Subjects -> BIOLOGY (Total: 3447 journals)
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    - BIOENGINEERING (143 journals)
    - BIOLOGY (1643 journals)
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    - BIOTECHNOLOGY (269 journals)
    - BOTANY (250 journals)
    - CYTOLOGY AND HISTOLOGY (32 journals)
    - ENTOMOLOGY (75 journals)
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    - MICROBIOLOGY (286 journals)
    - MICROSCOPY (12 journals)
    - ORNITHOLOGY (29 journals)
    - PHYSIOLOGY (73 journals)
    - ZOOLOGY (147 journals)

BIOLOGY (1643 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 30)
Achievements in the Life Sciences     Open Access   (Followers: 8)
ACS Pharmacology & Translational Science     Hybrid Journal   (Followers: 2)
ACS Synthetic Biology     Hybrid Journal   (Followers: 31)
Acta Biologica Colombiana     Open Access   (Followers: 7)
Acta Biologica Hungarica     Full-text available via subscription   (Followers: 5)
Acta Biologica Sibirica     Open Access   (Followers: 2)
Acta Biologica Turcica     Open Access   (Followers: 1)
Acta Biologica Venezuelica     Open Access  
Acta Biomaterialia     Hybrid Journal   (Followers: 30)
Acta Biotheoretica     Hybrid Journal   (Followers: 3)
Acta Chiropterologica     Full-text available via subscription   (Followers: 6)
acta ethologica     Hybrid Journal   (Followers: 4)
Acta Fytotechnica et Zootechnica     Open Access   (Followers: 1)
Acta Limnologica Brasiliensia     Open Access   (Followers: 4)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Musei Silesiae, Scientiae Naturales     Open Access   (Followers: 2)
Acta Neurobiologiae Experimentalis     Open Access  
Acta Parasitologica     Hybrid Journal   (Followers: 12)
Acta Scientiae Biological Research     Open Access   (Followers: 1)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis     Open Access   (Followers: 1)
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Biosystems     Hybrid Journal  
Advanced Health Care Technologies     Open Access   (Followers: 10)
Advanced Journal of Graduate Research     Open Access   (Followers: 1)
Advanced Nonlinear Studies     Hybrid Journal  
Advanced Quantum Technologies     Hybrid Journal  
Advanced Studies in Biology     Open Access   (Followers: 1)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Bioinformatics     Open Access   (Followers: 20)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biology     Open Access   (Followers: 12)
Advances in Cell Biology/ Medical Journal of Cell Biology     Open Access   (Followers: 30)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 14)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 19)
Advances in Enzyme Research     Open Access   (Followers: 11)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 9)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in High Energy Physics     Open Access   (Followers: 22)
Advances in Human Biology     Open Access   (Followers: 5)
Advances in Life Science and Technology     Open Access   (Followers: 20)
Advances in Life Sciences     Open Access   (Followers: 7)
Advances in Marine Biology     Full-text available via subscription   (Followers: 21)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 26)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 7)
Advances in Structural Biology     Full-text available via subscription   (Followers: 6)
Advances in Tropical Biodiversity and Environmental Sciences     Open Access   (Followers: 3)
Advances in Virus Research     Full-text available via subscription   (Followers: 6)
Adversity and Resilience Science : Journal of Research and Practice     Hybrid Journal   (Followers: 1)
African Journal of Range & Forage Science     Hybrid Journal   (Followers: 12)
AFRREV STECH : An International Journal of Science and Technology     Open Access   (Followers: 3)
Ageing Research Reviews     Hybrid Journal   (Followers: 12)
Aging Cell     Open Access   (Followers: 26)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
AJP Cell Physiology     Hybrid Journal   (Followers: 18)
AJP Endocrinology and Metabolism     Hybrid Journal   (Followers: 25)
AJP Lung Cellular and Molecular Physiology     Hybrid Journal   (Followers: 3)
Al-Kauniyah : Jurnal Biologi     Open Access  
Alasbimn Journal     Open Access   (Followers: 2)
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: 9)
American Journal of Bioethics     Hybrid Journal   (Followers: 16)
American Journal of Human Biology     Hybrid Journal   (Followers: 18)
American Journal of Medical and Biological Research     Open Access   (Followers: 10)
American Journal of Plant Sciences     Open Access   (Followers: 21)
American Journal of Primatology     Hybrid Journal   (Followers: 16)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 81)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anadol University Journal of Science and Technology B : Theoritical Sciences     Open Access  
Anadolu University Journal of Science and Technology : C Life Sciences and Biotechnology     Open Access   (Followers: 2)
Anaerobe     Hybrid Journal   (Followers: 4)
Anales de Biología     Open Access   (Followers: 2)
Analytical Methods     Full-text available via subscription   (Followers: 13)
Anatomical Science International     Hybrid Journal   (Followers: 3)
Animal Cells and Systems     Hybrid Journal   (Followers: 5)
Animal Models and Experimental Medicine     Open Access  
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 Universitatis Mariae Curie-Sklodowska, sectio C – Biologia     Open Access   (Followers: 1)
Annals of Applied Biology     Hybrid Journal   (Followers: 8)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 19)
Annals of Human Biology     Hybrid Journal   (Followers: 6)
Annals of Science and Technology     Open Access  
Annual Research & Review in Biology     Open Access   (Followers: 2)
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 15)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 26)
Annual Review of Cancer Biology     Full-text available via subscription   (Followers: 4)
Annual Review of Cell and Developmental Biology     Full-text available via subscription   (Followers: 42)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 15)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 27)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 13)
Anthropological Review     Open Access   (Followers: 24)
Antibiotics     Open Access   (Followers: 9)
Antioxidants     Open Access   (Followers: 5)
Antioxidants & Redox Signaling     Hybrid Journal   (Followers: 9)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apidologie     Hybrid Journal   (Followers: 5)
Apmis     Hybrid Journal   (Followers: 2)
APOPTOSIS     Hybrid Journal   (Followers: 9)
Applied Biology     Open Access   (Followers: 2)
Applied Bionics and Biomechanics     Open Access   (Followers: 7)
Applied Vegetation Science     Full-text available via subscription   (Followers: 10)
Aquaculture Environment Interactions     Open Access   (Followers: 4)
Aquaculture International     Hybrid Journal   (Followers: 26)
Aquaculture Reports     Open Access   (Followers: 3)
Aquaculture, Aquarium, Conservation & Legislation - International Journal of the Bioflux Society     Open Access   (Followers: 7)
Aquatic Biology     Open Access   (Followers: 8)
Aquatic Ecology     Hybrid Journal   (Followers: 38)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 16)
Aquatic Science and Technology     Open Access   (Followers: 4)
Aquatic Toxicology     Hybrid Journal   (Followers: 24)
Archaea     Open Access   (Followers: 4)
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: 10)
Archives of Natural History     Hybrid Journal   (Followers: 8)
Archives of Oral Biology     Hybrid Journal   (Followers: 3)
Archives of Virology     Hybrid Journal   (Followers: 5)
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2)
Arid Ecosystems     Hybrid Journal   (Followers: 3)
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)
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Journal of Biodiversity     Open Access   (Followers: 5)
Asian Journal of Biological Sciences     Open Access   (Followers: 3)
Asian Journal of Biology     Open Access   (Followers: 2)
Asian Journal of Biotechnology and Bioresource Technology     Open Access   (Followers: 1)
Asian Journal of Cell Biology     Open Access   (Followers: 6)
Asian Journal of Developmental Biology     Open Access   (Followers: 3)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 5)
Asian Journal of Nematology     Open Access   (Followers: 4)
Asian Journal of Poultry Science     Open Access   (Followers: 5)
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: 8)
Autophagy     Hybrid Journal   (Followers: 4)
Avian Biology Research     Full-text available via subscription   (Followers: 6)
Avian Conservation and Ecology     Open Access   (Followers: 15)
Bacterial Empire     Open Access   (Followers: 1)
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  
Bio-Lectura     Open Access  
BIO-SITE : Biologi dan Sains Terapan     Open Access   (Followers: 1)
Bioanalytical Reviews     Hybrid Journal   (Followers: 2)
Biocatalysis and Biotransformation     Hybrid Journal   (Followers: 6)
BioCentury Innovations     Full-text available via subscription   (Followers: 2)
Biochemistry and Cell Biology     Hybrid Journal   (Followers: 17)
Biochimie     Hybrid Journal   (Followers: 6)
BioControl     Hybrid Journal   (Followers: 6)
Biocontrol Science and Technology     Hybrid Journal   (Followers: 8)
Biodemography and Social Biology     Hybrid Journal  
BIODIK : Jurnal Ilmiah Pendidikan Biologi     Open Access   (Followers: 1)
BioDiscovery     Open Access   (Followers: 2)
Biodiversidade e Conservação Marinha : Revista CEPSUL     Open Access  
Biodiversitas : Journal of Biological Diversity     Open Access  
Biodiversity Data Journal     Open Access   (Followers: 4)
Biodiversity Informatics     Open Access   (Followers: 1)
Biodiversity Information Science and Standards     Open Access   (Followers: 2)
Biodiversity: Research and Conservation     Open Access   (Followers: 27)
Bioedukasi : Jurnal Pendidikan Biologi FKIP UM Metro     Open Access  
Bioeksperimen : Jurnal Penelitian Biologi     Open Access  
Bioelectrochemistry     Hybrid Journal   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 2)
Bioenergy Research     Hybrid Journal   (Followers: 4)
Bioengineering and Bioscience     Open Access   (Followers: 3)
BioEssays     Hybrid Journal   (Followers: 11)
Bioethics     Hybrid Journal   (Followers: 18)
BioéthiqueOnline     Open Access  
Biofabrication     Hybrid Journal   (Followers: 5)
Biofilms     Full-text available via subscription   (Followers: 2)
Biogeosciences (BG)     Open Access   (Followers: 12)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 3)

        1 2 3 4 5 6 7 8 | Last

Similar Journals
Journal Cover
AAPS Journal
Journal Prestige (SJR): 1.118
Citation Impact (citeScore): 4
Number of Followers: 30  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Online) 1550-7416
Published by Springer-Verlag Homepage  [2625 journals]
  • Structure-Based Design and Discovery of a Long-Acting Cocaine Hydrolase
           Mutant with Improved Binding Affinity to Neonatal Fc Receptor for
           Treatment of Cocaine Abuse
    • Abstract: Abstract Despite decades of efforts to develop a pharmacotherapy for cocaine abuse treatment, there is still no FDA-approved treatment of diseases associated with this commonly abused drug. Our previously designed highly efficient cocaine hydrolases (CocHs) and the corresponding Fc-fusion proteins (e.g., CocH3-Fc) are recognized as potentially promising therapeutic enzyme candidates for cocaine abuse treatment, but all with limited biological half-lives. In order to prolong the biological half-life and, thus, decrease the required frequency of the enzyme administration for cocaine abuse treatment, we have modeled the Fc-fusion CocH binding with neonatal Fc receptor (FcRn) in the present study. This approach led to the design and testing of CocH3-Fc(M6), a CocH3-Fc mutant with nearly 100-fold increased binding affinity: from Kd = ~ 4 μM to Kd = 43 nM. As a result, CocH3-Fc(M6) indeed revealed a markedly prolonged biological half-life (t1/2 = 206 ± 7 h or ~ 9 days) in rats, longer than other known Fc-fusion protein drugs such as abatacept and alefacept (for other therapeutic purposes) in the same species (rats). It has been demonstrated that a single dose of 3 mg/kg CocH3-Fc(M6) effectively blocked 20 mg/kg cocaine-induced hyperactivity on day 18 after CocH3-Fc(M6) administration. This is the first attempt to rationally design long-acting Fc-fusion enzyme mutant based on combined computational modeling and experimental measurement of the Fc-fusion CocH binding with FcRn. The similar structure-based design strategy may be used to prolong the biological half-lives of other Fc-fusion protein drugs.
      PubDate: 2020-03-18
       
  • Optimal Sampling Strategies for Irinotecan (CPT-11) and its Active
           Metabolite (SN-38) in Cancer Patients
    • Abstract: Abstract Irinotecan (CPT-11) is an anticancer agent widely used in the treatment of a variety of adult solid tumors. The objective of this study was to develop an optimal sampling strategy model that accurately estimates pharmacokinetic parameters of CPT-11 and its active metabolite, SN-38. This study included 221 patients with advanced solid tumors or lymphoma receiving CPT-11 single or combination therapy with 5-fluorouracil (5-FU)/leucovorin (LV) (FOLFIRI) plus bevacizumab from 4 separate clinical trials. Population pharmacokinetic analysis of CPT-11 and SN-38 was performed by non-linear mixed effects modeling. The optimal sampling strategy model was developed using D-optimality with expected distribution approach. The pharmacokinetic profiles of CPT-11 and SN-38 were best described by a 3- and 2-compartment model, respectively, with first-order elimination. Body surface area and co-administration with 5-FU/LV plus bevacizumab were significant covariates (p < 0.01) for volumes of the central compartment of CPT-11 and SN-38, and clearance of CPT-11. Pre-treatment total bilirubin and co-administration with 5-FU/LV and bevacizumab were significant covariates (p < 0.01) for clearance of SN-38. Accurate and precise predictive performance (r2 > 0.99, -2 < bias (%ME) < 0, precision (% RMSE) < 12) of both CPT-11 and SN-38 was achieved using: (i) 6 fixed sampling times collected at 1.5, 3.5, 4, 5.75, 22, 23.5 hours post-infusion; or (ii) 1 fixed time and 2 sampling windows collected at 1.5, [3-5.75], [22-23.5] hours post-infusion. The present study demonstrates that an optimal sampling design with three blood samples achieves accurate and precise pharmacokinetic parameter estimates for both CPT-11 and SN-38.
      PubDate: 2020-03-17
       
  • Applying Beta Distribution in Analyzing Bounded Outcome Score Data
    • Abstract: Abstract Disease status is often measured with bounded outcome scores (BOS) which report a discrete set of values on a finite range. The distribution of such data is often non-standard, such as J- or U-shaped, for which standard analysis methods assuming normal distribution become inappropriate. Most BOS analysis methods aim to either predict the data within its natural range or accommodate data skewness, but not both. In addition, a frequent modeling objective is to predict clinical response of treatment using derived disease endpoints, defined as meeting certain criteria of improvement from baseline in disease status. This objective has not yet been addressed in existing BOS data analyses. This manuscript compares a recently proposed beta distribution–based approach with the standard continuous analysis approach, using an established mechanism-based longitudinal exposure-response model to analyze data from two phase 3 clinical studies in psoriatic patients. The beta distribution–based approach is shown to be superior in describing the BOS data and in predicting the derived endpoints, along with predicting the response time course of a highly sensitive subpopulation.
      PubDate: 2020-03-17
       
  • Clinical Immunogenicity Risk Assessment Strategy for a Low Risk Monoclonal
           Antibody
    • Abstract: Abstract This article provides a theoretical case-study risk assessment report for a low-risk monoclonal antibody (mAb) therapeutic. In terms of risk, there are considerations around risks to safety, but also risks regarding effects on pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Much of the discussion in this document is around the risk of immunogenicity incidence. A higher incidence of immunogenicity would necessitate a detailed review of the PK, efficacy and safety in anti-drug antibody (ADA) positive and ADA negative subjects, in order to evaluate potential effects. The publication is intended to provide a framework of some the current thought processes around assessing immunogenicity risk and for building strategies to mitigate those risks. For this example, we have created a hypothetical antibody, ABC-123, targeting a membrane protein on antigen presenting cells, for the treatment of rheumatoid arthritis (RA). This hypothetical antibody therapeutic is provided as an example for the purposes of risk assessment for a low risk molecule, although any application of similar approach would be case by case.
      PubDate: 2020-03-17
       
  • Correction to: Development and Utility of an ELISA Method for Sensitive
           and Specific Detection of IgE Antidrug Antibodies
    • Abstract: During the production process, the author order of Zhandong Don Zhong and Lynn L. Jiang were inadvertently placed. Lynn L. Jiang is the first author of this manuscript; Zhandong Don Zhong is the last author.
      PubDate: 2020-03-16
       
  • Machine Learning Analysis of Individual Tumor Lesions in Four Metastatic
           Colorectal Cancer Clinical Studies: Linking Tumor Heterogeneity to Overall
           Survival
    • Abstract: Abstract Total tumor size (TS) metrics used in TS models in oncology do not consider tumor heterogeneity, which could help to better predict drug efficacy. We analyzed individual target lesions (iTLs) of patients with metastatic colorectal carcinoma (mCRC) to determine differences in TS dynamics by using the ClassIfication Clustering of Individual Lesions (CICIL) methodology. Results from subgroup analyses comparing genetic mutations and TS metrics were assessed and applied to survival analyses. Data from four mCRC clinical studies were analyzed (1781 patients, 6369 iTLs). CICIL was used to assess differences in lesion TS dynamics within a tissue (intra-class) or across different tissues (inter-class). First, lesions were automatically classified based on their location. Cross-correlation coefficients (CCs) determined if each pair of lesions followed similar or opposite dynamics. Finally, CCs were grouped by using the K-means clustering method. Heterogeneity in tumor dynamics was lower in the intra-class analysis than in the inter-class analysis for patients receiving cetuximab. More tumor heterogeneity was found in KRAS mutated patients compared to KRAS wild-type (KRASwt) patients and when using sum of longest diameters versus sum of products of diameters. Tumor heterogeneity quantified as the median patient’s CC was found to be a predictor of overall survival (OS) (HR = 1.44, 95% CI 1.08–1.92), especially in KRASwt patients. Intra- and inter-tumor tissue heterogeneities were assessed with CICIL. Derived metrics of heterogeneity were found to be a predictor of OS time. Considering differences between lesions’ TS dynamics could improve oncology models in favor of a better prediction of OS.
      PubDate: 2020-03-16
       
  • Development of a Cell-Based Assay for the Detection of Neutralizing
           Antibodies to PF-06730512 Using Homogenous Time-Resolved Fluorescence
    • Abstract: Abstract The administration of biotherapeutics has the potential to induce potent immune responses. Among these responses, the production of anti-drug antibodies (ADA), including a subset of ADA referred to as neutralizing antibodies (NAb), is of heightened concern. Aside from their capacity to alter the pharmacological profile of a given biotherapeutic, NAb can also pose significant safety risks, especially in instances where an endogenous counterpart to the drug exists. As such, the inclusion of an assay to detect NAb in clinical samples is critical to the effectiveness of a tiered approach to immunogenicity assessment. PF-06730512 is a biotherapeutic protein being developed for the treatment of primary Focal Segmental Glomerulosclerosis (FSGS). To support the immunogenicity assessment of PF-06730512, a cell-based assay was developed for the detection of NAb in FSGS serum samples. Herein, we describe the development of the assay with a focus on the challenges faced, including drug and blood collection tube interferences in NAb detection. The outcome of our efforts was a robust assay capable of detecting 1 μg/mL of a NAb positive control in the presence of clinically relevant drug concentrations up to 30 μg/mL.
      PubDate: 2020-03-12
       
  • Investigation on the Effect of Capillary Microsampling on Hematologic and
           Toxicokinetic Evaluation in Regulatory Safety Studies in Mice
    • Abstract: Abstract Microsampling techniques enable the minimization of blood collection volume from animals and subsequent handling of the blood samples or their derived plasma or serum samples. This offers advantages over conventional large-volume sampling, such as eliminating the need for satellite animals and improving animal welfare aspects, and providing the opportunity for additional assessments in small animals where blood volume constraints limit endpoints. This study evaluated the feasibility of implementation of capillary microsampling (CMS) in a single-dose study in mice with the ultimate goal of enabling its use in toxicology studies. The focus was on the impact of microsampling on toxicokinetic assessment and on the subsequent hematology assessment in the same animal. A seventy (70)-μL blood collection via CMS from the tail vein had a minimal effect on the hematology parameters of mice (strain C57BL/6) in samples taken within 24 h of blood collection. TK parameters were similar in plasma samples collected via CMS and cardiac puncture sampling. A bioanalytical assay was developed which enabled the quantification of concentration of both the parent drug and a metabolite using only 5-μL plasma sample per analysis. Incurred sample reanalysis (ISR), unexpected event investigation, and re-assay were successfully performed on the limited samples (≤ 20 μL) collected from CMS. The results of this study confirmed the feasibility of implementing CMS in regulated mouse toxicity studies and demonstrated that it is possible to eliminate or reduce satellite animals.
      PubDate: 2020-03-09
       
  • Co-administration of Paediatric Medicines with Food and Drinks in the
           Context of Their Physicochemical Properties—a Global Perspective on
           Practices and Recommendations
    • Abstract: Abstract Medicine co-administration with food or drink vehicles is a common administration practice in paediatrics. The aims of this review were (i) to describe the current recommended strategies for co-administration of paediatric medicines with food and drinks (vehicles); (ii) to compare current administration recommendations from different countries; and (iii) to obtain a global perspective on the rationale behind the choice of recommended vehicle, in the context of the physicochemical properties of the drug and formulation. This study used a defined search strategy on the practices of paediatric medicine co-administration with vehicles, recommended in a commonly used paediatric and neonatal handbook, in addition to the information previously gathered from UK formularies. Logistic regression analysis was performed to further understand the biopharmaceutical basis of the choice of recommended vehicle for medicine co-administration. Differences were identified in the type of vehicles globally recommended for medicine co-administration. Ultimately, a statistical model was developed which provided an understanding on which vehicle is recommended for use with drugs/formulations, with basis on their biopharmaceutical properties. Overall, this review highlights the areas where further information is needed to support standardised procedures and guide the recommendation of age-appropriate and acceptable vehicles for use in the co-administration of paediatric medicines. Unified requirements are needed for harmonisation of the practice of medicine co-administration with vehicles. In vitro and/or in silico tools should be developed to evaluate the potential clinical outcomes of this practice during paediatric drug development.
      PubDate: 2020-03-04
       
  • A Microfluidic Perfusion Platform for In Vitro Analysis of Drug
           Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships
    • Abstract: Abstract Static in vitro cell culture studies cannot capture the dynamic concentration profiles of drugs, nutrients, and other factors that cells experience in physiological systems. This limits the confidence in the translational relevance of in vitro experiments and increases the reliance on empirical testing of exposure-response relationships and dose optimization in animal models during preclinical drug development, introducing additional challenges owing to species-specific differences in drug pharmacokinetics (PK) and pharmacodynamics (PD). Here, we describe the development of a microfluidic cell culture device that enables perfusion of cells under 2D or 3D culture conditions with temporally programmable concentration profiles. Proof-of-concept studies using doxorubicin and gemcitabine demonstrated the ability of the microfluidic PK-PD device to examine dose- and time-dependent effects of doxorubicin as well as schedule-dependent effects of doxorubicin and gemcitabine combination therapy on cell viability using both step-wise drug concentration profiles and species-specific (i.e., mouse, human) drug PK profiles. The results demonstrate the importance of including physiologically relevant dynamic drug exposure profiles during in vitro drug testing to more accurately mimic in vivo drug effects, thereby improving translatability across nonclinical studies and reducing the reliance on animal models during drug development.
      PubDate: 2020-03-02
       
  • Systematic Review of Device Parameters and Design of Studies Bridging
           Biologic-Device Combination Products Using Prefilled Syringes and
           Autoinjectors
    • Abstract: Abstract Biologic-device combination products using prefilled syringes (PFSs) and autoinjectors (AIs) are popular for biological products administered subcutaneously. Pharmacokinetic (PK) comparability studies commonly provide the scientific data to support introduction of AI presentations via bridging with PFS. A survey of biological products approved by FDA’s Center for Drug Evaluation and Research identified 17 biologics license applications (BLAs) with both PFS and AI presentations for subcutaneous (SC) administration, including 16 approved on February 1, 2018, and one with AI presentation under review. A systematic review on the device parameters and the PK comparability studies bridging the two presentations was conducted. Subsequently, whether device parameters or the PK study design may have influenced the PK comparability study results was evaluated. The reported device parameters for AI and PFS are generally consistent across BLAs, whereas the approach to assess PK comparability varied, including the study design. Most PK comparability studies met bioequivalence (BE) criteria. Upon inspection of the studies that did not meet BE criteria, injection depth of AI and the injection site for either AI or PFS were identified as potential influencing factors to the outcome of PK comparability study. This study represents an initial attempt to identify the potential influencing factors on device bridging, including the characteristics of the device and the clinical pharmacology study. These findings may inform the combination product development strategy, specifically design considerations for device and PK comparability studies.
      PubDate: 2020-02-27
       
  • Physiologically Based Pharmacokinetic Modeling and Tissue Distribution
           Characteristics of SHetA2 in Tumor-Bearing Mice
    • Abstract: Abstract The orally available novel small molecule SHetA2 is the lead sulfur-containing heteroarotinoid that selectively inhibits cancer cells over normal cells, and is currently under clinical development for anticancer treatment and cancer prevention. The objective of this study was to assess and characterize the tissue distribution of SHetA2 in tumor-bearing mice by developing a physiologically based pharmacokinetic (PBPK) model. An orthotopic SKOV3 ovarian cancer xenograft mouse model was used to most accurately mimic the ovarian cancer tumor microenvironment in the peritoneal cavity. SHetA2 concentrations in plasma and 14 different tissues were measured at various time points after a single intravenous dose of 10 mg/kg and oral dose of 60 mg/kg, and these data were used to develop a whole-body PBPK model. SHetA2 exhibited a multi-exponential plasma concentration decline with an elimination half-life of 4.5 h. Rapid and extensive tissue distribution, which was best described by a perfusion rate–limited model, was observed with the tissue-to-plasma partition coefficients (kp = 1.4–21.2). The PBPK modeling estimated the systemic clearance (76.4 mL/h) from circulation as a main elimination pathway of SHetA2. It also indicated that the amount absorbed into intestine was the major determining factor for the oral bioavailability (22.3%), while the first-pass loss from liver and intestine contributed minimally (< 1%). Our results provide an insight into SHetA2 tissue distribution characteristics. The developed PBPK model can be used to predict the drug exposure at tumors or local sites of action for different dosing regimens and scaled up to humans to correlate with efficacy.
      PubDate: 2020-02-21
       
  • Bayesian Individual Dynamic Predictions with Uncertainty of Longitudinal
           Biomarkers and Risks of Survival Events in a Joint Modelling Framework: a
           Comparison Between Stan, Monolix, and NONMEM
    • Abstract: Abstract Given a joint model and its parameters, Bayesian individual dynamic prediction (IDP) of biomarkers and risk of event can be performed for new patients at different landmark times using observed biomarker values. The aim of the present study was to compare IDP, with uncertainty, using Stan 2.18, Monolix 2018R2 and NONMEM 7.4. Simulations of biomarker and survival were performed using a nonlinear joint model of prostate-specific antigen (PSA) kinetics and survival in metastatic prostate cancer. Several scenarios were evaluated, according to the strength of the association between PSA and survival. For various landmark times, a posteriori distribution of PSA kinetic individual parameters was estimated, given individual observations, with each software. Samples of individual parameters were drawn from the posterior distribution. Bias and imprecision of individual parameters as well as coverage of 95% credibility interval for PSA and risk of death were evaluated. All software performed equally well with small biases on individual parameters. Imprecision on individual parameters was comparable across software and showed marked improvements with increasing landmark time. In terms of coverage, results were also comparable and all software were able to well predict PSA kinetics and survival. As for computing time, Stan was faster than Monolix and NONMEM to obtain individual parameters. Stan 2.18, Monolix 2018R2 and NONMEM 7.4 are able to characterize IDP of biomarkers and risk of event in a nonlinear joint modelling framework with correct uncertainty and hence could be used in the context of individualized medicine.
      PubDate: 2020-02-19
       
  • Biopharmaceutical Understanding of Excipient Variability on Drug Apparent
           Solubility Based on Drug Physicochemical Properties: Case
           Study—Hypromellose (HPMC)
    • Abstract: Abstract Identification of the biopharmaceutical risks of excipients and excipient variability on oral drug performance can be beneficial for the development of robust oral drug formulations. The current study investigated the impact of Hypromellose (HPMC) presence and varying viscosity type, when used as a binder in immediate release formulations, on the apparent solubility of drugs with wide range of physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility). The role of physiological conditions on the impact of excipients on drug apparent solubility was assessed with the use of pharmacopoeia (compendial) and biorelevant media. Presence of HPMC affected drug solubility according to the physicochemical properties of studied compounds. The possible combined effects of polymer adsorption (drug shielding effect) or the formation of a polymeric viscous layer around drug particles may have retarded drug dissolution leading to reduced apparent solubility of highly soluble and/or highly ionized compounds and were pronounced mainly at early time points. Increase in the apparent solubility of poorly soluble low ionized drugs containing a neutral amine group was observed which may relate to enhanced drug solubilization or reduced drug precipitation. The use of multivariate data analysis confirmed the importance of drug physicochemical properties on the impact of excipients on drug apparent solubility and revealed that changes in HPMC material properties or amount may not be critical for oral drug performance when HPMC is used as a binder. The construction of a roadmap combining drug, excipient, and medium characteristics allowed the identification of the cases where HPMC presence may present risks in oral drug performance and bioavailability.
      PubDate: 2020-02-18
       
  • Development of an Aerosol Dose Collection Apparatus for In Vitro
           Dissolution Measurements of Orally Inhaled Drug Products
    • Abstract: Abstract The aim of the study was to develop a robust and standardized in vitro dissolution methodology for orally inhaled drug products (OIDPs). An aerosol dose collection (ADC) system was designed to uniformly deposit the whole impactor stage mass (ISM) over a large filter area for dissolution testing. All dissolution tests were performed under sink conditions in a sodium phosphate buffered saline solution containing 0.2%w/w sodium dodecyl sulphate. An adapted USP Apparatus V, Paddle over Disk (POD), was used throughout the study. The dissolution characteristics of the ISM dose of a commercial metered-dose inhaler (MDI) and a range of dry powder inhaler (DPI) formulations containing inhaled corticosteroids were tested. The uniform distribution of the validated ISM dose considerably reduced drug loading effects on the dissolution profiles for both MDI and DPI formulations. The improvement in the robustness and discriminatory capability of the technique enabled characterization of dissolution rate differences between inhaler platforms and between different DPI product strengths containing fluticasone propionate. A good correlation between in vivo mean absorption time and in vitro dissolution half-life was found for a range of the inhaled corticosteroids. The ADC system and the reproducible in vitro POD dissolution measurements provided a quantitative-based approach for measuring the relationship between the influence of device and the dispersion characteristics on the aerosol dissolution of low solubility compounds. The in vitro dissolution method could potentially be applied as a dissolution methodology for compendial, quality control release testing, and during development of both branded orally inhaled drug products and their generic counterparts.
      PubDate: 2020-02-13
       
  • Model Averaging in Viral Dynamic Models
    • Abstract: Abstract The paucity of experimental data makes both inference and prediction particularly challenging in viral dynamic models. In the presence of several candidate models, a common strategy is model selection (MS), in which models are fitted to the data but only results obtained with the “best model” are presented. However, this approach ignores model uncertainty, which may lead to inaccurate predictions. When several models provide a good fit to the data, another approach is model averaging (MA) that weights the predictions of each model according to its consistency to the data. Here, we evaluated by simulations in a nonlinear mixed-effect model framework the performances of MS and MA in two realistic cases of acute viral infection, i.e., (1) inference in the presence of poorly identifiable parameters, namely, initial viral inoculum and eclipse phase duration, (2) uncertainty on the mechanisms of action of the immune response. MS was associated in some scenarios with a large rate of false selection. This led to a coverage rate lower than the nominal coverage rate of 0.95 in the majority of cases and below 0.50 in some scenarios. In contrast, MA provided better estimation of parameter uncertainty, with coverage rates ranging from 0.72 to 0.98 and mostly comprised within the nominal coverage rate. Finally, MA provided similar predictions than those obtained with MS. In conclusion, parameter estimates obtained with MS should be taken with caution, especially when several models well describe the data. In this situation, MA has better performances and could be performed to account for model uncertainty.
      PubDate: 2020-02-13
       
  • Biopharmaceutical Understanding of Excipient Variability on Drug Apparent
           Solubility Based on Drug Physicochemical Properties. Case Study:
           Superdisintegrants
    • Abstract: Abstract The presence of different excipient types/brands in solid oral dosage forms may affect product performance and drug bioavailability. Understanding the biopharmaceutical implications of superdisintegrant variability (changes in material properties), variation (changes in excipient amount) and interchangeability (use of different excipient types with the same intended functionality) in oral drug performance would be beneficial for the development of robust final dosage forms. The current study investigated the impact of superdisintegrants (sodium starch glycolate, croscarmellose sodium, crospovidone) on the apparent solubility of drugs with different physicochemical properties (drug ionisation, drug lipophilicity, drug aqueous solubility). Compendial and biorelevant media were used to assess the impact of gastrointestinal conditions on the effects of excipient on drug apparent solubility. For the majority of compounds, changes in drug apparent solubility were not observed in superdisintegrant presence, apart from the cases of highly ionised compounds (significant decrease in drug solubility) and/or compounds that aggregate/precipitate in solution (significant increase in drug solubility). Excipient variability did not greatly affect the impact of excipients on drug apparent solubility. The use of multivariate data analysis identified the biopharmaceutical factors affecting excipient performance. The construction of roadmaps revealed that superdisintegrants may be of low risk for the impact of excipients on oral drug performance based on drug solubility alone; superdisintegrants activity could still be a risk for oral bioavailability due to their effects on tablet disintegration.
      PubDate: 2020-02-11
       
  • Mechanistic Pharmacokinetic/Pharmacodynamic Model of Sunitinib and
           Dopamine in MCF-7/Adr Xenografts: Linking Cellular Heterogeneity to Tumour
           Burden
    • Abstract: Abstract The self-renewal and differentiation of cancer stem-like cells (CSCs) leads to cellular heterogeneity, causing one of the greatest challenges in cancer therapy. Growing evidence suggests that CSC-targeting therapy enhances the effect of concomitant antitumour therapy. To gain an in-depth understanding of this enhanced effect, the kinetic profile of estimated CSC frequency (the fraction of CSCs in tumour) was evaluated for in vivo characterization of cellular heterogeneity using sunitinib and dopamine as a paradigm combination therapy. Female MCF-7/Adr xenografted Balb/c nude mice were treated with sunitinib (p.o., 20 mg/kg) and dopamine (i.p., 50 mg/kg), alone or in combination. Estimated CSC frequency and tumour size were measured over time. Mechanistic PK/PD modelling was performed to quantitatively describe the relationship between drug concentration, estimated CSC frequency and tumour size. Sunitinib reduced tumour size by inducing apoptosis of differentiated tumour cells (DTCs) and enriched CSCs by stimulating its proliferation. Dopamine exhibited anti-CSC effects by suppressing the capacity of CSCs and inducing its differentiation. Simulation and animal studies indicated that concurrent administration was superior to sequential administration under current experimental conditions. Alongside tumour size, the current study provides mechanistic insights into the estimation of CSC frequency as an indicator for cellular heterogeneity. This forms the conceptual basis for in vivo characterization of other combination therapies in preclinical cancer studies.
      PubDate: 2020-02-10
       
  • Reference Datasets for Studies in a Replicate Design Intended for Average
           Bioequivalence with Expanding Limits
    • Abstract: Abstract In order to help companies qualify and validate the software used to evaluate bioequivalence trials in a replicate design intended for average bioequivalence with expanding limits, this work aims to define datasets with known results. This paper releases 30 reference datasets into the public domain along with proposed consensus results. A proposal is made for results that should be used as validation targets. The datasets were evaluated by seven different software packages according to methods proposed by the European Medicines Agency. For the estimation of CVwR and Method A, all software packages produced results that are in agreement across all datasets. Due to different approximations of the degrees of freedom, slight differences were observed in two software packages for Method B in highly incomplete datasets. All software packages were suitable for the estimation of CVwR and Method A. For Method B, different methods for approximating the denominator degrees of freedom could lead to slight differences, which eventually could lead to contrary decisions in very rare borderline cases.
      PubDate: 2020-02-07
       
  • Quantification of T Cell Binding Polyclonal Rabbit Anti-thymocyte Globulin
           in Human Plasma with Liquid Chromatography Tandem-Mass Spectrometry
    • Abstract: Abstract The addition of rabbit anti-human thymocyte globulin (ATG) to the conditioning regimen prior to allogeneic hematopoietic cell transplantation has significantly reduced the risk of graft-versus-host disease (GvHD) and graft failure. However, ATG has a small therapeutic window. Overexposure of ATG post-HCT hampers T cell immune reconstitution and has been associated with increased relapse rates and viral reactivations, whereas underexposure has been associated with an increased incidence of GvHD, both of which lead to increased mortality. Therapeutic drug monitoring of T cell binding ATG plasma levels provides a means to optimize dosing for patients at high risk for graft failure to ensure timely T cell immune reconstitution and subsequently increase survival chances. This manuscript describes the first liquid chromatography tandem-mass spectrometry (LC-MS/MS) method to quantify the pharmacologically active fraction of polyclonal ATG in plasma. This was achieved through immunoaffinity purification of active ATG from plasma with Jurkat T cells. After the binding and washing, samples were eluted, denatured, and trypsin-digested. Signature peptides originating from the IgG constant chain were measured with LC-MS/MS. Critical method parameters were optimized, and the method was successfully validated following European Medicines Agency (EMA) guidelines. The method covered the therapeutic range of ATG and was validated at a lower limit of quantification (LLOQ) of 1 AU/mL with an overall CV and bias of 11.8% and − 2.5%, respectively. In conclusion, we developed a LC-MS/MS-based method to quantify active polyclonal rabbit ATG in human plasma. We suggest that this novel assay can be used to monitor and optimize dosing of ATG in clinical practice.
      PubDate: 2020-02-06
       
 
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