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  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
Showing 1 - 200 of 253 Journals sorted by number of followers
Nature Reviews Drug Discovery     Full-text available via subscription   (Followers: 333)
International Journal of Drug Policy     Hybrid Journal   (Followers: 249)
Journal of Clinical Oncology     Hybrid Journal   (Followers: 246)
Journal of Medicinal Chemistry     Hybrid Journal   (Followers: 160)
Journal of Pharmaceutical Sciences     Hybrid Journal   (Followers: 159)
Drugs     Full-text available via subscription   (Followers: 143)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 98)
Pharmaceutical Research     Hybrid Journal   (Followers: 94)
European Journal of Pharmaceutical Sciences     Hybrid Journal   (Followers: 87)
Drug Safety     Full-text available via subscription   (Followers: 84)
Annals of Pharmacotherapy     Hybrid Journal   (Followers: 56)
Biomaterials     Hybrid Journal   (Followers: 54)
Clinical Pharmacology & Therapeutics     Hybrid Journal   (Followers: 45)
Regulatory Toxicology and Pharmacology     Hybrid Journal   (Followers: 42)
Journal of Controlled Release     Hybrid Journal   (Followers: 38)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 38)
International Journal of Pharmaceutics     Hybrid Journal   (Followers: 37)
European Journal of Pharmaceutics and Biopharmaceutics     Hybrid Journal   (Followers: 35)
Clinical Therapeutics     Hybrid Journal   (Followers: 34)
Pharmacoepidemiology and Drug Safety     Hybrid Journal   (Followers: 33)
British Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 32)
Drug Development and Industrial Pharmacy     Hybrid Journal   (Followers: 30)
AAPS Journal     Hybrid Journal   (Followers: 28)
Clinical Pharmacokinetics     Full-text available via subscription   (Followers: 27)
PharmacoEconomics     Full-text available via subscription   (Followers: 26)
Journal of Pharmacy and Pharmacology     Full-text available via subscription   (Followers: 26)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 25)
Toxicology and Applied Pharmacology     Hybrid Journal   (Followers: 24)
Journal of Clinical Psychopharmacology     Hybrid Journal   (Followers: 24)
International Journal of Pharmacy Practice     Full-text available via subscription   (Followers: 24)
Journal of Pain & Palliative Care Pharmacotherapy     Hybrid Journal   (Followers: 23)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Journal of Pharmacokinetics and Pharmacodynamics     Hybrid Journal   (Followers: 22)
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 20)
American Journal of Cardiovascular Drugs     Hybrid Journal   (Followers: 20)
Journal of Applied Toxicology     Hybrid Journal   (Followers: 19)
Pharmaceutical Development and Technology     Hybrid Journal   (Followers: 19)
Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 19)
Clinical Trials     Hybrid Journal   (Followers: 18)
Toxicology     Hybrid Journal   (Followers: 18)
Journal of Pharmaceutical and Biomedical Analysis     Hybrid Journal   (Followers: 18)
Clinical Toxicology     Hybrid Journal   (Followers: 18)
International Journal of Toxicology     Hybrid Journal   (Followers: 17)
Critical Reviews in Clinical Laboratory Sciences     Hybrid Journal   (Followers: 16)
Journal of Clinical Pharmacy and Therapeutics     Hybrid Journal   (Followers: 16)
Journal of Natural Products     Hybrid Journal   (Followers: 16)
Pharmaceutical Statistics     Hybrid Journal   (Followers: 15)
Toxicology Letters     Hybrid Journal   (Followers: 15)
Journal of Pharmacy Practice     Hybrid Journal   (Followers: 15)
Psychopharmacology     Hybrid Journal   (Followers: 15)
European Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 14)
Cardiovascular Drugs and Therapy     Hybrid Journal   (Followers: 14)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 14)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 13)
Journal of the American Pharmacists Association     Full-text available via subscription   (Followers: 13)
Current Medicinal Chemistry     Hybrid Journal   (Followers: 13)
American Journal of Therapeutics     Hybrid Journal   (Followers: 13)
Journal of Oncology Pharmacy Practice     Hybrid Journal   (Followers: 13)
Drug Discovery Today: Technologies     Full-text available via subscription   (Followers: 12)
Current Pharmaceutical Design     Hybrid Journal   (Followers: 12)
Seminars in Hematology     Hybrid Journal   (Followers: 12)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 11)
Drug Development Research     Hybrid Journal   (Followers: 11)
Drug Metabolism and Disposition     Hybrid Journal   (Followers: 11)
Journal of Psychopharmacology     Hybrid Journal   (Followers: 11)
Toxicology in Vitro     Hybrid Journal   (Followers: 11)
Journal of Separation Science     Hybrid Journal   (Followers: 10)
Seminars in Oncology Nursing     Full-text available via subscription   (Followers: 10)
CNS Drugs     Full-text available via subscription   (Followers: 10)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Drugs & Aging     Full-text available via subscription   (Followers: 10)
Current Pharmaceutical Biotechnology     Hybrid Journal   (Followers: 10)
Food Additives & Contaminants Part A     Hybrid Journal   (Followers: 9)
Clinical Research and Regulatory Affairs     Hybrid Journal   (Followers: 9)
Journal of Pharmacology and Experimental Therapeutics     Hybrid Journal   (Followers: 9)
Journal of Medical Marketing     Hybrid Journal   (Followers: 9)
Biometrical Journal     Hybrid Journal   (Followers: 9)
Environmental Toxicology and Pharmacology     Hybrid Journal   (Followers: 9)
European Neuropsychopharmacology     Hybrid Journal   (Followers: 9)
Medicinal Chemistry     Hybrid Journal   (Followers: 9)
Prescriber     Hybrid Journal   (Followers: 9)
Drugs & Therapy Perspectives     Full-text available via subscription   (Followers: 9)
ChemMedChem     Hybrid Journal   (Followers: 9)
Current Opinion in Pharmacology     Hybrid Journal   (Followers: 9)
Inhalation Toxicology     Hybrid Journal   (Followers: 8)
Antiviral Research     Hybrid Journal   (Followers: 8)
Drug Metabolism Reviews     Hybrid Journal   (Followers: 8)
Progress in Neuro-Psychopharmacology and Biological Psychiatry     Hybrid Journal   (Followers: 8)
Human & Experimental Toxicology     Hybrid Journal   (Followers: 8)
BioDrugs     Full-text available via subscription   (Followers: 8)
Drug Delivery     Open Access   (Followers: 8)
Expert Review of Pharmacoeconomics & Outcomes Research     Full-text available via subscription   (Followers: 8)
European Journal of Pharmacology     Hybrid Journal   (Followers: 8)
Journal of Veterinary Pharmacology and Therapeutics     Hybrid Journal   (Followers: 7)
Experimental and Clinical Psychopharmacology     Full-text available via subscription   (Followers: 7)
Frontiers in Drug Design & Discovery     Hybrid Journal   (Followers: 7)
Clinical and Experimental Pharmacology and Physiology     Hybrid Journal   (Followers: 7)
Journal of Pharmacological and Toxicological Methods     Hybrid Journal   (Followers: 7)
Epilepsy Research     Hybrid Journal   (Followers: 7)
Clinical Drug Investigation     Full-text available via subscription   (Followers: 7)
Toxicology Mechanisms and Methods     Hybrid Journal   (Followers: 7)
Scandinavian Journal of Clinical and Laboratory Investigation     Hybrid Journal   (Followers: 7)
Journal of Cardiovascular Pharmacology     Hybrid Journal   (Followers: 7)
Toxicology and Industrial Health     Hybrid Journal   (Followers: 6)
Skin Pharmacology and Physiology     Full-text available via subscription   (Followers: 6)
AAPS PharmSciTech     Hybrid Journal   (Followers: 6)
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry     Hybrid Journal   (Followers: 6)
Current Drug Discovery Technologies     Hybrid Journal   (Followers: 6)
Current Therapeutic Research     Open Access   (Followers: 6)
Expert Review of Cardiovascular Therapy     Full-text available via subscription   (Followers: 6)
Current Drug Delivery     Hybrid Journal   (Followers: 6)
Current Drug Metabolism     Hybrid Journal   (Followers: 5)
Investigational New Drugs     Hybrid Journal   (Followers: 5)
Toxicon     Hybrid Journal   (Followers: 5)
Medicinal Research Reviews     Hybrid Journal   (Followers: 5)
Anti-Infective Agents     Hybrid Journal   (Followers: 5)
Expert Review of Anti-infective Therapy     Full-text available via subscription   (Followers: 5)
Expert Review of Molecular Diagnostics     Full-text available via subscription   (Followers: 5)
Current Cancer Therapy Reviews     Hybrid Journal   (Followers: 5)
Neuropharmacology     Hybrid Journal   (Followers: 5)
Fitoterapia     Hybrid Journal   (Followers: 5)
Immunopharmacology and Immunotoxicology     Hybrid Journal   (Followers: 4)
Journal of Cardiovascular Pharmacology and Therapeutics     Hybrid Journal   (Followers: 4)
Planta Medica     Hybrid Journal   (Followers: 4)
Current Vascular Pharmacology     Hybrid Journal   (Followers: 4)
Reviews of Physiology, Biochemistry and Pharmacology     Hybrid Journal   (Followers: 4)
Journal of Child and Adolescent Psychopharmacology     Hybrid Journal   (Followers: 4)
International Journal of Pharmaceutical and Healthcare Marketing     Hybrid Journal   (Followers: 4)
Pharmaceutical Medicine     Full-text available via subscription   (Followers: 4)
Journal of Pain Management & Medicine     Open Access   (Followers: 4)
Cancer Chemotherapy and Pharmacology     Hybrid Journal   (Followers: 4)
Journal of Labelled Compounds and Radiopharmaceuticals     Hybrid Journal   (Followers: 4)
Inpharma Weekly     Full-text available via subscription   (Followers: 4)
Inflammation Research     Hybrid Journal   (Followers: 4)
CNS Drug Reviews     Open Access   (Followers: 4)
Therapeutic Drug Monitoring     Hybrid Journal   (Followers: 3)
Research in Social and Administrative Pharmacy     Hybrid Journal   (Followers: 3)
Current Drug Therapy     Hybrid Journal   (Followers: 3)
Chemotherapy     Full-text available via subscription   (Followers: 3)
Cardiovascular Therapeutics     Open Access   (Followers: 3)
International Journal of Neuropsychopharmacology     Open Access   (Followers: 3)
Pharmacopsychiatry     Hybrid Journal   (Followers: 3)
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 3)
ASSAY and Drug Development Technologies     Hybrid Journal   (Followers: 3)
Physiology International     Full-text available via subscription   (Followers: 3)
Journal of Aerosol Medicine and Pulmonary Drug Delivery     Hybrid Journal   (Followers: 3)
Human Psychopharmacology Clinical and Experimental     Hybrid Journal   (Followers: 3)
Frontiers in Medicinal Chemistry     Hybrid Journal   (Followers: 3)
Acta Pharmacologica Sinica     Hybrid Journal   (Followers: 3)
Drug Resistance Updates     Hybrid Journal   (Followers: 3)
Microbial Drug Resistance     Hybrid Journal   (Followers: 3)
Journal of Infection and Chemotherapy     Hybrid Journal   (Followers: 3)
Journal of Ethnopharmacology     Hybrid Journal   (Followers: 3)
Current Pharmacogenomics and Personalized Medicine     Hybrid Journal   (Followers: 3)
Canadian Journal of Physiology and Pharmacology     Hybrid Journal   (Followers: 2)
International Immunopharmacology     Hybrid Journal   (Followers: 2)
Journal of Drug Targeting     Hybrid Journal   (Followers: 2)
BMC Pharmacology     Open Access   (Followers: 2)
Vascular Pharmacology     Hybrid Journal   (Followers: 2)
Journal of Inflammation     Open Access   (Followers: 2)
Biomedicine & Pharmacotherapy     Full-text available via subscription   (Followers: 2)
Clinical Neuropharmacology     Hybrid Journal   (Followers: 2)
Toxicological & Environmental Chemistry     Hybrid Journal   (Followers: 2)
Inflammopharmacology     Hybrid Journal   (Followers: 2)
The Brown University Psychopharmacology Update     Hybrid Journal   (Followers: 2)
Behavioural Pharmacology     Hybrid Journal   (Followers: 2)
Archiv der Pharmazie     Hybrid Journal   (Followers: 2)
Fundamental & Clinical Pharmacology     Hybrid Journal   (Followers: 2)
International Clinical Psychopharmacology     Hybrid Journal   (Followers: 2)
Pulmonary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 2)
Pharmacological Reviews     Hybrid Journal   (Followers: 2)
Molecular Pharmacology     Hybrid Journal   (Followers: 2)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 2)
Journal of Microencapsulation: Microcapsules, Liposomes, Nanoparticles, Microcells, Microspheres     Hybrid Journal   (Followers: 2)
Letters in Drug Design & Discovery     Hybrid Journal   (Followers: 2)
Drugs in R & D     Full-text available via subscription   (Followers: 2)
Journal of Neuroimmune Pharmacology     Hybrid Journal   (Followers: 1)
Current Pharmaceutical Analysis     Hybrid Journal   (Followers: 1)
Current Enzyme Inhibition     Hybrid Journal   (Followers: 1)
Journal of Texture Studies     Hybrid Journal   (Followers: 1)
Pharmacogenetics and Genomics     Hybrid Journal   (Followers: 1)
Particulate Science and Technology: An International Journal     Hybrid Journal   (Followers: 1)
Current Neuropharmacology     Hybrid Journal   (Followers: 1)
Pharmacological Research     Hybrid Journal   (Followers: 1)
Pharmaceutical Biology     Open Access  
Journal of Liposome Research     Hybrid Journal  
Toxin Reviews     Hybrid Journal  
Kaohsiung Journal of Medical Sciences     Open Access  
Redox Report     Open Access  
Pharmacology     Full-text available via subscription  
PharmacoEconomics & Outcomes News     Full-text available via subscription  
Pharmaceutical Chemistry Journal     Hybrid Journal  
NeuroMolecular Medicine     Hybrid Journal  
Journal of Ocular Pharmacology and Therapeutics     Hybrid Journal  
Harm Reduction Journal     Open Access  
Current Nanoscience     Hybrid Journal  
Infectious Disorders - Drug Targets     Hybrid Journal  
Current Bioactive Compounds     Hybrid Journal  
Cancer Biotherapy & Radiopharmaceuticals     Hybrid Journal  
Autonomic & Autacoid Pharmacology     Hybrid Journal  

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AAPS Journal
Journal Prestige (SJR): 1.118
Citation Impact (citeScore): 4
Number of Followers: 28  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Online) 1550-7416
Published by Springer-Verlag Homepage  [2467 journals]
  • Vinyl Sulfone-functionalized Acetalated Dextran Microparticles as a
           Subunit Broadly Acting Influenza Vaccine

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      Abstract: Influenza is a global health concern with millions of infections occurring yearly. Seasonal flu vaccines are one way to combat this virus; however, they are poorly protective against influenza as the virus is constantly mutating, particularly at the immunodominant hemagglutinin (HA) head group. A more broadly acting approach involves Computationally Optimized Broadly Reactive Antigen (COBRA). COBRA HA generates a broad immune response that is capable of protecting against mutating strains. Unfortunately, protein-based vaccines are often weekly immunogenic, so to help boost the immune response, we employed the use of acetalated dextran (Ace-DEX) microparticles (MPs) two ways: one to conjugate COBRA HA to the surface and a second to encapsulate cGAMP. To conjugate the COBRA HA to the surface of the Ace-DEX MPs, a poly(L-lactide)-polyethylene glycol co-polymer with a vinyl sulfone terminal group (PLLA-PEG-VS) was used. MPs encapsulating the STING agonist cGAMP were co-delivered with the antigen to form a broadly active influenza vaccine. This vaccine approach was evaluated in vivo with a prime-boost-boost vaccination schedule and illustrated generation of a humoral and cellular response that could protect against a lethal challenge of A/California/07/2009 in BALB/c mice. Graphical
      PubDate: 2023-01-31
       
  • The Development and Characterization of a Highly Sensitive Mature TGFβ3
           Assay to Evaluate Anti-TGFβ3 Target Engagement

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      Abstract: MTBT 1466A is a monoclonal antibody designed to bind to mature human TGFβ3 in human tissue and systemic circulation. To evaluate binding of this therapeutic, a mature TGFβ3 assay was needed to be able to monitor pharmacodynamic responses in non-human primate (NHP) studies. However, mature TGFβ3 levels in systemic circulation are very low and require development of a highly sensitive assay for detection. This study describes the development of a highly sensitive, drug-tolerant pharmacodynamic biomarker assay for demonstrating target engagement in a pre-clinical study using MTBT1466A. Since mature TGFβ3 is a dimer, a single MAb was used as both the capture and detection antibodies. This assay was developed on the SMCxPRO platform and qualified based on current accepted criteria for biomarker assays. The assay demonstrated specificity to mature TGFβ3, with a lower limit of quantification of 31.3pg/mL. Although baseline levels of mature TGFβ3 were below the assay detection limit in 40% of animals within our study, 2- to 16-fold increases were observed in many of the animals following multiple-dosing regimen. Graphical
      PubDate: 2023-01-26
       
  • Product Quality Research for Developing and Assessing Regulatory
           Submissions for Generic Cyclosporine Ophthalmic Emulsions

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      Abstract: Approval of the first generic 0.05% cyclosporine ophthalmic emulsion (COE) in the U.S. represents a milestone achievement of the science and research program in the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research (CDER). COE is a locally acting complex drug product indicated to increase tear production in patients whose production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. The path to approval required overcoming numerous scientific challenges to determining therapeutic equivalence to the reference listed drug. Researchers in CDER’s Office of Pharmaceutical Quality and Office of Generic Drugs developed a quality by design approach to understand the effects of process and formulation variables on the product’s critical quality attributes, including globule size distribution (GSD), turbidity, viscosity, zeta potential, surface tension, and osmolality. CDER researchers explored multiple techniques to perform physicochemical characterization and analyze the GSD including laser diffraction, nanoparticle tracking analysis, cryogenic transmission electron microscopy, dynamic light scattering, asymmetric field flow fractionation, and two-dimensional diffusion ordered spectroscopy nuclear magnetic resonance. Biphasic models to study drug transfer kinetics demonstrated that COEs with qualitative and quantitative sameness and comparable GSDs, analyzed using earth mover’s distance, can be therapeutic equivalents. This body of research facilitated the review and approval of the first U.S. generic COE. In addition, the methods and fundamental understanding developed from this research may support the development and assessment of other complex generics. The approval of a generic COE should improve the availability of this complex drug product to U.S. patients. Graphical
      PubDate: 2023-01-26
       
  • Theoretical Examination Seeking Tangible Physical Meanings of Slopes and
           Intercepts of Plasma Concentration–Time Relationships in Minimal
           Physiologically Based Pharmacokinetic Models

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      Abstract: In minimal physiologically based pharmacokinetic (mPBPK) models, physiological (e.g., cardiac output) and anatomical (e.g., blood/tissue volumes) variables are utilized in the domain of differential equations (DEs) for mechanistic understanding of the plasma concentration–time relationships \({C}_{p}(t)\) . Although fundamental biopharmaceutical variables in terms of distribution (e.g., \({K}_{p}\) and \({f}_{d}\) ) and elimination kinetics (e.g., \(CL\) ) in mPBPK provide greater insights in comparison to classical compartment models, an absence of kinetic elucidation of slopes and intercepts in light of such DE model parameters hinders more intuitive appreciation of \({C}_{p}(t)\) . Therefore, this study seeks the tangible physical meanings of slopes and intercepts of the plasma concentration–time relationships in one- and two-tissue mPBPK models (i.e., m2CM and m3CM), with respect to time parameters that are readily understandable in PK analyses, i.e., the mean residence ( \(MRT\) ) and transit ( \(MTT\) ) times. Utilizing the explicit equations (EEs) for the slopes, intercepts, and areas of each exponential phase in the m2CM and m3CM, we theoretically and numerically examined the limiting/boundary conditions of such kinetic properties, based on the ratio of the longest tissue \(MTT\) to the \(MRT\) in the body (i.e., \({K}_{det}={MTT}_{max}/MR{T}_{B}\) ) that is useful for dissecting complex PBPK systems. The kinetic contribution of the area of each exponential phase to the total drug exposure was assessed to identify the elimination phase between the terminal and non-terminal phases of the \({C}_{p}\left(t\right)\) in the m2CM and m3CM. This assessment provides improved understanding of the complexities inherent in all PBPK profiles and models. Graphical
      PubDate: 2023-01-26
       
  • A Novel Neutralization Antibody Assay Method to Overcome Drug Interference
           with Better Compatibility with Acid-Sensitive Neutralizing Antibodies

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      Abstract: Immunogenicity testing to detect and characterize anti-drug antibody (ADA) is required for almost all biotherapeutics. Monoclonal antibody biotherapeutics usually have long half-lives and for high-dose indications such as oncology, high level of drug will be present in the testing samples and interfere with ADA and/or neutralization antibody (NAb) measurement. To overcome this drug interference, acid-dissociation-based sample pre-treatment such as Bead-Extraction and Acid Dissociation (BEAD) has been successfully applied. The main concern for these acid-dissociation-based methods, however, is that harsh acid treatment could denature positive control Abs as well as NAb species in testing samples. In addition, high amount of biotinylated drug is needed in order to have effective competition with high level of drug in the samples, which in turn requires expensive magnetic beads. And the whole process of magnetic beads handling is tedious if doing manually and often causes trouble during assay transfer. Here, we describe a novel method which we named as Precipitation, Acid Dissociation and Biotin-drug as Assay Drug (PABAD). This novel method will need only one step of acid dissociation, with much milder and shorter acid treatment to maximally preserve NAb activity. In addition, only a fraction of biotinylated-drug is needed and there is no need to use additional streptavidin (SA)-plate or SA-magnetic beads for extraction. Compared to a BEAD-based assay, PABAD demonstrates significantly improved recovery of acid-sensitive NAb positive controls (PCs) and similar recovery of acid-resistant NAb PCs. Graphical
      PubDate: 2023-01-25
       
  • Best Practices for Submission of NMR Data to Support Higher Order
           Structure Assessment of Generic Peptide Drugs

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      PubDate: 2023-01-20
       
  • Model-Informed Approach Supporting Approval of Nexviazyme (Avalglucosidase
           Alfa-ngpt) in Pediatric Patients with Late-Onset Pompe Disease

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      Abstract: Abstract In August 2021, the US Food and Drug Administration approved Nexviazyme (avalglucosidase alfa-ngpt) for intravenous infusion to treat patients 1 year of age and older with late-onset Pompe disease (LOPD). The effectiveness and safety were studied in patients with LOPD and patients with infantile-onset Pompe disease (IOPD). The dosage(s) tested in clinical trials was 20 mg/kg every other week (qow) in patients with LOPD and 20 mg/kg and 40 mg/kg qow in patients with IOPD. While patients 3 years old and greater with LOPD were eligible for participation in the pivotal trial, the youngest patient enrolled was 16 years old. Therefore, pediatric patients with LOPD were not well represented in the clinical trial. The prevalence of LOPD in pediatrics is extremely low. Thus, conducting a clinical trial in pediatric patients with LOPD would be challenging. Given the similar pathophysiology, mechanism of action, and disease manifestations across the age spectrum of patients with LOPD, the approved dosages for pediatric patients younger than 16 years old with LOPD were based on extrapolation of efficacy using a model-informed exposure bridging strategy, leveraging the safety data from pediatric patients with IOPD. Specifically, the exposure associated with 20 mg/kg qow in adult patients with LOPD was the target exposure for bridging of efficacy. The safety data obtained with 40 mg/kg qow in patients with IOPD was leveraged to support approval in pediatric patients with LOPD aged 1 year and older. This article illustrates a regulatory use of model-informed extrapolation approach for dose selection in pediatric patients with a rare disease.
      PubDate: 2023-01-18
       
  • Correction: End-to-End Approach to Surfactant Selection, Risk Mitigation,
           and Control Strategies for Protein-Based Therapeutics

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      PubDate: 2023-01-11
       
  • Lessons from CDER’s Quality Management Maturity Pilot Programs

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      Abstract: Between October 2020 and March 2022, FDA’s Center for Drug Evaluation and Research (CDER) completed two pilot programs to assess the quality management maturity (QMM) of drug manufacturing establishments. Mature quality systems promote proactive detection of vulnerabilities, prevent problems before they occur, and foster a culture that rewards process and system improvements. A CDER QMM program may help to advance supply chain resiliency and robustness and mitigate drug shortages. One pilot program evaluated seven establishments located within the U.S. that produce finished dosage form products marketed in the U.S. A second pilot program evaluated eight establishments located outside the U.S. that produce active pharmaceutical ingredients used in drug products marketed in the U.S. The execution of these pilot programs afforded FDA the opportunity to learn important lessons about the establishment QMM assessment process, scoring approach, assessor behaviors, and perceptions of the assessment questions, reports, and ratings. Many of the participating establishments reported that the QMM pilot assessments helped to identify their strengths, weaknesses, and new areas for improvement which they had not previously identified through internal audits or CGMP inspections. There has been a great deal of interest in the outcomes of CDER’s QMM pilot programs and this paper describes, for the first time, the lessons CDER learned and will continue to heed in the development of a QMM program. Graphical
      PubDate: 2023-01-10
       
  • Pancreatic Hormone Insulin Modulates Organic Anion Transporter 1 in the
           Kidney: Regulation via Remote Sensing and Signaling Network

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      Abstract: Organic anion transporter 1 (OAT1) expressed in the kidney plays an important role in the elimination of numerous anionic drugs used in the clinic. We report here that insulin, a pancreas-secreted hormone, regulated the expression and activity of kidney-specific OAT1 both in cultured cells and in rats. We showed that treatment of OAT1-expressing cells with insulin led to an increase in OAT1 expression, transport activity, and SUMOylation. Such insulin-induced increase was blocked by afuresertib, a specific inhibitor for protein kinase B (PKB), suggesting insulin regulates OAT1 through PKB signaling pathway. Furthermore, insulin stimulated transport activity and SUMOylation of endogenously expressed OAT1 in rat kidneys. In conclusion, our data support a remote sensing and signaling model, in which OAT1 plays an essential role in intercellular and inter-organ communication and in maintaining local and whole-body homeostasis. Such complex and dedicated communication is carried out by insulin, and PKB signaling and membrane sorting. Graphical
      PubDate: 2023-01-10
       
  • Development and Validation of a Western Blot Method to Quantify
           Mini-Dystrophin in Human Skeletal Muscle Biopsies

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      Abstract: Duchenne muscular dystrophy (DMD) is a degenerative muscular disease affecting roughly one in 5000 males at birth. The disease is often caused by inherited X-linked recessive pathogenic variants in the dystrophin gene, but may also arise from de novo mutations. Disease-causing variants include nonsense, out of frame deletions or duplications that result in loss of dystrophin protein expression. There is currently no cure for DMD and the few treatment options available aim at slowing muscle degradation. New advances in gene therapy and understanding of dystrophin (DYS) expression in other muscular dystrophies have opened new opportunities for treatment. Therefore, reliable methods are needed to monitor dystrophin expression and assess the efficacy of new therapies for muscular dystrophies such as DMD and Becker muscular dystrophy (BMD). Here, we describe the validation of a novel Western blot (WB) method for the quantitation of mini-dystrophin protein in human skeletal muscle tissues that is easy to adopt in most laboratory settings. This WB method was assessed through precision, accuracy, selectivity, dilution linearity, stability, and repeatability. Based on mini-DYS standard performance, the assay has a dynamic range of 0.5–15 ng protein (per 5 µg total protein per lane), precision of 3.3 to 25.5%, and accuracy of − 7.5 to 3.3%. Our stability assessment showed that the protein is stable after 4 F/T cycles, up to 2 h at RT and after 7 months at − 70°C. Furthermore, our WB method was compared to the results from our recently published LC–MS method. Graphical Workflow for our quantitative WB method to determine mini-dystrophin levels in muscle tissues (created in Biorender.com). Step 1 involves protein extraction from skeletal muscle tissue lysates from control, DMD, or BMD biospecimen. Step 2 measures total protein concentrations. Step 3 involves running gel electrophoresis with wild-type dystrophin (wt-DYS) from muscle tissue extracts alongside mini-dystrophin STD curve and mini-DYS and protein normalization with housekeeping GAPDH.
      PubDate: 2022-12-20
       
  • Challenges and Strategies for Solubility Measurements and Dissolution
           Method Development for Amorphous Solid Dispersion Formulations

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      Abstract: Abstract This manuscript represents the view of the Dissolution Working Group of the IQ Consortium on the challenges of and recommendations on solubility measurements and development of dissolution methods for immediate release (IR) solid oral dosage forms formulated with amorphous solid dispersions. Nowadays, numerous compounds populate the industrial pipeline as promising drug candidates yet suffer from low aqueous solubility. In the oral drug product development process, solubility along with permeability is a key determinant to assure sufficient drug absorption along the intestinal tract. Formulating the drug candidate as an amorphous solid dispersion (ASD) is one potential option to address this issue. These formulations demonstrate the rapid onset of drug dissolution and can achieve supersaturated concentrations, which poses significant challenges to appropriately characterize solubility and develop quality control dissolution methods. This review strives to categorize the different dissolution and solubility challenges for ASD associated with 3 different topics: (i) definition of solubility and sink conditions for ASD dissolution, (ii) applications and development of non-sink dissolution (according to conventional definition) for ASD formulation screening and QC method development, and (iii) the advantages and disadvantages of using dissolution in detecting crystallinity in ASD formulations. Related to these challenges, successful examples of dissolution experiments in the context of control strategies are shared and may lead as an example for scientific consensus concerning dissolution testing of ASD.
      PubDate: 2022-12-13
       
  • Development of a Near-Infrared Spectroscopy (NIRS)–Based
           Characterization Approach for Inherent Powder Blend Heterogeneity in
           Direct Compression Formulations

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      Abstract: With the advent of continuous direct compression (CDC) process, it becomes increasingly desirable to characterize inherent powder blend heterogeneity at a small batch scale for a robust and CDC-amenable formulation. To accomplish this goal, a near infrared spectroscopy (NIRS)-based characterization approach was developed and implemented on multiple direct compression (DC) blends in this study, with the intended purpose of complementing existing formulation development tools and enabling to build an early CMC data package for late-phased process analytical technology (PAT) method development. Three fumaric acid DC blends, designed to harbor varied degrees of inherent blend heterogeneity, were employed. Near infrared spectral data were collected on a kg-scale batch blender via both time- and angle-based triggering modes. The time-triggered data were used to investigate the blending heterogeneity with respect to rotation angles, while the angle-triggered data were used to provide blending variability characterization and compare against off-line HPLC-based results. The time-triggered data revealed that the greatest blend variability was observed between revolutions, while the blending variability within a single revolution stayed relatively low with respect to rotation angles. This confirmed earlier literature findings that the bottom layer of powder blends tends to move with the blender within each revolution, and the most intense powder mixing takes place across revolutions. This also indicates the use of blending speed and the number of co-adds are not able to increase sampling volume to improve signal-to-noise ratio under a tumble-bin blender as what were typically done in a feedframe application. The angle-triggered data showed that there is a consistent trend between NIRS and HPLC-based methods on characterizing blend heterogeneity across the blends at a given sample size. This study contributes to establishing NIRS as a potential characterization approach for inherent powder blend heterogeneity for early R&D. It also highlights the promise of continuous characterization of inherent powder blend heterogeneity from gram scale to mini-batch CDC scale. Graphical
      PubDate: 2022-12-08
       
  • Overcoming Biopharmaceutical Interferents for Quantitation of Host Cell
           DNA Using an Automated, High-Throughput Methodology

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      Abstract: The rapid development of biologics and vaccines in response to the current pandemic has highlighted the need for robust platform assays to characterize diverse biopharmaceuticals. A critical aspect of biopharmaceutical development is achieving a highly pure product, especially with respect to residual host cell material. Specifically, two important host cell impurities of focus within biopharmaceuticals are residual DNA and protein. In this work, a novel high-throughput host cell DNA quantitation assay was developed for rapid screening of complex vaccine drug substance samples. The developed assay utilizes the commercially available, fluorescent-sensitive Picogreen dye within a 96-well plate configuration to allow for a cost effective and rapid analysis. The assay was applied to in-process biopharmaceutical samples with known interferences to the dye, including RNA and protein. An enzymatic digestion pre-treatment was found to overcome these interferences and thus allow this method to be applied to wide-ranging, diverse analyses. In addition, the use of deoxycholate in the digestion treatment allowed for disruption of interactions in a given sample matrix in order to more accurately and selectively quantitate DNA. Critical analytical figures of merit for assay performance, such as precision and spike recovery, were evaluated and successfully demonstrated. This new analytical method can thus be successfully applied to both upstream and downstream process analysis for biologics and vaccines using an innovative and automated high-throughput approach. Graphical
      PubDate: 2022-12-08
       
  • End-to-End Approach to Surfactant Selection, Risk Mitigation, and Control
           Strategies for Protein-Based Therapeutics

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      Abstract: A survey performed by the AAPS Drug Product Handling community revealed a general, mostly consensus, approach to the strategy for the selection of surfactant type and level for biopharmaceutical products. Discussing and building on the survey results, this article describes the common approach for surfactant selection and control strategy for protein-based therapeutics and focuses on key studies, common issues, mitigations, and rationale. Where relevant, each section is prefaced by survey responses from the 22 anonymized respondents. The article format consists of an overview of surfactant stabilization, followed by a strategy for the selection of surfactant level, and then discussions regarding risk identification, mitigation, and control strategy. Since surfactants that are commonly used in biologic formulations are known to undergo various forms of degradation, an effective control strategy for the chosen surfactant focuses on understanding and controlling the design space of the surfactant material attributes to ensure that the desired material quality is used consistently in DS/DP manufacturing. The material attributes of a surfactant added in the final DP formulation can influence DP performance (e.g., protein stability). Mitigation strategies are described that encompass risks from host cell proteins (HCP), DS/DP manufacturing processes, long-term storage, as well as during in-use conditions. Graphical
      PubDate: 2022-12-05
       
  • Stability and Function of Extracellular Vesicles Derived from Immortalized
           Human Corneal Stromal Stem Cells: A Proof of Concept Study

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      Abstract: With significant advancement and development of extracellular vesicle (EV)-based therapies, there is a growing need to understand how their storage affects their physical and functional characteristics. EVs were isolated from the conditioned medium of a corneal stromal stem cell line (imCSSC) using Total Exosome isolation kit (TEI) and ultracentrifugation (UC) combined protocol. Purified EVs were stored at 4°C, − 80°C, room temperature (RT) after lyophilization with or without trehalose for 4 weeks. EVs stored at − 80°C and RT (lyophilization with trehalose) demonstrated a comparable morphology, while the freeze-dried samples without trehalose showed aggregation and degradation under a transmission electron microscope (TEM). Lyophilized samples without trehalose demonstrated a decreased particle concentration, recovery rate and protein concentration, which was remediated by the addition of trehalose. EVs stored at − 80℃ showed no change in the protein expression of CD9, CD63, and CD81. Regardless of the storage condition, all EV samples investigated reduced inflammation, as well as inhibited expression of fibrotic markers in vitro. Lyophilization of EVs with trehalose was a feasible storage method that retained the physical property and in vitro biological activities of EVs after 4 weeks of storage, while − 80°C offered the best retention of imCSSC-derived EV physical properties. For the first time, this data demonstrated a practical and translatable method for the storage of CSSC-derived EVs for clinical use. Graphical
      PubDate: 2022-12-05
       
  • Addressing the Accuracy of Plasma Protein Binding Measurement for Highly
           Bound Compounds Using the Dilution Method

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      Abstract: Currently, regulatory guidelines recommend using 0.01 as the lower limit of plasma fraction unbound (fu) for prediction of drug-drug interactions (DDI) to err on the conservative side. One way to increase experimental fu of highly bound compounds is to dilute the plasma. With the dilution method, a diluted fu, or fu,d, of ≥ 0.01 can be achieved by adjusting the dilution factor. The undiluted fu can be calculated from fu,d and be used for DDI prediction. In this study, the dilution method was evaluated, and the results showed that it gave similar fu values as those determined using the pre-saturation method without plasma dilution. The dilution method enables generation of accurate fu values and alignment with the regulatory recommendation of reportable fu values of ≥ 0.01 for DDI prediction. We recommend using the dilution method to bridge the regulatory recommended fu limit of 0.01 for DDI prediction and the pre-saturation or equivalent methods for definitive plasma protein binding studies. As the pharmaceutical industry continues to generate high quality PPB data, regulatory agencies will gain confidence in the accuracy of fu measurements for highly bound compounds, and the fu lower limit may no longer be needed in the future. Graphical
      PubDate: 2022-12-05
       
  • Monoclonal Antibody Pharmacokinetics in Cynomolgus Monkeys Following
           Subcutaneous Administration: Physiologically Based Model Predictions from
           Physiochemical Properties

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      Abstract: An integrated physiologically based modeling framework is presented for predicting pharmacokinetics and bioavailability of subcutaneously administered monoclonal antibodies in cynomolgus monkeys, based on in silico structure-derived metrics characterizing antibody size, overall charge, local charge, and hydrophobicity. The model accounts for antibody-specific differences in pinocytosis, transcapillary transport, local lymphatic uptake, and pre-systemic degradation at the subcutaneous injection site and reliably predicts the pharmacokinetics of five different wild-type mAbs and their Fc variants following intravenous and subcutaneous administration. Significant associations were found between subcutaneous injection site degradation rate and the antibody’s local positive charge of its complementarity-determining region (R = 0.56, p = 0.0012), antibody pinocytosis rate and its overall positive charge (R = 0.59, p = 0.00063), and antibody paracellular transport and its overall charge together with hydrophobicity (R = 0.63, p = 0.00096). Based on these results, population simulations were performed to predict the relationship between bioavailability and antibody local positive charge. In addition, model simulations were conducted to calculate the relative contribution of absorption pathways (lymphatic and blood), pre-systemic degradation pathways (interstitial and lysosomal), and the influence of injection site lymph flow on antibody bioavailability and pharmacokinetics. The proposed physiologically based modeling framework integrates fundamental mechanisms governing antibody subcutaneous absorption and disposition, with structured-based physiochemical properties, to predict antibody bioavailability and pharmacokinetics in vivo. Graphical
      PubDate: 2022-12-01
       
  • Pharmacokinetics of Long-Acting Aqueous Nano-/Microsuspensions After
           Intramuscular Administration in Different Animal Species and Humans—a
           Review

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      Abstract: Formulating aqueous suspensions is an attractive strategy to incorporate poorly water-soluble drugs, where the drug release can be tailored to maintain desired release profiles of several weeks to months after parenteral (i.e., intramuscular or subcutaneous) administration. A sustained drug release can be desirable to combat chronic diseases by overcoming pill fatigue of a daily oral intake, hence, improving patient compliance. Although the marketed aqueous suspensions for intramuscular injection efficiently relieve the daily pill burden in chronic diseases, the exact drug release mechanisms remain to be fully unraveled. The in vivo drug release and subsequent absorption to the systemic circulation are influenced by a plethora of variables, resulting in a complex in vivo behavior of aqueous suspensions after intramuscular administration. A better understanding of the factors influencing the in vivo performance of aqueous suspensions could advance their drug development. An overview of the potential influential variables on the drug release after intramuscular injection of aqueous suspensions is provided with, where possible, available pharmacokinetic parameters in humans or other species derived from literature, patents, and clinical trials. These variables can be categorized into drug substance and formulation properties, administration site properties, and the host response towards drug particles. Based on the findings, the most critical factors are particle size, dose level, stabilizing excipient, drug lipophilicity, gender, body mass index, and host response. Graphical
      PubDate: 2022-12-01
       
  • ACUVRA: Anion-Exchange Chromatography UV-Ratio Analysis—A QC-Friendly
           Method for Monitoring Adeno-Associated Virus Empty Capsid Content To
           Support Process Development and GMP Release Testing

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      Abstract:   The genome content of adeno-associated virus (AAV) vectors is critical to the safety and potency of AAV-based gene therapy products. Empty capsids are considered a product-related impurity and a critical quality attribute (CQA) of the drug product, thus requiring characterization throughout the production process to demonstrate they are controlled to acceptable levels in the final drug product. Anion exchange chromatography has been used to achieve separation between empty and full capsids, but requires method development and gradient optimization for different serotypes and formulations. Here, we describe an alternative approach to quantitation that does not rely on achieving separation between empty and full capsids, but instead uses the well-established relationship between absorbance at UV A260/A280 and relation to DNA/protein content, in combination with anion-exchange chromatography to allow one to calculate the relative proportion of empty and full capsids in AAV samples from a single peak. We call this approach ACUVRA: Anion-exchange Chromatography UV-Ratio Analysis, and show the applicability of the method through a case study with recombinant AAV2 (rAAV2) process intermediates and drug substance. Method qualification and GMP validation in a quality control (QC) laboratory results show that ACUVRA is a fit-for-purpose method for process development support and characterization, while also being a QC-friendly option for GMP release testing at all stages of clinical development. Graphical abstract
      PubDate: 2022-11-22
      DOI: 10.1208/s12248-022-00768-0
       
 
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