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BIOLOGY (1497 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 22)
Achievements in the Life Sciences     Open Access   (Followers: 5)
ACS Synthetic Biology     Hybrid Journal   (Followers: 24)
Acta Biologica Colombiana     Open Access   (Followers: 7)
Acta Biologica Hungarica     Full-text available via subscription   (Followers: 4)
Acta Biologica Sibirica     Open Access  
Acta Biomaterialia     Hybrid Journal   (Followers: 27)
Acta Biotheoretica     Hybrid Journal   (Followers: 4)
Acta Chiropterologica     Full-text available via subscription   (Followers: 6)
acta ethologica     Hybrid Journal   (Followers: 4)
Acta Limnologica Brasiliensia     Open Access   (Followers: 3)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Musei Silesiae, Scientiae Naturales : The Journal of Silesian Museum in Opava     Open Access  
Acta Neurobiologiae Experimentalis     Open Access  
Acta Parasitologica     Hybrid Journal   (Followers: 10)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis     Open Access  
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advanced Journal of Graduate Research     Open Access  
Advanced Studies in Biology     Open Access  
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Bioinformatics     Open Access   (Followers: 17)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biology     Open Access   (Followers: 8)
Advances in Biosensors and Bioelectronics     Open Access   (Followers: 7)
Advances in Cell Biology     Open Access   (Followers: 25)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Ecological Research     Full-text available via subscription   (Followers: 43)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 17)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Genome Biology     Full-text available via subscription   (Followers: 8)
Advances in High Energy Physics     Open Access   (Followers: 19)
Advances in Human Biology     Open Access   (Followers: 3)
Advances in Life Science and Technology     Open Access   (Followers: 16)
Advances in Life Sciences     Open Access   (Followers: 6)
Advances in Marine Biology     Full-text available via subscription   (Followers: 14)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 21)
Advances in Organ Biology     Full-text available via subscription   (Followers: 1)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Regenerative Biology     Open Access   (Followers: 1)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
African Journal of Range & Forage Science     Hybrid Journal   (Followers: 6)
AFRREV STECH : An International Journal of Science and Technology     Open Access   (Followers: 1)
Ageing Research Reviews     Hybrid Journal   (Followers: 11)
Aging Cell     Open Access   (Followers: 13)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
AJP Cell Physiology     Hybrid Journal   (Followers: 15)
AJP Endocrinology and Metabolism     Hybrid Journal   (Followers: 23)
AJP Lung Cellular and Molecular Physiology     Hybrid Journal   (Followers: 3)
Al-Kauniyah : Jurnal Biologi     Open Access  
Alasbimn Journal     Open Access   (Followers: 1)
Alces : A Journal Devoted to the Biology and Management of Moose     Open Access  
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Biology Teacher     Full-text available via subscription   (Followers: 14)
American Fern Journal     Full-text available via subscription   (Followers: 1)
American Journal of Agricultural and Biological Sciences     Open Access   (Followers: 8)
American Journal of Bioethics     Hybrid Journal   (Followers: 10)
American Journal of Human Biology     Hybrid Journal   (Followers: 13)
American Journal of Medical and Biological Research     Open Access   (Followers: 8)
American Journal of Plant Sciences     Open Access   (Followers: 19)
American Journal of Primatology     Hybrid Journal   (Followers: 14)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 72)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anadolu University Journal of Science and Technology : C Life Sciences and Biotechnology     Open Access  
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 10)
Anatomical Science International     Hybrid Journal   (Followers: 2)
Animal Cells and Systems     Hybrid Journal   (Followers: 4)
Annales de Limnologie - International Journal of Limnology     Hybrid Journal   (Followers: 1)
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annales Henri Poincaré     Hybrid Journal   (Followers: 3)
Annales UMCS, Biologia     Open Access   (Followers: 1)
Annals of Applied Biology     Hybrid Journal   (Followers: 7)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18)
Annals of Human Biology     Hybrid Journal   (Followers: 5)
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 15)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 23)
Annual Review of Cancer Biology     Full-text available via subscription   (Followers: 1)
Annual Review of Cell and Developmental Biology     Full-text available via subscription   (Followers: 37)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 13)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 23)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 12)
Anthropological Review     Open Access   (Followers: 23)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antibiotics     Open Access   (Followers: 9)
Antioxidants     Open Access   (Followers: 4)
Antioxidants & Redox Signaling     Hybrid Journal   (Followers: 8)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apidologie     Hybrid Journal   (Followers: 4)
Apmis     Hybrid Journal   (Followers: 1)
APOPTOSIS     Hybrid Journal   (Followers: 8)
Applied Bionics and Biomechanics     Open Access   (Followers: 8)
Applied Vegetation Science     Full-text available via subscription   (Followers: 10)
Aquaculture Environment Interactions     Open Access   (Followers: 2)
Aquaculture International     Hybrid Journal   (Followers: 23)
Aquaculture Reports     Open Access   (Followers: 3)
Aquaculture, Aquarium, Conservation & Legislation - International Journal of the Bioflux Society     Open Access   (Followers: 6)
Aquatic Biology     Open Access   (Followers: 5)
Aquatic Ecology     Hybrid Journal   (Followers: 34)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 14)
Aquatic Science and Technology     Open Access   (Followers: 3)
Aquatic Toxicology     Hybrid Journal   (Followers: 21)
Archaea     Open Access   (Followers: 3)
Archiv für Molluskenkunde: International Journal of Malacology     Full-text available via subscription   (Followers: 3)
Archives of Biological Sciences     Open Access  
Archives of Microbiology     Hybrid Journal   (Followers: 8)
Archives of Natural History     Hybrid Journal   (Followers: 6)
Archives of Oral Biology     Hybrid Journal   (Followers: 2)
Archives of Virology     Hybrid Journal   (Followers: 5)
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2)
Arid Ecosystems     Hybrid Journal   (Followers: 2)
Arquivos do Instituto Biológico     Open Access   (Followers: 1)
Arquivos do Museu Dinâmico Interdisciplinar     Open Access  
Arthropod Structure & Development     Hybrid Journal   (Followers: 2)
Arthropods     Open Access   (Followers: 1)
Artificial DNA: PNA & XNA     Hybrid Journal   (Followers: 3)
Artificial Photosynthesis     Open Access   (Followers: 1)
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Journal of Biodiversity     Open Access   (Followers: 4)
Asian Journal of Biological Sciences     Open Access   (Followers: 3)
Asian Journal of Cell Biology     Open Access   (Followers: 5)
Asian Journal of Developmental Biology     Open Access   (Followers: 2)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 3)
Asian Journal of Nematology     Open Access   (Followers: 4)
Asian Journal of Poultry Science     Open Access   (Followers: 3)
Atti della Accademia Peloritana dei Pericolanti - Classe di Scienze Medico-Biologiche     Open Access  
Australian Life Scientist     Full-text available via subscription   (Followers: 2)
Australian Mammalogy     Hybrid Journal   (Followers: 6)
Autophagy     Hybrid Journal   (Followers: 2)
Avian Biology Research     Full-text available via subscription   (Followers: 4)
Avian Conservation and Ecology     Open Access   (Followers: 11)
Bacteriology Journal     Open Access   (Followers: 1)
Bacteriophage     Full-text available via subscription   (Followers: 3)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Plant Taxonomy     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Batman Üniversitesi Yaşam Bilimleri Dergisi     Open Access  
Berita Biologi     Open Access   (Followers: 1)
Between the Species     Open Access   (Followers: 1)
Bio Tribune Magazine     Hybrid Journal  
BIO Web of Conferences     Open Access  
BIO-Complexity     Open Access  
Bio-Grafía. Escritos sobre la Biología y su enseñanza     Open Access  
Bioanalytical Reviews     Hybrid Journal   (Followers: 2)
Biocatalysis and Biotransformation     Hybrid Journal   (Followers: 6)
BioCentury Innovations     Full-text available via subscription   (Followers: 1)
Biochemistry and Cell Biology     Hybrid Journal   (Followers: 15)
Biochimie     Hybrid Journal   (Followers: 7)
BioControl     Hybrid Journal   (Followers: 5)
Biocontrol Science and Technology     Hybrid Journal   (Followers: 5)
Biodemography and Social Biology     Hybrid Journal  
BioDiscovery     Open Access   (Followers: 2)
Biodiversitas : Journal of Biological Diversity     Open Access  
Biodiversity : Research and Conservation     Open Access   (Followers: 26)
Biodiversity Data Journal     Open Access   (Followers: 3)
Biodiversity Informatics     Open Access   (Followers: 1)
Biodiversity Information Science and Standards     Open Access  
Bioedukasi : Jurnal Pendidikan Biologi FKIP UM Metro     Open Access  
Bioeksperimen : Jurnal Penelitian Biologi     Open Access  
Bioelectrochemistry     Hybrid Journal   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 1)
Bioenergy Research     Hybrid Journal   (Followers: 2)
Bioengineering and Bioscience     Open Access   (Followers: 1)
BioEssays     Hybrid Journal   (Followers: 10)
Bioethics     Hybrid Journal   (Followers: 14)
BioéthiqueOnline     Open Access  
Biofabrication     Hybrid Journal   (Followers: 5)
Biofilms     Full-text available via subscription   (Followers: 1)
Biogeosciences (BG)     Open Access   (Followers: 10)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 2)
Bioinformatics     Hybrid Journal   (Followers: 294)
Bioinformatics and Biology Insights     Open Access   (Followers: 11)
Bioinspiration & Biomimetics     Hybrid Journal   (Followers: 7)
Biointerphases     Open Access   (Followers: 1)
Biojournal of Science and Technology     Open Access  
Biologia     Hybrid Journal  
Biologia on-line : Revista de divulgació de la Facultat de Biologia     Open Access  
Biological Bulletin     Partially Free   (Followers: 6)
Biological Control     Hybrid Journal   (Followers: 4)
Biological Invasions     Hybrid Journal   (Followers: 19)
Biological Journal of the Linnean Society     Hybrid Journal   (Followers: 18)
Biological Letters     Open Access   (Followers: 5)
Biological Procedures Online     Open Access  
Biological Psychiatry     Hybrid Journal   (Followers: 47)
Biological Psychology     Hybrid Journal   (Followers: 7)
Biological Research     Open Access  
Biological Rhythm Research     Hybrid Journal   (Followers: 2)
Biological Theory     Hybrid Journal   (Followers: 3)
Biological Trace Element Research     Hybrid Journal  

        1 2 3 4 5 6 7 8 | Last

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]
  • Implementing Optimal Designs for Dose–Response Studies Through Adaptive
           Randomization for a Small Population Group
    • Authors: Yevgen Ryeznik; Oleksandr Sverdlov; Andrew C. Hooker
      Abstract: In dose–response studies with censored time-to-event outcomes, D-optimal designs depend on the true model and the amount of censored data. In practice, such designs can be implemented adaptively, by performing dose assignments according to updated knowledge of the dose–response curve at interim analysis. It is also essential that treatment allocation involves randomization—to mitigate various experimental biases and enable valid statistical inference at the end of the trial. In this work, we perform a comparison of several adaptive randomization procedures that can be used for implementing D-optimal designs for dose–response studies with time-to-event outcomes with small to moderate sample sizes. We consider single-stage, two-stage, and multi-stage adaptive designs. We also explore robustness of the designs to experimental (chronological and selection) biases. Simulation studies provide evidence that both the choice of an allocation design and a randomization procedure to implement the target allocation impact the quality of dose–response estimation, especially for small samples. For best performance, a multi-stage adaptive design with small cohort sizes should be implemented using a randomization procedure that closely attains the targeted D-optimal design at each stage. The results of the current work should help clinical investigators select an appropriate randomization procedure for their dose–response study.
      PubDate: 2018-07-19
      DOI: 10.1208/s12248-018-0242-5
      Issue No: Vol. 20, No. 5 (2018)
  • Effect of Inhalation Flow Rate on Mass-Based Plume Geometry of
           Commercially Available Suspension pMDIs
    • Authors: Daniel F. Moraga-Espinoza; Eli Eshaghian; Albert Shaver; Hugh D. C. Smyth
      Abstract: Although high-speed laser imaging is the current standard to characterize the plume angle of suspension-based pressurized metered dose inhalers (pMDIs), this method is limited by the inability to identify the drug content in a droplet and simulate inhalation flow. The Plume Induction Port Evaluator (PIPE) is a modified induction port for cascade impactors that allows for the calculation of the angle of a plume based on direct drug mass quantification rather than indirect droplet illumination under airflow conditions. The objective of this study was to investigate the use of the PIPE apparatus to evaluate the effect of airflow on the Mass Median Plume Angle (MMPA) of commercially available suspension-based pMDIs (Ventolin® HFA, ProAir® HFA, and Proventil® HFA). Deposition patterns within PIPE were log-normally distributed allowing for the calculation of the MMPA for the three suspension products. Mass-based plume angles were significantly smaller (narrower angle) when inhalation airflow was used compared to no flow conditions (reduction of MMPA was 8, 16, and 13% for Ventolin® HFA, ProAir® HFA, and Proventil® HFA, respectively). Additionally, new parameters for characterizing plume geometry were calculated (MMPA ex-actuator and plume orientation). Mass-based plume angles of the suspension-based pMDI formulations were highly reproducible and demonstrated the effect of inhalation flow rate. These results suggest that plume geometry tests should be evaluated under flow conditions which is not possible using current methodologies. Graphical ᅟ
      PubDate: 2018-07-12
      DOI: 10.1208/s12248-018-0241-6
      Issue No: Vol. 20, No. 5 (2018)
  • Virtual Thorough QT (TQT) Trial—Extrapolation of In Vitro Cardiac Safety
           Data to In Vivo Situation Using Multi-Scale Physiologically Based
    • Authors: Nikunjkumar Patel; Barbara Wisniowska; Sebastian Polak
      Abstract: QT interval prolongation typically assessed with dedicated clinical trials called thorough QT/QTc (TQT) studies is used as surrogate to identify the proarrhythmic risk of drugs albeit with criticism in terms of cost-effectiveness in establishing the actual risk of torsade de pointes (TdP). Quantitative systems toxicology and safety (QSTS) models have potential to quantitatively translate the in vitro cardiac safety data to clinical level including simulation of TQT trials. Virtual TQT simulations have been exemplified with use of two related drugs tolterodine and fesoterodine. The impact of bio-relevant concentration in plasma versus estimated heart tissue exposure on predictions was also assessed. Tolterodine and its therapeutically equipotent metabolite formed via CYP2D6 pathway, 5-HMT, inhibit multiple cardiac ion currents (IKr, INa, ICaL). The QSTS model was able to accurately simulate the QT prolongation at therapeutic and supra-therapeutic dose levels of tolterodine well within 95% confidence interval limits of observed data. The model was able to predict the QT prolongation difference between CYP2D6 extensive and poor metaboliser subject groups at both dose levels thus confirming the ability of the model to account for electrophysiologically active metabolite. The QSTS model was able to simulate the negligible QT prolongation observed with fesoterodine establishing that the 5-HMT does not prolong QT interval even though it is a blocker of hERG channel. With examples of TOL and FESO, we demonstrated the utility of the QSTS approaches to simulate virtual TQT trials, which in turn could complement and reduce the clinical studies or help optimise clinical trial designs.
      PubDate: 2018-07-11
      DOI: 10.1208/s12248-018-0244-3
      Issue No: Vol. 20, No. 5 (2018)
  • A Non-invasive Liquid Biopsy Screening of Urine-Derived Exosomes for
           miRNAs as Biomarkers in Endometrial Cancer Patients
    • Authors: Akhil Srivastava; Katherine Moxley; Rachel Ruskin; Danny Natarajan Dhanasekaran; Yan Daniel Zhao; Rajagopal Ramesh
      Abstract: Exosomes have great potential to serve as a source of diagnostic and prognostic biomarkers for endometrial cancer (EC). Urine-derived exosomes from patients with EC and patients with symptoms of EC, but without established EC, were used to evaluate a unique miRNA expression profile. Of the 84 miRNA studied, 57 were amplified in qPCR, suggesting the differential packaging of miRNA in exosomes. Further, hsa-miR-200c-3p was identified to be enriched the most. Various bioinformatics and in silico tools were used to evaluate the biological significance of hsa-miR-200c-3p in EC. We conclude that differential miRNA in exosomes can be utilized for discovery of biomarker signatures and EC diagnosis; hsa-miR-200c-3p is one such candidate. Urine-derived exosomes pave the way for the development of non-invasive biomarkers.
      PubDate: 2018-07-09
      DOI: 10.1208/s12248-018-0220-y
      Issue No: Vol. 20, No. 5 (2018)
  • Model-Based Residual Post-Processing for Residual Model Identification
    • Authors: Moustafa M. A. Ibrahim; Rikard Nordgren; Maria C. Kjellsson; Mats O. Karlsson
      Abstract: The purpose of this study was to investigate if model-based post-processing of common diagnostics can be used as a diagnostic tool to quantitatively identify model misspecifications and rectifying actions. The main investigated diagnostic is conditional weighted residuals (CWRES). We have selected to showcase this principle with residual unexplained variability (RUV) models, where the new diagnostic tool is used to scan extended RUV models and assess in a fast and robust way whether, and what, extensions are expected to provide a superior description of data. The extended RUV models evaluated were autocorrelated errors, dynamic transform both sides, inter-individual variability on RUV, power error model, t-distributed errors, and time-varying error magnitude. The agreement in improvement in goodness-of-fit between implementing these extended RUV models on the original model and implementing these extended RUV models on CWRES was evaluated in real and simulated data examples. Real data exercise was applied to three other diagnostics: conditional weighted residuals with interaction (CWRESI), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE). CWRES modeling typically predicted (i) the nature of model misspecifications, (ii) the magnitude of the expected improvement in fit in terms of difference in objective function value (ΔOFV), and (iii) the parameter estimates associated with the model extension. Alternative metrics (CWRESI, IWRES, and NPDE) also provided valuable information, but with a lower predictive performance of ΔOFV compared to CWRES. This method is a fast and easily automated diagnostic tool for RUV model development/evaluation process; it is already implemented in the software package PsN.
      PubDate: 2018-07-02
      DOI: 10.1208/s12248-018-0240-7
      Issue No: Vol. 20, No. 5 (2018)
  • Assessment of Three-Drug Combination Pharmacodynamic Interactions in
           Pancreatic Cancer Cells
    • Authors: Emilie A. G. Molins; William J. Jusko
      Abstract: The pharmacodynamic interactions among trifluoperazine (TFP), gemcitabine (GEM), and paclitaxel (PTX) were assessed in pancreatic cancer cells (PANC-1). The phenothiazine TFP was chosen for its potential activity on cancer stem cells, while GEM and PTX cause apoptosis. Effects of each drug alone and in various combinations on cell growth inhibition of PANC-1 cells were studied in vitro to determine the drug-specific parameters and assess the nature of drug interactions. Joint inhibition (JI) and competitive inhibition (CI) equations were applied with a ψ interaction term. TFP fully inhibited growth of cells (Imax = 1) with an IC50 = 9887 nM. Near-maximum inhibition was achieved for GEM (Imax = 0.825) and PTX (Imax= 0.844) with an IC50 = 17.4 nM for GEM and IC50 = 7.08 nM for PTX. Estimates of an interaction term ψ revealed that the combination of TFP-GEM was apparently synergistic; close to additivity, the combination TFP-PTX was antagonistic. The interaction of GEM-PTX was additive, and TFP-GEM-PTX was synergistic but close to additive. The combination of TFP IC60–GEM IC60–PTX IC60 seemed optimal in producing inhibition of PANC-1 cells with an inhibitory effect of 82.1–90.2%. The addition of ψ terms to traditional interaction equations allows assessment of the degree of perturbation of assumed mechanisms.
      PubDate: 2018-06-27
      DOI: 10.1208/s12248-018-0235-4
      Issue No: Vol. 20, No. 5 (2018)
  • Correction to: Deep Learning for Drug Design: an Artificial Intelligence
           Paradigm for Drug Discovery in the Big Data Era
    • Authors: Yankang Jing; Yuemin Bian; Ziheng Hu; Lirong Wang; Xiang-Qun Xie
      Abstract: The name of the corresponding author should be ‘Xiang-Qun Xie’, rather than ‘Xiang-Qun Sean Xie’.
      PubDate: 2018-06-25
      DOI: 10.1208/s12248-018-0243-4
      Issue No: Vol. 20, No. 4 (2018)
  • A Simple Approach for Comparing the In Vitro Dissolution Profiles of
           Highly Variable Drug Products: a Proposal
    • Authors: Marilyn N. Martinez; Xiongce Zhao
      Abstract: When in vitro dissolution profile variability prohibits the use of the F2 metric, there currently is no satisfactory alternative available. Published reports evaluating alternative approaches such as Multivariate Statistical Distance and use of a bootstrap F2 identify sources of bias that can limit the utility of these alternatives. Within veterinary medicine, an additional complication is the potential magnitude of interlot variability associated with dosage forms containing “natural” ingredients. In situations when both interlot and intralot variability need to be factored in the test and reference profile comparison, we designed a method that integrates such concepts as F2, USP S1 and S2 criteria and statistical tolerance limits. Unlike F2, this alternative approach integrates a statistical confidence into the determination through the use of tolerance limits about the reference product profile. Moreover, while differences in product variability, along with differences in mean profiles, will influence the comparability assessment, this method does not impose the need to confirm homogeneity of variances: there is not direct statistical comparison of test versus reference dissolution data. For more typical situations when interlot variability is not a concern, the F2 component can be omitted from the profile comparison. Lastly, by being a model-independent approach, we avoid the potential for introducing error into the comparability determination due either to model misspecification or problems associated with a lack of collinearity. This manuscript details this alternative approach and the results of performance characterization efforts to illustrate its behavior under a range of potential situations.
      PubDate: 2018-06-25
      DOI: 10.1208/s12248-018-0238-1
      Issue No: Vol. 20, No. 4 (2018)
  • Comparisons of Analysis Methods for Assessment of Pharmacodynamic
           Interactions Including Design Recommendations
    • Authors: Chunli Chen; Sebastian G. Wicha; Rikard Nordgren; Ulrika S. H. Simonsson
      Abstract: Quantitative evaluation of potential pharmacodynamic (PD) interactions is important in tuberculosis drug development in order to optimize Phase 2b drug selection and ultimately to define clinical combination regimens. In this work, we used simulations to (1) evaluate different analysis methods for detecting PD interactions between two hypothetical anti-tubercular drugs in in vitro time-kill experiments, and (2) provide design recommendations for evaluation of PD interactions. The model used for all simulations was the Multistate Tuberculosis Pharmacometric (MTP) model linked to the General Pharmacodynamic Interaction (GPDI) model. Simulated data were re-estimated using the MTP–GPDI model implemented in Bliss Independence or Loewe Additivity, or using a conventional model such as an Empirical Bliss Independence-based model or the Greco model based on Loewe Additivity. The GPDI model correctly characterized different PD interactions (antagonism, synergism, or asymmetric interaction), regardless of the underlying additivity criterion. The commonly used conventional models were not able to characterize asymmetric PD interactions, i.e., concentration-dependent synergism and antagonism. An optimized experimental design was developed that correctly identified interactions in ≥ 94% of the evaluated scenarios using the MTP–GPDI model approach. The MTP–GPDI model approach was proved to provide advantages to other conventional models for assessing PD interactions of anti-tubercular drugs and provides key information for selection of drug combinations for Phase 2b evaluation.
      PubDate: 2018-06-21
      DOI: 10.1208/s12248-018-0239-0
      Issue No: Vol. 20, No. 4 (2018)
  • Dashboards for Therapeutic Monoclonal Antibodies: Learning and Confirming
    • Authors: Diane R. Mould; Richard N. Upton; Jessica Wojciechowski; Becky L. Phan; Stacy Tse; Marla C. Dubinsky
      Abstract: Inflammatory diseases (ID) are incurable, progressive diseases. Literature evidence cites increasing incidence of these diseases worldwide. When treatments with chemical immunosuppressive agents fail, patients are often treated with monoclonal antibodies (MAbs). However, MAb failure rates are generally high, with approximately half the patients being discontinued within 4 years, necessitating switching to another MAb. One potential cause of treatment failure is subtherapeutic exposure. Several studies demonstrated associations between trough MAb concentrations and clinical response, supporting the notion that improving drug exposure may result in improved outcomes. MAbs exhibit complex and highly variable pharmacokinetics in ID patients with numerous factors affecting clearance. Bayesian-guided dosing with dashboard systems is a new tool being investigated in the treatment of ID to reduce variability in exposure. Simulations suggest dashboards will be effective at maintaining patients at target troughs. However, when patients are dosed using doses or intervals outside those listed in prescribing information, there is concern that patients may have drug exposures beyond or below the ranges found to be safe and efficacious. This manuscript reviews the rationale behind dashboard development, evaluations of expected performance, and a simulated assessment of MAb exposure with dashboard-based dosing versus dosing based on the prescribing information. We introduce the concept of pharmacologic equivalence—if patients are dosed based on individual pharmacokinetics, the resulting exposure is consistent with exposures achieved using labeled dosing. We further show that dashboard-based dosing results in observed exposures that are generally contained within the range of exposures achieved with labeled dosing.
      PubDate: 2018-06-14
      DOI: 10.1208/s12248-018-0237-2
      Issue No: Vol. 20, No. 4 (2018)
  • Correction to: Strategies of Drug Transporter Quantitation by LC-MS:
           Importance of Peptide Selection and Digestion Efficiency
    • Authors: Buyun Chen; Liling Liu; Hoangdung Ho; Yuan Chen; Ze Yang; Xiaorong Liang; Jian Payandeh; Brian Dean; Cornelis E. C. A. Hop; Yuzhong Deng
      Abstract: Liling Liu was not noted as the co-first author in the original article. Buyun Chen and Liling Liu contributed equally to the article.
      PubDate: 2018-06-06
      DOI: 10.1208/s12248-018-0236-3
      Issue No: Vol. 20, No. 4 (2018)
  • Application of the Stable Isotope Label Approach in Clinical
           Development—Supporting Dissolution Specifications for a Commercial
           Tablet Product with Tafenoquine, a Long Half-life Compound
    • Authors: Navin Goyal; Khadeeja Mohamed; Katie Rolfe; Satty Sahota; Terry Ernest; Stephan Duparc; Maxine Taylor; Linda Casillas; Gavin C. K. W. Koh
      Abstract: Bioavailability/bioequivalence studies supporting clinical drug development or commercial supply of drug formulations are often time, cost, and resource intensive. The drug’s pharmacokinetic (PK) variability, systemic half-life, and safety issues may pose additional challenges. The stable isotope label (SIL) approach provides a useful tool to significantly reduce the study size in clinical PK studies. Tafenoquine (TQ) is an 8-aminoquinoline under development for preventing Plasmodium vivax malaria relapse. This SIL study assessed the impact of differences in the in vitro dissolution profiles on in vivo exposure of TQ tablets. Fourteen healthy volunteers received a single dose of 300 mg TQ Intermediate Aged or 300 mg TQ Control formulations in this single-center, two-arm, randomized, open-label, parallel-group study. Endpoints included the geometric means ratio of the area under the concentration-time curve (AUC(0-t) and AUC(0-∞); primary endpoint) and maximum plasma concentration (Cmax) for Intermediate Aged versus Control TQ; correlation of PK parameters for venous versus peripheral (via microsample) blood samples; and safety and tolerability endpoints. Geometric mean ratios for PK parameters (AUC and Cmax) and their 90% confidence intervals fell well within standard bioequivalence limits (0.80–1.25). Only one mild adverse event (skin abrasion) was reported. In summary, this SIL methodology-based study demonstrates that the observed differences in the in vitro dissolution profiles between the Control and Intermediate Aged TQ tablets have no clinically relevant effect on systemic TQ exposure. The SIL approach was successfully implemented to enable the setting of a clinically relevant dissolution specification. Clinical trial: This study (GSK study number 201780) is registered at with identifier NCT02751294.
      PubDate: 2018-06-04
      DOI: 10.1208/s12248-018-0234-5
      Issue No: Vol. 20, No. 4 (2018)
  • Vaccine Adjuvant Incorporation Strategy Dictates Peptide Amphiphile
           Micelle Immunostimulatory Capacity
    • Authors: Rui Zhang; Jake S. Kramer; Josiah D. Smith; Brittany N. Allen; Caitlin N. Leeper; Xiaolei Li; Logan D. Morton; Fabio Gallazzi; Bret D. Ulery
      Abstract: Current vaccine research has shifted from traditional vaccines (i.e., whole-killed or live-attenuated) to subunit vaccines (i.e., protein, peptide, or DNA) as the latter is much safer due to delivering only the bioactive components necessary to produce a desirable immune response. Unfortunately, subunit vaccines are very weak immunogens requiring delivery vehicles and the addition of immunostimulatory molecules termed adjuvants to convey protective immunity. An interesting type of delivery vehicle is peptide amphiphile micelles (PAMs), unique biomaterials where the vaccine is part of the nanomaterial itself. Due to the modularity of PAMs, they can be readily modified to deliver both vaccine antigens and adjuvants within a singular construct. Through the co-delivery of a model antigenic epitope (Ovalbumin319–340—OVABT) and a known molecular adjuvant (e.g., 2,3-dipalmitoyl-S-glyceryl cysteine—Pam2C), greater insight into the mechanisms by which PAMs can exert immunostimulatory effects was gained. It was found that specific combinations of antigen and adjuvant can significantly alter vaccine immunogenicity both in vitro and in vivo. These results inform fundamental design rules that can be leveraged to fabricate optimal PAM-based vaccine formulations for future disease-specific applications. Graphical
      PubDate: 2018-06-01
      DOI: 10.1208/s12248-018-0233-6
      Issue No: Vol. 20, No. 4 (2018)
  • A Prediction Model of Tumor Progression and Survival in HER2-Positive
           Metastatic Gastric Cancer Patients Treated with Trastuzumab and
    • Authors: Dongwoo Chae; Chung Mo Nam; Joo Hoon Kim; Choong-Kun Lee; Seung-Seob Kim; Hyo Song Kim; Minkyu Jung; Jae Ho Cheong; Hyun Cheol Chung; Sun Young Rha; Kyungsoo Park
      Abstract: The effects of different patient factors and dose levels of chemotherapeutic agents on clinical outcomes in advanced gastric cancer are not as yet fully characterized. We aimed at developing an integrative model that incorporates dose and covariate information to predict tumor growth and patient survival in advanced gastric cancer patients treated with trastuzumab (T), 5-FU(F)/capecitabine (X) (F or X), and cisplatin (P). Sixty-nine patients (training dataset) were used for model building and a separate 86 patients (test dataset) for model validation. A fraction of tumor cells sensitive to each drug was incorporated as a model parameter, and T was assumed as cytostatic and X/F and P as cytotoxic. Cox proportional hazards analyses were performed on model parameters and patient covariates. The model well described the time course of observed tumor size changes, and revealed that the pretreatment tumor growth rate constant k g , which was formulated as a function of pretreatment disease duration and baseline tumor size, was positively correlated with baseline tumor size (p = 0.0084) and histologic grade (p = 0.034), and the efficacy of 5-FU with body weight (p < 2e−16) and that of cisplatin with histologic grade (p = 0.00013). Prior gastrectomy and Eastern Cooperative Oncology Group scores were significant prognostic factors for progression-free survival (PFS). For hazards analysis, a unit increase of k g was associated with a relative risk of 3.19 for PFS (p = 0.00055) and 4.45 for OS (p = 2e−04) in the test dataset, with a similar trend observed in the training dataset. Dose-response simulations showed that, for small baseline tumor size or low histologic grade, a maximum cytotoxic effect was attainable with a dose smaller than the current recommended dose.
      PubDate: 2018-05-29
      DOI: 10.1208/s12248-018-0223-8
      Issue No: Vol. 20, No. 4 (2018)
  • A General LC-MS/MS Method for Monitoring Potential β-Lactam Contamination
           in Drugs and Drug-Manufacturing Surfaces
    • Authors: Chen Qiu; Hongbin Zhu; Connie Ruzicka; David Keire; Hongping Ye
      Abstract: Penicillins and some non-penicillin β-lactams may cause potentially life-threatening allergic reactions. Thus, possible cross contamination of β-lactams in food or drugs can put people at risk. Therefore, when there is a reasonable possibility that a non-penicillin product could be contaminated by penicillin, the drug products are tested for penicillin contamination. Here, a sensitive and rapid method for simultaneous determination of multiple β-lactam antibiotics using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated. Mass spectral acquisition was performed on a Q-Exactive HF mass spectrometer in positive ion mode with parallel reaction monitoring (PRM). The method was validated for seven β-lactam antibiotics including one or two from each class and a synthetic intermediate. The quantification precision and accuracy at 200 ppb were in the range of ± 1.84 to ± 4.56 and − 5.20 to 3.44%, respectively. The limit of detection (LOD) was 0.2 ppb, and the limit of quantitation (LOQ) was 2 ppb with a linear dynamic range (LDR) of 2–2000 ppb for all eight β-lactams. From various drug products, the recoveries of eight β-lactams at 200 and 2 ppb ranged from 93.8 ± 3.2 to 112.1 ± 4.2% and 89.7 ± 4.6 to 110.6 ± 1.9%, respectively. The application of the method for detecting cross contamination of trace β-lactams (0.2 ppb) and for monitoring facility surface cleaning was also investigated. This sensitive and fast method was fit-for-purpose for detecting and quantifying trace amount of β-lactam contamination, monitoring cross contamination in manufacturing processes, and determining potency for regulatory purposes and for quality control.
      PubDate: 2018-05-15
      DOI: 10.1208/s12248-018-0224-7
      Issue No: Vol. 20, No. 4 (2018)
  • New Equilibrium Models of Drug-Receptor Interactions Derived from
           Target-Mediated Drug Disposition
    • Authors: Lambertus A. Peletier; Johan Gabrielsson
      Abstract: In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between-individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such.
      PubDate: 2018-05-14
      DOI: 10.1208/s12248-018-0221-x
      Issue No: Vol. 20, No. 4 (2018)
  • Rational Selection, Criticality Assessment, and Tiering of Quality
           Attributes and Test Methods for Analytical Similarity Evaluation of
    • Authors: Kristof Vandekerckhove; Andreas Seidl; Hiten Gutka; Manish Kumar; Gyöngyi Gratzl; David Keire; Todd Coffey; Henriette Kuehne
      Abstract: Leading regulatory agencies recommend biosimilar assessment to proceed in a stepwise fashion, starting with a detailed analytical comparison of the structural and functional properties of the proposed biosimilar and reference product. The degree of analytical similarity determines the degree of residual uncertainty that must be addressed through downstream in vivo studies. Substantive evidence of similarity from comprehensive analytical testing may justify a targeted clinical development plan, and thus enable a shorter path to licensing. The importance of a careful design of the analytical similarity study program therefore should not be underestimated. Designing a state-of-the-art analytical similarity study meeting current regulatory requirements in regions such as the USA and EU requires a methodical approach, consisting of specific steps that far precede the work on the actual analytical study protocol. This white paper discusses scientific and methodological considerations on the process of attribute and test method selection, criticality assessment, and subsequent assignment of analytical measures to US FDA’s three tiers of analytical similarity assessment. Case examples of selection of critical quality attributes and analytical methods for similarity exercises are provided to illustrate the practical implementation of the principles discussed.
      PubDate: 2018-05-10
      DOI: 10.1208/s12248-018-0230-9
      Issue No: Vol. 20, No. 4 (2018)
  • The Phenotypic Effects of Exosomes Secreted from Distinct Cellular
           Sources: a Comparative Study Based on miRNA Composition
    • Authors: Scott Ferguson; Sera Kim; Christine Lee; Michael Deci; Juliane Nguyen
      Abstract: Exosomes are nano-sized vesicles composed of lipids, proteins, and nucleic acids. Their molecular landscape is diverse, and exosomes derived from different cell types have distinct biological activities. Since exosomes are now being utilized as delivery vehicles for exogenous therapeutic cargoes, their intrinsic properties and biological effects must be understood. We performed miRNA profiling and found substantial differences in the miRNA landscape of prostate cancer (PC3) and human embryonic kidney (HEK) 293 exosomes with little correlation in abundance of common miRNAs (R2 = 0.16). Using a systems-level bioinformatics approach, the most abundant miRNAs in PC3 exosomes but not HEK exosomes were predicted to significantly modulate integrin signaling, with integrin-β3 loss inducing macrophage M2 polarization. PC3 but not HEK exosomes downregulated integrin-β3 expression levels by 70%. There was a dose-dependent polarization of RAW 264.7 macrophages toward an M2 phenotype when treated with PC3-derived exosomes but not HEK-derived exosomes. Conversely, HEK exosomes, widely utilized as delivery vehicles, were predicted to target cadherin signaling, with experimental validation showing a significant increase in the migratory potential of MCF7 breast cancer cells treated with HEK exosomes. Even widely utilized exosomes are unlikely to be inert, and their intrinsic activity ought to be assessed before therapeutic deployment.
      PubDate: 2018-04-30
      DOI: 10.1208/s12248-018-0227-4
      Issue No: Vol. 20, No. 4 (2018)
  • Integrative Pharmacology: Advancing Development of Effective
    • Authors: Mohammad Tabrizi; Daping Zhang; Vaishnavi Ganti; Glareh Azadi
      Abstract: With the recent advances in cancer immunotherapy, it is now evident that the antigen-specific activation of the patients’ immune responses can be utilized for achieving significant therapeutic benefits. Novel molecules have been developed and promising advances have been achieved in cancer therapy. The recent success of cancer immunotherapy clearly reflects the novelty of the approach and importance of this class of therapeutics. Due to the nature of immunotherapy, i.e., harnessing the patient’s immune system, it becomes critical to evaluate the important variables that can guide preclinical development, translational strategies, patient selection, and effective clinical dosing paradigms following single and combination therapies. To further boost the durability and efficacy profiles of IO (immuno-oncology) drugs following single agent therapy, novel combination therapies are being sought. Combination strategies have become critical for enhancing the anti-tumor immunity in broader cancer indications. Comprehensive methods are being developed to quantify the synergistic combination effect profiles at various development phases. Further evaluation of the signaling and pathway components can potentially establish a unique “signature” characteristic for specific combination therapies following modulation of various immunomodulatory pathways. In this article, critical topics related to preclinical, translational, and clinical development of IO agents are discussed.
      PubDate: 2018-04-27
      DOI: 10.1208/s12248-018-0229-2
      Issue No: Vol. 20, No. 4 (2018)
  • The BioGIT System: a Valuable In Vitro Tool to Assess the Impact of Dose
           and Formulation on Early Exposure to Low Solubility Drugs After Oral
    • Abstract: The purpose of this study was to evaluate the usefulness of the in vitro biorelevant gastrointestinal transfer (BioGIT) system in assessing the impact of dose and formulation on early exposure by comparing in vitro data with previously collected human plasma data of low solubility active pharmaceutical ingredients. Eight model active pharmaceutical ingredients were tested; Lu 35-138C (salt of weak base in a HP-beta-CD solution, three doses), fenofibrate (solid dispersion, tablet, two doses), AZD2207 EQ (salt of weak base, capsule, three doses), posaconazole (Noxafil® suspension, two doses), SB705498 (weak base, tablets vs. capsules), cyclosporine A (Sandimmun® vs. Sandimmun® Neoral), nifedipine (Adalat® capsule vs. Macorel® tablet), and itraconazole (Sporanox® capsule vs. Sporanox® solution). AUC0–0.75h values were calculated from the apparent concentration versus time data in the duodenal compartment of the BioGIT system. Differences in AUC0–0.75h values were evaluated versus differences in AUC0–1h and in AUC0–2h values calculated from previously collected plasma data in healthy adults. Ratios of mean AUC0–0.75h, mean AUC0–1h, and mean AUC0–2h values were estimated using the lowest dose or the formulation with the lower AUC0–0.75h value as denominator. The BioGIT system qualitatively identified the impact of dose and of formulation on early exposure in all cases. Log-transformed mean BioGIT AUC0–0.75h ratios correlated significantly with log-transformed mean plasma AUC0–1h ratios. Based on this correlation, BioGIT AUC0–0.75h ratios between 0.3 and 10 directly reflect corresponding plasma AUC0–1h ratios. BioGIT system is a valuable tool for the assessment of the impact of dose and formulation on early exposure to low solubility drugs.
      PubDate: 2018-05-24
      DOI: 10.1208/s12248-018-0231-8
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