus time profiles were analyzed with nonlinear mixed-effect modeling. Structural model building was performed by NONMEM (version VII, level 2.0). Intranasal administration showed better potential to deliver HIV-1 replication inhibitor DB213 to the brain with 290-fold higher brain to plasma ratio compared with intravenous administration. Based on that, a model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) was developed and demonstrated 72.4% of total absorbed unbound HIV-1 replication inhibitor DB213 after intranasal administration was transported directly into the brain through nose-to-brain pathway.
      PubDate: 2017-12-27
      DOI: 10.1208/s12248-017-0179-0
      Issue No: Vol. 20, No. 1 (2017)
  • The Drug of Abuse Gamma-Hydroxybutyric Acid Exhibits Tissue-Specific
           Nonlinear Distribution
    • Authors: Melanie A. Felmlee; Bridget L. Morse; Kristin E. Follman; Marilyn E. Morris
      Abstract: ABSTRACT The drug of abuse γ-hydroxybutyric acid (GHB) demonstrates complex toxicokinetics with dose-dependent metabolic and renal clearance. GHB is a substrate of monocarboxylate transporters (MCTs) which are responsible for the saturable renal reabsorption of GHB. MCT expression is observed in many tissues and therefore may impact the tissue distribution of GHB. The objective of the present study was to evaluate the tissue distribution kinetics of GHB at supratherapeutic doses. GHB (400, 600, and 800 mg/kg iv) or GHB 600 mg/kg plus l-lactate (330 mg/kg iv bolus followed by 121 mg/kg/h infusion) was administered to rats and blood and tissues were collected for up to 330 min post-dose. K p values for GHB varied in both a tissue- and dose-dependent manner and were less than 0.5 (except in the kidney). Nonlinear partitioning was observed in the liver (0.06 at 400 mg/kg to 0.30 at 800 mg/kg), kidney (0.62 at 400 mg/kg to 0.98 at 800 mg/kg), and heart (0.15 at 400 mg/kg to 0.29 at 800 mg/kg), with K p values increasing with dose consistent with saturation of transporter-mediated efflux. In contrast, lung partitioning decreased in a dose-dependent manner (0.43 at 400 mg/kg to 0.25 at 800 mg/kg) suggesting saturation of active uptake. l-lactate administration decreased K p values in liver, striatum, and hippocampus and increased K p values in lung and spleen. GHB demonstrates tissue-specific nonlinear distribution consistent with the involvement of monocarboxylate transporters. These observed complexities are likely due to the involvement of MCT1 and 4 with different affinities and directionality for GHB transport.
      PubDate: 2017-12-26
      DOI: 10.1208/s12248-017-0180-7
      Issue No: Vol. 20, No. 1 (2017)
  • Pluripotent Stem Cell-Derived Human Tissue: Platforms to Evaluate Drug
           Metabolism and Safety
    • Authors: Jose Meseguer-Ripolles; Salman R. Khetani; Javier G. Blanco; Miari Iredale; David C. Hay
      Abstract: Abstract Despite the improvements in drug screening, high levels of drug attrition persist. Although high-throughput screening platforms permit the testing of compound libraries, poor compound efficacy or unexpected organ toxicity are major causes of attrition. Part of the reason for drug failure resides in the models employed, most of which are not representative of normal organ biology. This same problem affects all the major organs during drug development. Hepatotoxicity and cardiotoxicity are two interesting examples of organ disease and can present in the late stages of drug development, resulting in major cost and increased risk to the patient. Currently, cell-based systems used within industry rely on immortalized or primary cell lines from donated tissue. These models possess significant advantages and disadvantages, but in general display limited relevance to the organ of interest. Recently, stem cell technology has shown promise in drug development and has been proposed as an alternative to current industrial systems. These offerings will provide the field with exciting new models to study human organ biology at scale and in detail. We believe that the recent advances in production of stem cell-derived hepatocytes and cardiomyocytes combined with cutting-edge engineering technologies make them an attractive alternative to current screening models for drug discovery. This will lead to fast failing of poor drugs earlier in the process, delivering safer and more efficacious medicines for the patient.
      PubDate: 2017-12-21
      DOI: 10.1208/s12248-017-0171-8
      Issue No: Vol. 20, No. 1 (2017)
  • In Vitro - In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and
           Curcumin in Cancer Prevention
    • Authors: Christina N. Ramirez; Wenji Li; Chengyue Zhang; Renyi Wu; Shan Su; Chao Wang; Linbo Gao; Ran Yin; Ah-Ng Tony Kong
      Abstract: Abstract According to the National Center of Health Statistics, cancer was the culprit of nearly 600,000 deaths in 2016 in the USA. It is by far one of the most heterogeneous diseases to treat. Treatment for metastasized cancers remains a challenge despite modern diagnostics and treatment regimens. For this reason, alternative approaches are needed. Chemoprevention using dietary phytochemicals such as triterpenoids, isothiocyanates, and curcumin in the prevention of initiation and/or progression of cancer poses a promising alternative strategy. However, significant challenges exist in the extrapolation of in vitro cell culture data to in vivo efficacy in animal models and to humans. In this review, the dose at which these phytochemicals elicit a response in vitro and in vivo of a multitude of cellular signaling pathways will be reviewed highlighting Nrf2-mediated antioxidative stress, anti-inflammation, epigenetics, cytoprotection, differentiation, and growth inhibition. The in vitro-in vivo dose response of phytochemicals can vary due, in part, to the cell line/animal model used, the assay system of the biomarker used for the readout, chemical structure of the functional analog of the phytochemical, and the source of compounds used for the treatment study. While the dose response varies across different experimental designs, the chemopreventive efficacy appears to remain and demonstrate the therapeutic potential of triterpenoids, isothiocyanates, and curcumin in cancer prevention and in health in general.
      PubDate: 2017-12-20
      DOI: 10.1208/s12248-017-0177-2
      Issue No: Vol. 20, No. 1 (2017)
  • Therapeutic Delivery of Simvastatin Loaded in PLA-PEG Polymersomes
           Resulted in Amplification of Anti-inflammatory Effects in Activated
    • Authors: Dharani Manickavasagam; Kimberly Novak; Moses O. Oyewumi
      Abstract: Abstract Simvastatin (Sim), a lipid-lowering drug has been studied in chronic neuroinflammation associated with degenerative brain disorders due to its potential protective properties against inflammatory reaction, oxidative damage, neuronal dysfunction, and death. Meanwhile, potential application of Sim in neuroinflammation will require a suitable delivery system that can overcome notable challenges pertaining to poor blood–brain barrier (BBB) permeability and side/off-target effects. Herein, we engineered and characterized nano-sized polymersomes loaded with Sim (Sim-Ps) using PEG-PdLLA (methoxy polyethylene glycol-poly(d,l) lactic acid) diblock co-polymers. Studies in BV2 microglia indicated that Sim-Ps was superior to Sim alone in suppressing nitric oxide (NO) and proinflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) secretion against LPS activation. The effectiveness of Sim-Ps as compared with Sim alone, in attenuating NO and cytokine production by activated BV2 cells can be attributed to (a) colloidal stability of the delivery platform, (b) protracted release of biologically active Sim, and (c) particulate internalization coupled with enhanced Sim exposure to BV2 cells. Intranasal delivery in BALB/c mice demonstrated enhanced brain distribution with increasing time after administration. Overall data demonstrated suitability of PEG-PdLLA polymersomes in Sim delivery for potential application in treating neuroinflammation.
      PubDate: 2017-12-14
      DOI: 10.1208/s12248-017-0176-3
      Issue No: Vol. 20, No. 1 (2017)
  • Intestinal Stem Cells to Advance Drug Development, Precision, and
           Regenerative Medicine: A Paradigm Shift in Translational Research
    • Authors: Jonathan P. Mochel; Albert E. Jergens; Dawn Kingsbury; Hyun Jung Kim; Martín G. Martín; Karin Allenspach
      Abstract: Abstract Recent advances in our understanding of the intestinal stem cell niche and the role of key signaling pathways on cell growth and maintenance have allowed the development of fully differentiated epithelial cells in 3D organoids. Stem cell-derived organoids carry significant levels of proteins that are natively expressed in the gut and have important roles in drug transport and metabolism. They are, therefore, particularly relevant to study the gastrointestinal (GI) absorption of oral medications. In addition, organoids have the potential to serve as a robust preclinical model for demonstrating the effectiveness of new drugs more rapidly, with more certainty, and at lower costs compared with live animal studies. Importantly, because they are derived from individuals with different genotypes, environmental risk factors and drug sensitivity profiles, organoids are a highly relevant screening system for personalized therapy in both human and veterinary medicine. Lastly, and in the context of patient-specific congenital diseases, orthotopic transplantation of engineered organoids could repair and/or replace damaged epithelial tissues reported in various GI diseases, such as inflammatory bowel disease, cystic fibrosis, and tuft enteropathy. Ongoing translational research on organoids derived from dogs with naturally occurring digestive disorders has the potential to improve the predictability of preclinical models used for optimizing the therapeutic management of severe chronic enteropathies in human patients.
      PubDate: 2017-12-12
      DOI: 10.1208/s12248-017-0178-1
      Issue No: Vol. 20, No. 1 (2017)
  • Demonstration of Nucleoside Transporter Activity in the Nose-to-Brain
           Distribution of [ 18 F]Fluorothymidine Using PET Imaging
    • Authors: Laura L. Boles Ponto; Jiangeng Huang; Susan A. Walsh; Michael R. Acevedo; Christine Mundt; John Sunderland; Maureen Donovan
      Abstract: Abstract To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [18F]fluorothymidine (FLT), an equilibrative nucleoside transporter (ENT1,2) and concentrative nucleoside transporter (CNT1–3) substrate, using PET to measure local tissue concentrations. Anesthetized Sprague-Dawley rats were administered FLT by intranasal (IN) instillation or tail-vein injection (IV). NBMPR (nitrobenzylmercaptopurine riboside), an ENT1 inhibitor, was administered either IN or intraperitoneally (IP). Dynamic PET imaging was performed for up to 40 min. A CT was obtained for anatomical co-registration and attenuation correction. Time-activity curves (TACs) were generated for the olfactory bulb (OB) and remaining brain, and the area-under-the-curve (AUC) for each TAC was calculated to determine the total tissue exposure of FLT. FLT concentrations were higher in the OB than in the rest of the brain following IN administration. IP administration of NBMPR resulted in increased OB and brain FLT exposure following both IN and IV administration, suggesting that NBMPR decreases the clearance rate of FLT from the brain. When FLT and NBMPR were co-administered IN, there was a decrease in the OB AUC while an increase in the brain AUC was observed. The decrease in OB exposure was likely the result of inhibition of ENT1 uptake activity in the nose-to-brain transport pathway. FLT distribution patterns show that nucleoside transporters, including ENT1, play a key role in the distribution of transporter substrates between the nasal cavity and the brain via the OB.
      PubDate: 2017-12-07
      DOI: 10.1208/s12248-017-0158-5
      Issue No: Vol. 20, No. 1 (2017)
  • Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable
           (FLT) Substrates After Intranasal (IN) Administration
    • Authors: Laura L. Boles Ponto; Susan Walsh; Jiangeng Huang; Christine Mundt; Katherine Thede-Reynolds; G. Leonard Watkins; John Sunderland; Michael Acevedo; Maureen Donovan
      Abstract: Abstract To illustrate the use of imaging to quantify the transfer of materials from the nasal cavity to other anatomical compartments, specifically, transfer to the brain using the thymidine analogue, [18F]fluorothymidine (FLT), and the glucose analogue, [18F]fluorodeoxyglucose (FDG). Anesthetized rats were administered FLT or FDG by intranasal instillation (IN) or tail-vein injection (IV). PET/CT imaging was performed for up to 60 min. Volumes-of-interest (VOIs) for the olfactory bulb (OB) and the remaining brain were created on the CT and transferred to the co-registered dynamic PET. Time-activity curves (TACs) were generated and compared. The disposition patterns were successfully visualized and quantified and differences in brain distribution patterns were observed. For FDG, the concentration was substantially higher in the OB than the brain only after IN administration. For FLT, the concentration was higher in the OB than the brain after both IN and IV and higher after IN than after IV administration at all times, whereas the concentration in the brain was higher after IN than after IV administration at early times only. Approximately 50 and 9% of the IN FDG and FLT doses, respectively, remained in the nasal cavity at 20 min post-administration. The initial phase of clearance was similar for both agents (t1/2 = 2.53 and 3.36 min) but the slow clearance phase was more rapid for FLT than FDG (t1/2 = 32.1 and 85.2 min, respectively). Pharmacoimaging techniques employing PET/CT can be successfully implemented to quantitatively investigate and compare the disposition of radiolabeled agents administered by a variety of routes.
      PubDate: 2017-12-07
      DOI: 10.1208/s12248-017-0157-6
      Issue No: Vol. 20, No. 1 (2017)
  • Target and Tissue Selectivity Prediction by Integrated Mechanistic
           Pharmacokinetic-Target Binding and Quantitative Structure Activity
    • Authors: Anna H. C. Vlot; Wilhelmus E. A. de Witte; Meindert Danhof; Piet H. van der Graaf; Gerard J. P. van Westen; Elizabeth C. M. de Lange
      Abstract: Abstract Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D) and the target dissociation rate constant on target and tissue selectivity. The K D values of CB1 ligands in the ChEMBL database are predicted by QSAR random forest (RF) modeling for the CB1 receptor and known off-targets (TRPV1, mGlu5, 5-HT1a). Of these CB1 ligands, rimonabant, CP-55940, and Δ8-tetrahydrocanabinol, one of the active ingredients of cannabis, were selected for simulations of target occupancy for CB1, TRPV1, mGlu5, and 5-HT1a in three brain regions, to illustrate the principles of the combined PBPK-QSAR modeling. Our combined PBPK and target binding modeling demonstrated that the optimal values of the K D and k off for target and tissue selectivity were dependent on target concentration and tissue distribution kinetics. Interestingly, if the target concentration is high and the perfusion of the target site is low, the optimal K D value is often not the lowest K D value, suggesting that optimization towards high drug-target affinity can decrease the benefit-risk ratio. The presented integrative structure-pharmacokinetic-pharmacodynamic modeling provides an improved understanding of tissue and target selectivity.
      PubDate: 2017-12-04
      DOI: 10.1208/s12248-017-0172-7
      Issue No: Vol. 20, No. 1 (2017)
  • Roles of Organic Anion Transporting Polypeptide 2A1 (OATP2A1/ SLCO2A1 ) in
           Regulating the Pathophysiological Actions of Prostaglandins
    • Authors: Takeo Nakanishi; Ikumi Tamai
      Abstract: Abstract Solute carrier organic anion transporter family member 2A1 (OATP2A1, encoded by the SLCO2A1 gene), which was initially identified as prostaglandin transporter (PGT), is expressed ubiquitously in tissues and mediates the distribution of prostanoids, such as PGE2, PGF2α, PGD2 and TxB2. It is well known to play a key role in the metabolic clearance of prostaglandins, which are taken up into the cell by OATP2A1 and then oxidatively inactivated by 15-ketoprostaglandin dehydrogenase (encoded by HPGD); indeed, OATP2A1-mediated uptake is the rate-limiting step of PGE2 catabolism. Consequently, since OATP2A1 activity is required for termination of prostaglandin signaling via prostanoid receptors, its inhibition can enhance such signaling. On the other hand, OATP2A1 can also function as an organic anion exchanger, mediating efflux of prostaglandins in exchange for import of anions such as lactate, and in this context, it plays a role in the release of newly synthesized prostaglandins from cells. These different functions likely operate in different compartments within the cell. OATP2A1 is reported to function at cytoplasmic vesicle/organelle membranes. As a regulator of the levels of physiologically active prostaglandins, OATP2A1 is implicated in diverse physiological and pathophysiological processes in many organs. Recently, whole exome analysis has revealed that recessive mutations in SLCO2A1 cause refractory diseases in humans, including primary hypertrophic osteoarthropathy (PHO) and chronic non-specific ulcers in small intestine (CNSU). Here, we review and summarize recent information on the molecular functions of OATP2A1 and on its physiological and pathological significance.
      PubDate: 2017-12-04
      DOI: 10.1208/s12248-017-0163-8
      Issue No: Vol. 20, No. 1 (2017)
  • Balancing Antibacterial Efficacy and Reduction in Renal Function to
           Optimise Initial Gentamicin Dosing in Paediatric Oncology Patients
    • Authors: Carolina Consuelo Llanos-Paez; Christine Staatz; Stefanie Hennig
      Abstract: Abstract This study aimed to determine the optimal starting dose of gentamicin in paediatric oncology patients. A population pharmacokinetic model describing drug exposure, a semi-mechanistic model describing bacterial killing and an Emax model describing renal cortex accumulation were linked in a utility function using NONMEM®. The optimal gentamicin starting dose was estimated in patients aged from 0.1 to 18.2 years, by balancing the probability of efficacy on day 1 against relative renal function reduction on day 7 with continued dosing. Using achievement of a gentamicin area under the concentration time curve to bacterial minimum inhibitor concentration (MIC) ratio of ≥ 100 and maximum concentration to MIC ratio of ≥ 10 as the efficacy endpoints, a starting dose of 7.1, 9.5, 10.8 and 14.6 mg/kg/q24h was optimal at a MIC of 0.5, 1, 2 and 4 mg/L respectively, with ≥ 75% probability of obtainment. Using achievement of a 2-log10 bacterial count reduction at 24-h post-dose as the efficacy endpoint, a starting dose of 12.8 mg/kg/q24h was optimal, with 85.6% probability of obtainment. Under these different dosing scenarios, relative reduction in renal function ranged on average from 6.9 to 14.5% on day 7. The current recommended starting dose of gentamicin of 7.5 mg/kg/q24h may not be sufficient to achieve efficacy on day 1 if bacterial MIC is > 0.5 mg/L. A higher initial dose (up to 14.6 mg/kg/q24h), in less sensitive microorganisms, would likely cause only a relatively small reduction in renal function at day 7. Close monitoring is crucial if high doses are given, especially for longer than 7 days.
      PubDate: 2017-12-04
      DOI: 10.1208/s12248-017-0173-6
      Issue No: Vol. 20, No. 1 (2017)
  • The Na + /Cl − -Coupled, Broad-Specific, Amino Acid Transporter SLC6A14
           (ATB 0,+ ): Emerging Roles in Multiple Diseases and Therapeutic Potential
           for Treatment and Diagnosis
    • Authors: Mohd Omar F. Sikder; Shengping Yang; Vadivel Ganapathy; Yangzom D. Bhutia
      Abstract: Abstract Amino acids are essential building blocks of all mammalian cells, and amino acid transporters play a vital role in transporting them into cells and their further distribution among the various cellular compartments. There are ~ 430 known transporters in the solute-linked carrier (SLC) gene family, divided into 52 distinct families. Eleven of these gene families contain one or more amino acid transporters. These transporters differ significantly from each other in terms of substrate specificity, ion dependence, and energetics. Given the variety of roles they fulfill in human physiology, it is not surprising that a number of diseases are associated with the malfunction of these transporters. In particular, as amino acids are critical for cell growth, survival, and proliferation, the role of amino acid transporters in cancer is gaining increasing attention in recent years. The present review primarily focuses on one particular amino acid transporter, SLC6A14 (also known as ATB0,+), with regard to its relevance to specific diseases, including cancer, and the molecular mechanisms underlying the disease-related alterations in the expression of the transporter. Furthermore, the review highlights the possible utility of this transporter in drug delivery and also its therapeutic potential for the treatment and diagnosis of cancer.
      PubDate: 2017-12-04
      DOI: 10.1208/s12248-017-0164-7
      Issue No: Vol. 20, No. 1 (2017)
  • A Multi-site In-depth Evaluation of the Quanterix Simoa from a
           User’s Perspective
    • Authors: Allison Given Chunyk; Alison Joyce; Saloumeh K. Fischer; Mark Dysinger; Alvydas Mikulskis; Andreas Jeromin; Rosemary Lawrence-Henderson; Dana Baker; David Yeung
      Abstract: Abstract An in-depth evaluation of the Quanterix© Simoa™ platform was undertaken by scientists from the AAPS Emerging Technologies Focus Group to determine the overall performance of the technology as well as provide guidance to future users. In order to test the platform in a non-GLP bioanalytical setting, a cross-site evaluation of the Quanterix IL-6 biomarker kit was performed. Parameters tested during this evaluation included sensitivity, accuracy and precision, and parallelism in human serum from normal individuals. The results demonstrated improved sensitivity compared to the claimed sensitivity of other commercially available IL-6 kits and showed excellent site-to-site reproducibility. Observed issues included difficulties with system reliability and a lack of parallelism and specificity in a subset of samples. Overall, these results demonstrate that while there are challenges to the Simoa platform this technology offers automation capabilities and excellent sensitivity that enhance bioanalysis especially of low-abundance analytes.
      PubDate: 2017-12-01
      DOI: 10.1208/s12248-017-0156-7
      Issue No: Vol. 20, No. 1 (2017)
  • ABCB6, an ABC Transporter Impacting Drug Response and Disease
    • Authors: Rebba C. Boswell-Casteel; Yu Fukuda; John D. Schuetz
      Abstract: Abstract Recent findings have discovered how insufficiency of ATP-binding cassette (ABC) transporter, ABCB6, can negatively impact human health. These advances were made possible by, first, finding that ABCB6 deficiency was the genetic basis for some severe transfusion reactions and by, second, determining that functionally impaired ABCB6 variants enhanced the severity of porphyria, i.e., diseases associated with defects in heme synthesis. ABCB6 is a broad-spectrum porphyrin transporter that is capable of both exporting and importing heme and its precursors across the plasma membrane and outer mitochondrial membrane, respectively. Biochemical studies have demonstrated that while ABCB6 influences the antioxidant system by reducing the levels of reactive oxygen species, the exact mechanism is currently unknown, though effects on heme synthesis are likely. Furthermore, it is unknown what biochemical or cellular signals determine where ABCB6 localizes in the cell. This review highlights the major recent findings on ABCB6 and focuses on details of its structure, mechanism, transport, contributions to cellular stress, and current clinical implications.
      PubDate: 2017-11-30
      DOI: 10.1208/s12248-017-0165-6
      Issue No: Vol. 20, No. 1 (2017)
  • A View on the Importance of “Multi-Attribute Method” for Measuring
           Purity of Biopharmaceuticals and Improving Overall Control Strategy
    • Authors: Richard S. Rogers; Michael Abernathy; Douglas D. Richardson; Jason C. Rouse; Justin B. Sperry; Patrick Swann; Jette Wypych; Christopher Yu; Li Zang; Rohini Deshpande
      Abstract: Abstract Today, we are experiencing unprecedented growth and innovation within the pharmaceutical industry. Established protein therapeutic modalities, such as recombinant human proteins, monoclonal antibodies (mAbs), and fusion proteins, are being used to treat previously unmet medical needs. Novel therapies such as bispecific T cell engagers (BiTEs), chimeric antigen T cell receptors (CARTs), siRNA, and gene therapies are paving the path towards increasingly personalized medicine. This advancement of new indications and therapeutic modalities is paralleled by development of new analytical technologies and methods that provide enhanced information content in a more efficient manner. Recently, a liquid chromatography-mass spectrometry (LC-MS) multi-attribute method (MAM) has been developed and designed for improved simultaneous detection, identification, quantitation, and quality control (monitoring) of molecular attributes (Rogers et al. MAbs 7(5):881–90, 2015). Based on peptide mapping principles, this powerful tool represents a true advancement in testing methodology that can be utilized not only during product characterization, formulation development, stability testing, and development of the manufacturing process, but also as a platform quality control method in dispositioning clinical materials for both innovative biotherapeutics and biosimilars.
      PubDate: 2017-11-30
      DOI: 10.1208/s12248-017-0168-3
      Issue No: Vol. 20, No. 1 (2017)
  • Transporter-Mediated Interaction Between Platinum Drugs and Sorafenib at
           the Cellular Level
    • Authors: Verena Schneider; Selim Chaib; Claudia Spanier; Mandy Knapp; Violeta Moscvin; Laura Scordovillo; Alessandra Ewertz; Ulrich Jaehde; Ganna V. Kalayda
      Abstract: Abstract Combining the multikinase inhibitor sorafenib with the platinum-based chemotherapy of solid tumors was expected to improve treatment outcome. However, in many clinical trials, no benefit from sorafenib addition to the platinum-containing regimen could be demonstrated. Moreover, in some studies, decreased survival of ovarian cancer patients as well as non-small cell lung cancer patients with squamous cell histology was observed. The aim of this study was to investigate the cellular mechanisms of the pharmacological interaction between platinum drugs and sorafenib in different cancer cell lines. The interaction was characterized by combination index analysis, platinum accumulation and DNA platination were determined using flameless atomic absorption spectrometry, and protein expression was assessed with Western blot. In the sensitive A2780 ovarian carcinoma and H520 squamous cell lung carcinoma cell lines, sorafenib induced downregulation of Na+,K+-ATPase. In A2780 cells, the kinase inhibitor also decreased the expression of copper transporter 1 (CTR1). As a result, sorafenib treatment led to a diminished cellular accumulation of cisplatin and carboplatin and to a decrease in DNA platination in these cell lines. This was not the case in the cisplatin-resistant A2780cis ovarian carcinoma and H522 lung adenocarcinoma cell lines featuring lower basal expression of the above-mentioned transporters. In all cell lines studied, an antagonistic interaction between platinum drugs and sorafenib was found. Our results suggest that sorafenib impairs cisplatin and carboplatin uptake through downregulation of CTR1 and/or Na+,K+-ATPase resulting in reduction of DNA platination. This effect is not observed in cancer cells with defects in platinum accumulation.
      PubDate: 2017-11-30
      DOI: 10.1208/s12248-017-0169-2
      Issue No: Vol. 20, No. 1 (2017)
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