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Publisher: Springer-Verlag (Total: 2351 journals)

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Showing 1 - 200 of 2351 Journals sorted alphabetically
3D Printing in Medicine     Open Access   (Followers: 1)
3D Research     Hybrid Journal   (Followers: 21, SJR: 0.222, CiteScore: 1)
4OR: A Quarterly J. of Operations Research     Hybrid Journal   (Followers: 10, SJR: 0.825, CiteScore: 1)
AAPS J.     Hybrid Journal   (Followers: 22, SJR: 1.118, CiteScore: 4)
AAPS PharmSciTech     Hybrid Journal   (Followers: 7, SJR: 0.752, CiteScore: 3)
Abdominal Imaging     Hybrid Journal   (Followers: 15, SJR: 0.866, CiteScore: 2)
Abhandlungen aus dem Mathematischen Seminar der Universitat Hamburg     Hybrid Journal   (Followers: 4, SJR: 0.439, CiteScore: 0)
Academic Psychiatry     Full-text available via subscription   (Followers: 26, SJR: 0.53, CiteScore: 1)
Academic Questions     Hybrid Journal   (Followers: 8, SJR: 0.106, CiteScore: 0)
Accreditation and Quality Assurance: J. for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 27, SJR: 0.316, CiteScore: 1)
Acoustical Physics     Hybrid Journal   (Followers: 11, SJR: 0.359, CiteScore: 1)
Acoustics Australia     Hybrid Journal   (SJR: 0.232, CiteScore: 1)
Acta Analytica     Hybrid Journal   (Followers: 7, SJR: 0.367, CiteScore: 0)
Acta Applicandae Mathematicae     Hybrid Journal   (Followers: 1, SJR: 0.675, CiteScore: 1)
Acta Biotheoretica     Hybrid Journal   (Followers: 4, SJR: 0.284, CiteScore: 1)
Acta Diabetologica     Hybrid Journal   (Followers: 18, SJR: 1.587, CiteScore: 3)
Acta Endoscopica     Hybrid Journal   (Followers: 1)
acta ethologica     Hybrid Journal   (Followers: 4, SJR: 0.769, CiteScore: 1)
Acta Geochimica     Hybrid Journal   (Followers: 7, SJR: 0.24, CiteScore: 1)
Acta Geodaetica et Geophysica     Hybrid Journal   (Followers: 2, SJR: 0.305, CiteScore: 1)
Acta Geophysica     Hybrid Journal   (Followers: 10, SJR: 0.312, CiteScore: 1)
Acta Geotechnica     Hybrid Journal   (Followers: 7, SJR: 1.588, CiteScore: 3)
Acta Informatica     Hybrid Journal   (Followers: 5, SJR: 0.517, CiteScore: 1)
Acta Mathematica     Hybrid Journal   (Followers: 12, SJR: 7.066, CiteScore: 3)
Acta Mathematica Hungarica     Hybrid Journal   (Followers: 2, SJR: 0.452, CiteScore: 1)
Acta Mathematica Sinica, English Series     Hybrid Journal   (Followers: 6, SJR: 0.379, CiteScore: 1)
Acta Mathematica Vietnamica     Hybrid Journal   (SJR: 0.27, CiteScore: 0)
Acta Mathematicae Applicatae Sinica, English Series     Hybrid Journal   (SJR: 0.208, CiteScore: 0)
Acta Mechanica     Hybrid Journal   (Followers: 21, SJR: 1.04, CiteScore: 2)
Acta Mechanica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.607, CiteScore: 2)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 7, SJR: 0.576, CiteScore: 2)
Acta Meteorologica Sinica     Hybrid Journal   (Followers: 3, SJR: 0.638, CiteScore: 1)
Acta Neurochirurgica     Hybrid Journal   (Followers: 6, SJR: 0.822, CiteScore: 2)
Acta Neurologica Belgica     Hybrid Journal   (Followers: 1, SJR: 0.376, CiteScore: 1)
Acta Neuropathologica     Hybrid Journal   (Followers: 4, SJR: 7.589, CiteScore: 12)
Acta Oceanologica Sinica     Hybrid Journal   (Followers: 3, SJR: 0.334, CiteScore: 1)
Acta Physiologiae Plantarum     Hybrid Journal   (Followers: 2, SJR: 0.574, CiteScore: 2)
Acta Politica     Hybrid Journal   (Followers: 15, SJR: 0.605, CiteScore: 1)
Activitas Nervosa Superior     Hybrid Journal   (SJR: 0.147, CiteScore: 0)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 8, SJR: 0.103, CiteScore: 0)
ADHD Attention Deficit and Hyperactivity Disorders     Hybrid Journal   (Followers: 23, SJR: 0.72, CiteScore: 2)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Administration and Policy in Mental Health and Mental Health Services Research     Partially Free   (Followers: 16, SJR: 1.005, CiteScore: 2)
Adsorption     Hybrid Journal   (Followers: 4, SJR: 0.703, CiteScore: 2)
Advances in Applied Clifford Algebras     Hybrid Journal   (Followers: 4, SJR: 0.698, CiteScore: 1)
Advances in Atmospheric Sciences     Hybrid Journal   (Followers: 37, SJR: 0.956, CiteScore: 2)
Advances in Computational Mathematics     Hybrid Journal   (Followers: 19, SJR: 0.812, CiteScore: 1)
Advances in Contraception     Hybrid Journal   (Followers: 3)
Advances in Data Analysis and Classification     Hybrid Journal   (Followers: 56, SJR: 1.09, CiteScore: 1)
Advances in Gerontology     Partially Free   (Followers: 8, SJR: 0.144, CiteScore: 0)
Advances in Health Sciences Education     Hybrid Journal   (Followers: 28, SJR: 1.64, CiteScore: 2)
Advances in Manufacturing     Hybrid Journal   (Followers: 4, SJR: 0.475, CiteScore: 2)
Advances in Polymer Science     Hybrid Journal   (Followers: 45, SJR: 1.04, CiteScore: 3)
Advances in Therapy     Hybrid Journal   (Followers: 5, SJR: 1.075, CiteScore: 3)
Aegean Review of the Law of the Sea and Maritime Law     Hybrid Journal   (Followers: 6)
Aequationes Mathematicae     Hybrid Journal   (Followers: 2, SJR: 0.517, CiteScore: 1)
Aerobiologia     Hybrid Journal   (Followers: 3, SJR: 0.673, CiteScore: 2)
Aesthetic Plastic Surgery     Hybrid Journal   (Followers: 9, SJR: 0.825, CiteScore: 1)
African Archaeological Review     Hybrid Journal   (Followers: 18, SJR: 0.862, CiteScore: 1)
Afrika Matematika     Hybrid Journal   (Followers: 1, SJR: 0.235, CiteScore: 0)
AGE     Hybrid Journal   (Followers: 7)
Ageing Intl.     Hybrid Journal   (Followers: 7, SJR: 0.39, CiteScore: 1)
Aggiornamenti CIO     Hybrid Journal   (Followers: 1)
Aging Clinical and Experimental Research     Hybrid Journal   (Followers: 3, SJR: 0.67, CiteScore: 2)
Agricultural Research     Hybrid Journal   (Followers: 6, SJR: 0.276, CiteScore: 1)
Agriculture and Human Values     Hybrid Journal   (Followers: 14, SJR: 1.173, CiteScore: 3)
Agroforestry Systems     Hybrid Journal   (Followers: 20, SJR: 0.663, CiteScore: 1)
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 12, SJR: 1.864, CiteScore: 6)
AI & Society     Hybrid Journal   (Followers: 8, SJR: 0.227, CiteScore: 1)
AIDS and Behavior     Hybrid Journal   (Followers: 14, SJR: 1.792, CiteScore: 3)
Air Quality, Atmosphere & Health     Hybrid Journal   (Followers: 4, SJR: 0.862, CiteScore: 3)
Akupunktur & Aurikulomedizin     Full-text available via subscription   (Followers: 1)
Algebra and Logic     Hybrid Journal   (Followers: 6, SJR: 0.531, CiteScore: 0)
Algebra Universalis     Hybrid Journal   (Followers: 2, SJR: 0.583, CiteScore: 1)
Algebras and Representation Theory     Hybrid Journal   (Followers: 1, SJR: 1.095, CiteScore: 1)
Algorithmica     Hybrid Journal   (Followers: 9, SJR: 0.56, CiteScore: 1)
Allergo J.     Full-text available via subscription   (Followers: 1, SJR: 0.234, CiteScore: 0)
Allergo J. Intl.     Hybrid Journal   (Followers: 2)
Alpine Botany     Hybrid Journal   (Followers: 5, SJR: 1.11, CiteScore: 3)
ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3)
AMBIO     Hybrid Journal   (Followers: 10, SJR: 1.569, CiteScore: 4)
American J. of Cardiovascular Drugs     Hybrid Journal   (Followers: 16, SJR: 0.951, CiteScore: 3)
American J. of Community Psychology     Hybrid Journal   (Followers: 29, SJR: 1.329, CiteScore: 2)
American J. of Criminal Justice     Hybrid Journal   (Followers: 8, SJR: 0.772, CiteScore: 1)
American J. of Cultural Sociology     Hybrid Journal   (Followers: 16, SJR: 0.46, CiteScore: 1)
American J. of Dance Therapy     Hybrid Journal   (Followers: 4, SJR: 0.181, CiteScore: 0)
American J. of Potato Research     Hybrid Journal   (Followers: 2, SJR: 0.611, CiteScore: 1)
American J. of Psychoanalysis     Hybrid Journal   (Followers: 21, SJR: 0.314, CiteScore: 0)
American Sociologist     Hybrid Journal   (Followers: 13, SJR: 0.35, CiteScore: 0)
Amino Acids     Hybrid Journal   (Followers: 8, SJR: 1.135, CiteScore: 3)
AMS Review     Partially Free   (Followers: 4)
Analog Integrated Circuits and Signal Processing     Hybrid Journal   (Followers: 7, SJR: 0.211, CiteScore: 1)
Analysis and Mathematical Physics     Hybrid Journal   (Followers: 5, SJR: 0.536, CiteScore: 1)
Analysis in Theory and Applications     Hybrid Journal   (Followers: 1)
Analysis of Verbal Behavior     Hybrid Journal   (Followers: 5)
Analytical and Bioanalytical Chemistry     Hybrid Journal   (Followers: 32, SJR: 0.978, CiteScore: 3)
Anatomical Science Intl.     Hybrid Journal   (Followers: 3, SJR: 0.367, CiteScore: 1)
Angewandte Schmerztherapie und Palliativmedizin     Hybrid Journal  
Angiogenesis     Hybrid Journal   (Followers: 3, SJR: 2.177, CiteScore: 5)
Animal Cognition     Hybrid Journal   (Followers: 19, SJR: 1.389, CiteScore: 3)
Annales françaises de médecine d'urgence     Hybrid Journal   (Followers: 1, SJR: 0.192, CiteScore: 0)
Annales Henri Poincaré     Hybrid Journal   (Followers: 3, SJR: 1.097, CiteScore: 2)
Annales mathématiques du Québec     Hybrid Journal   (Followers: 4, SJR: 0.438, CiteScore: 0)
Annali dell'Universita di Ferrara     Hybrid Journal   (SJR: 0.429, CiteScore: 0)
Annali di Matematica Pura ed Applicata     Hybrid Journal   (Followers: 1, SJR: 1.197, CiteScore: 1)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18, SJR: 1.042, CiteScore: 3)
Annals of Combinatorics     Hybrid Journal   (Followers: 4, SJR: 0.932, CiteScore: 1)
Annals of Data Science     Hybrid Journal   (Followers: 12)
Annals of Dyslexia     Hybrid Journal   (Followers: 10, SJR: 0.85, CiteScore: 2)
Annals of Finance     Hybrid Journal   (Followers: 30, SJR: 0.579, CiteScore: 1)
Annals of Forest Science     Hybrid Journal   (Followers: 7, SJR: 0.986, CiteScore: 2)
Annals of Global Analysis and Geometry     Hybrid Journal   (Followers: 1, SJR: 1.228, CiteScore: 1)
Annals of Hematology     Hybrid Journal   (Followers: 15, SJR: 1.043, CiteScore: 2)
Annals of Mathematics and Artificial Intelligence     Hybrid Journal   (Followers: 13, SJR: 0.413, CiteScore: 1)
Annals of Microbiology     Hybrid Journal   (Followers: 11, SJR: 0.479, CiteScore: 2)
Annals of Nuclear Medicine     Hybrid Journal   (Followers: 4, SJR: 0.687, CiteScore: 2)
Annals of Operations Research     Hybrid Journal   (Followers: 10, SJR: 0.943, CiteScore: 2)
Annals of Ophthalmology     Hybrid Journal   (Followers: 12)
Annals of Regional Science     Hybrid Journal   (Followers: 7, SJR: 0.614, CiteScore: 1)
Annals of Software Engineering     Hybrid Journal   (Followers: 13)
Annals of Solid and Structural Mechanics     Hybrid Journal   (Followers: 9, SJR: 0.239, CiteScore: 1)
Annals of Surgical Oncology     Hybrid Journal   (Followers: 13, SJR: 1.986, CiteScore: 4)
Annals of Telecommunications     Hybrid Journal   (Followers: 9, SJR: 0.223, CiteScore: 1)
Annals of the Institute of Statistical Mathematics     Hybrid Journal   (Followers: 1, SJR: 1.495, CiteScore: 1)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5, SJR: 0.834, CiteScore: 2)
Apidologie     Hybrid Journal   (Followers: 4, SJR: 1.22, CiteScore: 3)
APOPTOSIS     Hybrid Journal   (Followers: 8, SJR: 1.424, CiteScore: 4)
Applicable Algebra in Engineering, Communication and Computing     Hybrid Journal   (Followers: 2, SJR: 0.294, CiteScore: 1)
Applications of Mathematics     Hybrid Journal   (Followers: 2, SJR: 0.602, CiteScore: 1)
Applied Biochemistry and Biotechnology     Hybrid Journal   (Followers: 43, SJR: 0.571, CiteScore: 2)
Applied Biochemistry and Microbiology     Hybrid Journal   (Followers: 17, SJR: 0.21, CiteScore: 1)
Applied Cancer Research     Open Access  
Applied Categorical Structures     Hybrid Journal   (Followers: 2, SJR: 0.49, CiteScore: 0)
Applied Composite Materials     Hybrid Journal   (Followers: 49, SJR: 0.58, CiteScore: 2)
Applied Entomology and Zoology     Partially Free   (Followers: 4, SJR: 0.422, CiteScore: 1)
Applied Geomatics     Hybrid Journal   (Followers: 3, SJR: 0.733, CiteScore: 3)
Applied Geophysics     Hybrid Journal   (Followers: 8, SJR: 0.488, CiteScore: 1)
Applied Intelligence     Hybrid Journal   (Followers: 12, SJR: 0.6, CiteScore: 2)
Applied Magnetic Resonance     Hybrid Journal   (Followers: 4, SJR: 0.319, CiteScore: 1)
Applied Mathematics & Optimization     Hybrid Journal   (Followers: 9, SJR: 0.886, CiteScore: 1)
Applied Mathematics - A J. of Chinese Universities     Hybrid Journal   (SJR: 0.17, CiteScore: 0)
Applied Mathematics and Mechanics     Hybrid Journal   (Followers: 5, SJR: 0.461, CiteScore: 1)
Applied Microbiology and Biotechnology     Hybrid Journal   (Followers: 65, SJR: 1.182, CiteScore: 4)
Applied Physics A     Hybrid Journal   (Followers: 10, SJR: 0.481, CiteScore: 2)
Applied Physics B: Lasers and Optics     Hybrid Journal   (Followers: 24, SJR: 0.74, CiteScore: 2)
Applied Psychophysiology and Biofeedback     Hybrid Journal   (Followers: 8, SJR: 0.519, CiteScore: 2)
Applied Research in Quality of Life     Hybrid Journal   (Followers: 12, SJR: 0.316, CiteScore: 1)
Applied Solar Energy     Hybrid Journal   (Followers: 18, SJR: 0.225, CiteScore: 0)
Applied Spatial Analysis and Policy     Hybrid Journal   (Followers: 5, SJR: 0.542, CiteScore: 1)
Aquaculture Intl.     Hybrid Journal   (Followers: 24, SJR: 0.591, CiteScore: 2)
Aquarium Sciences and Conservation     Hybrid Journal   (Followers: 2)
Aquatic Ecology     Hybrid Journal   (Followers: 34, SJR: 0.656, CiteScore: 2)
Aquatic Geochemistry     Hybrid Journal   (Followers: 4, SJR: 0.591, CiteScore: 1)
Aquatic Sciences     Hybrid Journal   (Followers: 13, SJR: 1.109, CiteScore: 3)
Arabian J. for Science and Engineering     Hybrid Journal   (Followers: 5, SJR: 0.303, CiteScore: 1)
Arabian J. of Geosciences     Hybrid Journal   (Followers: 2, SJR: 0.319, CiteScore: 1)
Archaeological and Anthropological Sciences     Hybrid Journal   (Followers: 21, SJR: 1.052, CiteScore: 2)
Archaeologies     Hybrid Journal   (Followers: 12, SJR: 0.224, CiteScore: 0)
Archiv der Mathematik     Hybrid Journal   (Followers: 1, SJR: 0.725, CiteScore: 1)
Archival Science     Hybrid Journal   (Followers: 62, SJR: 0.745, CiteScore: 2)
Archive for History of Exact Sciences     Hybrid Journal   (Followers: 7, SJR: 0.186, CiteScore: 1)
Archive for Mathematical Logic     Hybrid Journal   (Followers: 3, SJR: 0.909, CiteScore: 1)
Archive for Rational Mechanics and Analysis     Hybrid Journal   (SJR: 3.93, CiteScore: 3)
Archive of Applied Mechanics     Hybrid Journal   (Followers: 5, SJR: 0.79, CiteScore: 2)
Archives and Museum Informatics     Hybrid Journal   (Followers: 142, SJR: 0.101, CiteScore: 0)
Archives of Computational Methods in Engineering     Hybrid Journal   (Followers: 5, SJR: 1.41, CiteScore: 5)
Archives of Dermatological Research     Hybrid Journal   (Followers: 7, SJR: 1.006, CiteScore: 2)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 14, SJR: 0.773, CiteScore: 2)
Archives of Gynecology and Obstetrics     Hybrid Journal   (Followers: 16, SJR: 0.956, CiteScore: 2)
Archives of Microbiology     Hybrid Journal   (Followers: 8, SJR: 0.644, CiteScore: 2)
Archives of Orthopaedic and Trauma Surgery     Hybrid Journal   (Followers: 8, SJR: 1.146, CiteScore: 2)
Archives of Osteoporosis     Hybrid Journal   (Followers: 2, SJR: 0.71, CiteScore: 2)
Archives of Sexual Behavior     Hybrid Journal   (Followers: 10, SJR: 1.493, CiteScore: 3)
Archives of Toxicology     Hybrid Journal   (Followers: 17, SJR: 1.541, CiteScore: 5)
Archives of Virology     Hybrid Journal   (Followers: 5, SJR: 0.973, CiteScore: 2)
Archives of Women's Mental Health     Hybrid Journal   (Followers: 14, SJR: 1.274, CiteScore: 3)
Archivio di Ortopedia e Reumatologia     Hybrid Journal  
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2, SJR: 0.946, CiteScore: 3)
ArgoSpine News & J.     Hybrid Journal  
Argumentation     Hybrid Journal   (Followers: 6, SJR: 0.349, CiteScore: 1)
Arid Ecosystems     Hybrid Journal   (Followers: 2, SJR: 0.2, CiteScore: 0)
Arkiv för Matematik     Hybrid Journal   (Followers: 1, SJR: 0.766, CiteScore: 1)
Arnold Mathematical J.     Hybrid Journal   (Followers: 1, SJR: 0.355, CiteScore: 0)
Arthropod-Plant Interactions     Hybrid Journal   (Followers: 2, SJR: 0.839, CiteScore: 2)
Arthroskopie     Hybrid Journal   (Followers: 1, SJR: 0.131, CiteScore: 0)
Artificial Intelligence and Law     Hybrid Journal   (Followers: 11, SJR: 0.937, CiteScore: 2)
Artificial Intelligence Review     Hybrid Journal   (Followers: 16, SJR: 0.833, CiteScore: 4)
Artificial Life and Robotics     Hybrid Journal   (Followers: 9, SJR: 0.226, CiteScore: 0)
Asia Europe J.     Hybrid Journal   (Followers: 5, SJR: 0.504, CiteScore: 1)
Asia Pacific Education Review     Hybrid Journal   (Followers: 12, SJR: 0.479, CiteScore: 1)
Asia Pacific J. of Management     Hybrid Journal   (Followers: 16, SJR: 1.185, CiteScore: 2)
Asia-Pacific Education Researcher     Hybrid Journal   (Followers: 12, SJR: 0.353, CiteScore: 1)
Asia-Pacific Financial Markets     Hybrid Journal   (Followers: 2, SJR: 0.187, CiteScore: 0)
Asia-Pacific J. of Atmospheric Sciences     Hybrid Journal   (Followers: 19, SJR: 0.855, CiteScore: 1)
Asian Business & Management     Hybrid Journal   (Followers: 9, SJR: 0.378, CiteScore: 1)
Asian J. of Business Ethics     Hybrid Journal   (Followers: 9)
Asian J. of Criminology     Hybrid Journal   (Followers: 6, SJR: 0.543, CiteScore: 1)
AStA Advances in Statistical Analysis     Hybrid Journal   (Followers: 3, SJR: 0.548, CiteScore: 1)
AStA Wirtschafts- und Sozialstatistisches Archiv     Hybrid Journal   (Followers: 5, SJR: 0.183, CiteScore: 0)
ästhetische dermatologie & kosmetologie     Full-text available via subscription  

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Journal Cover
AAPS Journal
Journal Prestige (SJR): 1.118
Citation Impact (citeScore): 4
Number of Followers: 22  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Online) 1550-7416
Published by Springer-Verlag Homepage  [2351 journals]
  • Risk-Based Comparability Assessment for Monoclonal Antibodies During Drug
           Development: A Clinical Pharmacology Perspective
    • Authors: Yanli Zhuang; Di Chen; Amarnath Sharma; Zhenhua Xu
      Abstract: Due to complexities in the structure, function, and manufacturing process of antibody-based therapeutic proteins, comparability assessment for supporting manufacturing changes can sometimes be a challenging task. Regulatory guidance recommends a hierarchical risk-based approach, starting with Chemistry, Manufacturing, and Controls (CMC) analytical characterizations, followed by non-clinical and/or clinical studies to ensure that any potential changes in quality attributes have no adverse impact on efficacy and safety of the product. This review focuses on the changes in quality attributes which may potentially affect the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of a monoclonal antibody (mAb) product, and provides general guidelines in designing non-clinical and clinical PK/PD studies to help support comparability assessments. A decision tree for comparability assessment is proposed depending on the nature of the changes in quality attributes, the potential impact of such changes, and the timing of the manufacturing change relative to the development process. Ideally, the optimization of manufacturing process should take place in the early stage of drug development (i.e., preclinical to phase 2a) as more stringent comparability criteria would have to be met if manufacturing changes occur in the late stage of drug development (i.e., phase 2b and after), and consequently, major changes in manufacturing process should be avoided during confirmatory phase 3 studies and post-approval of drug products.
      PubDate: 2018-10-15
      DOI: 10.1208/s12248-018-0268-8
      Issue No: Vol. 20, No. 6 (2018)
       
  • Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Therapeutics
    • Authors: Brittany E. Givens; Youssef W. Naguib; Sean M. Geary; Eric J. Devor; Aliasger K. Salem
      Abstract: The recent progress in harnessing the efficient and precise method of DNA editing provided by CRISPR/Cas9 is one of the most promising major advances in the field of gene therapy. However, the development of safe and optimally efficient delivery systems for CRISPR/Cas9 elements capable of achieving specific targeting of gene therapy to the location of interest without off-target effects is a primary challenge for clinical therapeutics. Nanoparticles (NPs) provide a promising means to meet such challenges. In this review, we present the most recent advances in developing innovative NP-based delivery systems that efficiently deliver CRISPR/Cas9 constructs and maximize their effectiveness.
      PubDate: 2018-10-10
      DOI: 10.1208/s12248-018-0267-9
      Issue No: Vol. 20, No. 6 (2018)
       
  • Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and
           Implications for Translational Pharmacology
    • Authors: Danielle Mandikian; Isabel Figueroa; Amy Oldendorp; Hanine Rafidi; Sheila Ulufatu; Michelle G. Schweiger; Jessica A. Couch; Noel Dybdal; Sean B. Joseph; Saileta Prabhu; Gregory Z. Ferl; C. Andrew Boswell
      Abstract: We previously performed a comparative assessment of tissue-level vascular physiological parameters in mice and rats, two of the most commonly utilized species in translational drug development. The present work extends this effort to non-human primates by measuring tissue- and organ-level vascular volumes (Vv), interstitial volumes (Vi), and blood flow rates (Q) in cynomolgus monkeys. These measurements were accomplished by red blood cell labeling, extracellular marker infusion, and rubidium chloride bolus distribution, respectively, the same methods used in previous rodent measurements. In addition, whole-body blood volumes (BV) were determined across species. The results demonstrate that Vv, Vi, and Q, measured using our methods scale approximately by body weight across mouse, rat, and monkey in the tissues considered here, where allometric analysis allowed extrapolation to human parameters. Significant differences were observed between the values determined in this study and those reported in the literature, including Vv in muscle, brain, and skin and Q in muscle, adipose, heart, thymus, and spleen. The impact of these differences for selected tissues was evaluated via sensitivity analysis using a physiologically based pharmacokinetic model. The blood-brain barrier in monkeys was shown to be more impervious to an infused radioactive tracer, indium-111-pentetate, than in mice or rats. The body weight-normalized total BV measured in monkey agreed well with previously measured value in rats but was lower than that in mice. These findings have important implications for the common practice of scaling physiological parameters from rodents to primates in translational pharmacology.
      PubDate: 2018-10-08
      DOI: 10.1208/s12248-018-0264-z
      Issue No: Vol. 20, No. 6 (2018)
       
  • Reverse Engineering the 1-Month Lupron Depot®
    • Authors: Jia Zhou; Keiji Hirota; Rose Ackermann; Jennifer Walker; Yan Wang; Stephanie Choi; Anna Schwendeman; Steven P. Schwendeman
      Abstract: The 1-month Lupron Depot® (LD) encapsulating water-soluble leuprolide in poly(lactic-co-glycolic acid) (PLGA) microspheres is a benchmark product upon which modern long-acting release products are often compared. Despite expiration of patent coverage, no generic product for the LD has been approved in the USA, likely due to the complexity of components and manufacturing processes involved in the product. Here, we describe the reverse engineering of the LD composition and important product attributes. Specific attributes analyzed for microspheres were as follows: leuprolide content by three methods; gelatin content, type, and molecular weight distribution; PLGA content, lactic acid/glycolic acid ratio, and molecular weight distribution; mannitol content; in vitro drug release; residual solvent and moisture content; particle size distribution and morphology; and glass transition temperature. For the diluent, composition, viscosity, and specific gravity were analyzed. Analyzed contents of the formulation and the determined PLGA characteristics matched well with the official numbers stated in the package insert and those found in literature, respectively. The gelatin was identified as type B consistent with ~ 300 bloom. The 11-μm volume-median microspheres in the LD slowly released the drug in vitro in a zero-order manner after ~ 23% initial burst release. Very low content of residual moisture (< 0.5%) and methylene chloride (< 1 ppm) in the product indicates in-water drying is capable of removing solvents to extremely low levels during manufacturing. The rigorous approach of reverse engineering described here may be useful for development of generic leuprolide-PLGA microspheres as well as other new and generic PLGA microsphere formulations.
      PubDate: 2018-10-02
      DOI: 10.1208/s12248-018-0253-2
      Issue No: Vol. 20, No. 6 (2018)
       
  • A Gyrolab Assay for the Quantitation of Free Complement Protein C5a in
           Human Plasma
    • Authors: Mark Dysinger; Mark Ma
      Abstract: Complement protein C5a is recognized as an important component of the alternative complement pathway. Its role is prominent enough to garner interest not only as a biomarker, but also as a potential therapeutic target. Bioanalytical challenges have been posed in proper quantitation of free C5a due to interference from its precursor, C5. Additionally, free therapeutic target quantitation can be difficult due to effects of sample dilution and prolonged sample incubation when therapeutic is used as capture reagent. Gyrolab technology enables quantitation of free target analyte with minimal sample dilution and rapid sample incubations, thus enabling in vitro results that are more representative of in vivo pharmacodynamics. When coupled with strategic sample pretreatment, Gyrolab offers an opportunity to quantitate free C5a in human plasma with an assay that vastly diminishes C5 interference. A Gyrolab assay for the quantitation of free C5a in human plasma was developed and validated. Validation results confirmed that proper sample pretreatment and use of the Gyrolab platform yield accurate and reliable results. Due to the advantages that it provides, Gyrolab has become our default technology of choice for quantitation of free target.
      PubDate: 2018-10-02
      DOI: 10.1208/s12248-018-0266-x
      Issue No: Vol. 20, No. 6 (2018)
       
  • Correction to: Reflections on FDA Draft Guidance for Products Containing
           Nanomaterials: Is the Abbreviated New Drug Application (ANDA) a Suitable
           Pathway for Nanomedicines'
    • Authors: Emily Marden; Ioanna Ntai; Scott Bass; Beat Flühmann
      Abstract: In the published article the given name and the family name for each author is listed in the incorrect order and therefore cited incorrectly. The correct order (given name followed by family name) of names is listed above.
      PubDate: 2018-09-25
      DOI: 10.1208/s12248-018-0265-y
      Issue No: Vol. 20, No. 6 (2018)
       
  • The Properties of Cysteine-Conjugated Antibody-Drug Conjugates Are
           Impacted by the IgG Subclass
    • Authors: Amita Datta-Mannan; Hiuwan Choi; David Stokell; Jason Tang; Anthony Murphy; Aaron Wrobleski; Yiqing Feng
      Abstract: Among the numerous antibody-drug conjugate (ADC) clinical candidates, one of the most prevalent types utilizes the interchain cysteines in antibodies to conjugate auristatin via a maleimide-containing linker. In this class of ADCs, there are a paucity of systematic studies characterizing how IgG subclass influences the biophysical properties and in vivo pharmacokinetics of the ADC molecules. In the current investigation, we studied cysteine-conjugated ADCs using a model system consisting of human IgG1, IgG2, and IgG4 antibodies with the same variable region. Our findings identified some unforeseen differences among the three ADCs. Drug conjugation profiling by LC-MS revealed that 50% of inter heavy-light chain disulfide bonds are disrupted to conjugate drugs in IgG1 antibody while only 10% in IgG2 antibody and 20% in IgG4 antibody. The solution behavior of the ADCs was interrogated in concentrating experiments and diffusion interaction parameter measurements. We found that drug conjugation affected the solution property of the three antibodies differently, with the IgG2-based ADC having the most increased propensity to aggregate. Rat PK studies using a sensitive LC-MS-based bioanalytical method showed that the IgG1-based ADC has poor peripheral linker-payload stability while the IgG2- and IgG4-based ADCs are stable. The conjugate stability of the IgG2-based ADC was further confirmed in a cynomolgus monkey PK study. Overall, the IgG2-based ADC exhibited the best PK/conjugate stability but also the most deterioration in stability among the three ADCs. Our findings provide important information and present multifactorial considerations for the selection of IgG subclass during ADC drug discovery when employing stochastic cysteine conjugation.
      PubDate: 2018-09-25
      DOI: 10.1208/s12248-018-0263-0
      Issue No: Vol. 20, No. 6 (2018)
       
  • Additive Manufacturing with 3D Printing: Progress from Bench to Bedside
    • Authors: Ziyaur Rahman; Sogra F. Barakh Ali; Tanil Ozkan; Naseem A. Charoo; Indra K. Reddy; Mansoor A. Khan
      Abstract: Three-dimensional (3D) printing was discovered in the 1980s, and many industries have embraced it, but the pharmaceutical industry is slow or reluctant to adopt it. Spiritam® is the first and only 3D-printed drug product approved by FDA in 2015. Since then, the FDA has not approved any 3D-printed drug product due to technical and regulatory issues. The 3D printing process cannot compete with well-established and understood conventional processes for making solid dosage forms. However, pharmaceutical companies can utilize it where mass production is not required; rather, consistency, precision, and accuracy in quality are paramount. There are many 3D printing technologies available, and not all of them are amenable to pharmaceutical manufacturing. Each 3D technology has certain prerequisites in terms of material that it can handle. Some of the pertinent technical and regulatory issues are as follows: Current Good Manufacturing Practice, in-process tests and process control, and cleaning validation. Other promising area of 3D printing use is printing medications for patients with special needs in a hospital and/or pharmacy setting with minimum regulatory oversight. This technology provides a novel opportunity for in-hospital compounding of necessary medicines to support patient-specific medications. However, aspects of the manufacturing challenges and quality control considerations associated with the varying formulation and processing methods need to be fully understood before 3D printing can emerge as a therapeutic tool. With these points in mind, this review paper focuses on 3D technologies amenable for pharmaceutical manufacturing, excipient requirement, process understanding, and technical and regulatory challenges.
      PubDate: 2018-09-12
      DOI: 10.1208/s12248-018-0225-6
      Issue No: Vol. 20, No. 6 (2018)
       
  • Michaelis-Menten from an In Vivo Perspective: Open Versus Closed Systems
    • Authors: Johan Gabrielsson; Lambertus A. Peletier
      Abstract: After a century of applications of the seminal Michaelis-Menten equation since its advent it is timely to scrutinise its principal parts from an in vivo point of view. Thus, the Michaelis-Menten system was revisited in which enzymatic turnover, i.e. synthesis and elimination was incorporated. To the best of our knowledge, previous studies of the Michaelis-Menten system have been mainly based on the assumption that the total pool of enzyme, free and bound, is constant. However, in fact this may not always be the case, particularly for chronic indications. Chronic (periodic) administration of drugs is often related to induction or inhibition of enzymatic processes and even changes in the free enzymatic load per se. This may account for the fact that translation of in vitro metabolism data have shown to give systematic deviations from experimental in vivo data. Interspecies extrapolations of metabolic data are often challenged by poor predictability due to insufficient power of applied functions and methods. By incorporating enzyme turnover, a more mechanistic expression of substrate, free enzyme and substrate-enzyme complex concentrations is derived. In particular, it is shown that whereas in closed systems there is a threshold for chronic dosing beyond which the substrate concentration keeps rising, in open systems involving enzyme turnover this is no longer the case. However, in the presence of slow enzyme turnover, after an initial period of adjustment which may be quite long, the relation between substrate concentration and dose rate reduces to a linear expression. This new open framework is also applicable to transporter systems.
      PubDate: 2018-09-12
      DOI: 10.1208/s12248-018-0256-z
      Issue No: Vol. 20, No. 6 (2018)
       
  • In Vivo Predictive Dissolution and Simulation Workshop Report:
           Facilitating the Development of Oral Drug Formulation and the Prediction
           of Oral Bioperformance
    • Authors: Yasuhiro Tsume; Sanjaykumar Patel; Nikoletta Fotaki; Christel Bergstrӧm; Gordon L. Amidon; James G. Brasseur; Deanna M. Mudie; Duxin Sun; Marival Bermejo; Ping Gao; Wei Zhu; David C. Sperry; Maria Vertzoni; Neil Parrott; Robert Lionberger; Atsushi Kambayashi; Andre Hermans; Xujin Lu; Gregory E. Amidon
      PubDate: 2018-09-06
      DOI: 10.1208/s12248-018-0260-3
      Issue No: Vol. 20, No. 6 (2018)
       
  • Adding the T to ADME: Predictive Toxicity in Renal Drug Development
    • Authors: Raymond E. Lai; Rosalinde Masereeuw
      PubDate: 2018-09-05
      DOI: 10.1208/s12248-018-0258-x
      Issue No: Vol. 20, No. 6 (2018)
       
  • Imaging Techniques in the Diagnosis and Management of Ocular Tumors:
           Prospects and Challenges
    • Authors: Rabin Neupane; Ripal Gaudana; Sai H. S. Boddu
      Abstract: Different types of imaging modalities are used in the diagnosis of ocular cancer. Selection of an imaging modality is based on the features of a tumor as well as the inherent characteristics of the imaging technique. It is vital to select an appropriate imaging modality in diagnosis of ocular tumor with confidence. This review focuses on five most commonly used imaging modalities, i.e., positron emission tomography-computed tomography (PET/CT), single photon emission computed tomography (SPECT), optical coherence tomography (OCT), ultrasound (US), and magnetic resonance imaging (MRI). The principal of imaging modalities is briefly explained, along with their role in the diagnosis and management of the most common ocular tumors such as retinoblastoma and uveal melanoma. Further, the diagnostic features of ocular tumors corresponding to each imaging modality and possibilities of utilizing imaging techniques in the process of ocular drug development are included in this review.
      PubDate: 2018-09-05
      DOI: 10.1208/s12248-018-0259-9
      Issue No: Vol. 20, No. 6 (2018)
       
  • Individualized Dosing of Therapeutic Monoclonal Antibodies—a
           Changing Treatment Paradigm'
    • Authors: Anne S. Strik; Yow-Ming C. Wang; Laura E. Ruff; William Yashar; Bradley T. Messmer; Diane R. Mould
      Abstract: The introduction of monoclonal antibodies (mAbs) to the treatment of inflammatory bowel disease (IBD) was an important medical milestone. MAbs have been demonstrated as safe and efficacious treatments of IBD. However, a large percentage of patients either fail to respond initially or lose response to therapy after a period of treatment. Although there are factors associated with poor treatment outcomes in IBD, one cause for treatment failure may be low mAb exposure. Consequently, gastroenterologists have begun using therapeutic drug monitoring (TDM) to guide dose adjustment. However, while beneficial, TDM does not provide sufficient information to effectively adjust doses. The pharmacokinetics (PK) and pharmacodynamics (PD) of mAbs are complex, with numerous factors impacting on mAb PK and PD. The concept of dashboard-guided dosing based on Bayesian PK models allows physicians to combine TDM with factors influencing mAb PK to individualize therapy more effectively. One issue with TDM has been the slow turnaround of assay results, either necessitating an additional clinic visit for a sample or reacting to TDM results at a subsequent, rather than the current, dose. New point-of-care (POC) assays for mAbs are being developed that would potentially allow physicians to determine drug concentration quickly. However, work remains to understand how to determine what target exposure is needed for an individual patient, and whether the combination of POC assays and dashboards presents a safe approach with substantial outcome benefit over the current standard of care.
      PubDate: 2018-09-05
      DOI: 10.1208/s12248-018-0257-y
      Issue No: Vol. 20, No. 6 (2018)
       
  • Porcine and Human In Vivo Simulations for Doxorubicin-Containing
           Formulations Used in Locoregional Hepatocellular Carcinoma Treatment
    • Authors: Ilse R. Dubbelboer; Erik Sjögren; Hans Lennernäs
      Abstract: It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.
      PubDate: 2018-08-30
      DOI: 10.1208/s12248-018-0251-4
      Issue No: Vol. 20, No. 6 (2018)
       
  • Time Scaling for In Vitro-In Vivo Correlation: the Inverse Release
           Function (IRF) Approach
    • Authors: Jean Michel Cardot; John C Lukas; Paula Muniz
      Abstract: In vitro-in vivo correlations (IVIVC) are methods used to create a link between biopharmaceutical properties such as dissolution and physiological response such as plasma concentration. Level A IVIVC defines 1:1 relationship between the percent absorbed in vivo and the percent dissolved in vitro. A successful level A IVIVC provides the capacity to predict in vivo behavior based only on in vitro data with application in formulation development and support of biowaivers recognized by regulatory agencies across the world. Level A regression may be complicated due to differences in time scales as well as the lack of coincident times of similar release in vitro and in vivo leading to approximate time-to-time links and subsequent loss of information. Here, a novel method to establish Levy’s plot and to provide time scaling for improved IVIVC predictive capacity is presented. The method is mathematically closed and is an inverse release function (IRF) characterizing the single (or more) phases of dissolution/absorption. It uses the complete set of information available from all time points both in vitro and in vivo. An extended-release formulation development situation is presented with three increasing release rate test products compared in a trial versus a reference product. First, the standard level A regression was made. Prediction errors for internal validation were higher than 10% for Cmax. The IRF method was applied to obtain the in vitro times of percentage dissolved equivalent to percentage absorbed. The prediction errors from the IRF level A correlation were nearly negligible.
      PubDate: 2018-08-29
      DOI: 10.1208/s12248-018-0250-5
      Issue No: Vol. 20, No. 6 (2018)
       
  • Emerging Cancer Therapeutic Targets in Protein Homeostasis
    • Authors: Prabhakar Bastola; Derek B. Oien; Megan Cooley; Jeremy Chien
      Abstract: Genomic aberrations inside malignant cells through copy number alterations, aneuploidy, and mutations can exacerbate misfolded and unfolded protein burden resulting in increased proteotoxic stress. Increased proteotoxic stress can be deleterious to malignant cells; therefore, these cells rely heavily on the protein quality control mechanisms for survival and proliferation. Components of the protein quality control, such as the unfolded protein response, heat shock proteins, autophagy, and the ubiquitin proteasome system, orchestrate a cascade of downstream events that allow the mitigation of the proteotoxic stress. This dependency makes components of the protein quality control mechanisms attractive targets in cancer therapeutics. In this review, we explore the components of the protein homeostasis especially focusing on the emerging cancer therapeutic agents/targets that are being actively pursued actively.
      PubDate: 2018-08-27
      DOI: 10.1208/s12248-018-0254-1
      Issue No: Vol. 20, No. 6 (2018)
       
  • Applications of Clinically Relevant Dissolution Testing: Workshop Summary
           Report
    • Authors: Sandra Suarez-Sharp; Michael Cohen; Filippos Kesisoglou; Andreas Abend; Patrick Marroum; Poonam Delvadia; Evangelos Kotzagiorgis; Min Li; Anna Nordmark; Nagesh Bandi; Erik Sjögren; Andrew Babiskin; Tycho Heimbach; Shinichi Kijima; Haritha Mandula; Kimberly Raines; Paul Seo; Xinyuan Zhang
      Abstract: This publication summarizes the proceedings of day 3 of a 3-day workshop on “Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development.” Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product.
      PubDate: 2018-08-27
      DOI: 10.1208/s12248-018-0252-3
      Issue No: Vol. 20, No. 6 (2018)
       
  • Reflections on FDA Draft Guidance for Products Containing Nanomaterials:
           Is the Abbreviated New Drug Application (ANDA) a Suitable Pathway for
           Nanomedicines'
    • Authors: Marden Emily; Ntai Ioanna; Bass Scott; Flühmann Beat
      Abstract: The US Food and Drug Administration (FDA) recently released a draft guidance for industry titled “Drug Products, Including Biological Products, that Contain Nanomaterials.” The FDA’s attention to the unique safety and efficacy aspects of drugs containing nanomaterials is commendable. This Draft Guidance succeeds in acknowledging the complexity of these products, as well as the challenges associated with approving safe and therapeutically equivalent complex generic versions. However, the challenge posed by the manufacturing process for drugs containing nanomaterials is insufficiently addressed. The critical quality attributes of such products cannot be properly defined, and therefore it is not possible to design informative comparative physicochemical assessments for equivalence. As a consequence, the 505(j) Abbreviated New Drug Application (ANDA) pathway, currently advised as the standard from the FDA, is not suitable for the approval of complex generic products. Drawing from the successful story of biologics, we propose instead a stepwise totality-of-evidence approach, demonstrating similarity and including clinical studies when deemed necessary, as an appropriate alternative to the 505(j) ANDA pathway.
      PubDate: 2018-08-20
      DOI: 10.1208/s12248-018-0255-0
      Issue No: Vol. 20, No. 5 (2018)
       
  • A Population Pharmacokinetic-Pharmacodynamic Model of Pegfilgrastim
    • Authors: Ari Brekkan; Luis Lopez-Lazaro; Gunnar Yngman; Elodie L. Plan; Chayan Acharya; Andrew C. Hooker; Suresh Kankanwadi; Mats O. Karlsson
      Abstract: Neutropenia and febrile neutropenia (FN) are serious side effects of cytotoxic chemotherapy which may be alleviated with the administration of recombinant granulocyte colony-stimulating factor (GCSF) derivatives, such as pegfilgrastim (PG) which increases absolute neutrophil count (ANC). In this work, a population pharmacokinetic-pharmacodynamic (PKPD) model was developed based on data obtained from healthy volunteers receiving multiple administrations of PG. The developed model was a bidirectional PKPD model, where PG stimulated the proliferation, maturation, and margination of neutrophils and where circulating neutrophils in turn increased the elimination of PG. Simulations from the developed model show disproportionate changes in response with changes in dose. A dose increase of 10% from the 6 mg therapeutic dose taken as a reference leads to area under the curve (AUC) increases of ~50 and ~5% for PK and PD, respectively. A full random effects covariate model showed that little of the parameter variability could be explained by sex, age, body size, and race. As a consequence, little of the secondary parameter variability (Cmax and AUC of PG and ANC) could be explained by these covariates.
      PubDate: 2018-08-15
      DOI: 10.1208/s12248-018-0249-y
      Issue No: Vol. 20, No. 5 (2018)
       
  • Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal
           Tubules
    • Authors: Marianne K. Vormann; Linda Gijzen; Simon Hutter; Lisette Boot; Arnaud Nicolas; Angelique van den Heuvel; Jelle Vriend; Chee Ping Ng; Tom T. G. Nieskens; Vincent van Duinen; Bjorn de Wagenaar; Rosalinde Masereeuw; Laura Suter-Dick; Sebastiaan J. Trietsch; Martijn Wilmer; Jos Joore; Paul Vulto; Henriette L. Lanz
      Abstract: Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.
      PubDate: 2018-08-14
      DOI: 10.1208/s12248-018-0248-z
      Issue No: Vol. 20, No. 5 (2018)
       
 
 
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