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AAPS Journal

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https://www.readbyqxmd.com/read/28421428/how-has-cder-prepared-for-the-nano-revolution-a-review-of-risk-assessment-regulatory-research-and-guidance-activities
#1
Katherine M Tyner, Nan Zheng, Stephanie Choi, Xiaoming Xu, Peng Zou, Wenlei Jiang, Changning Guo, Celia N Cruz
The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration (FDA) was established to assess the potential impact of nanotechnology on drug products. One of the working group's major initiatives has been to conduct a comprehensive risk management exercise regarding the potential impact of nanomaterial pharmaceutical ingredients and excipients on drug product quality, safety, and efficacy. This exercise concluded that current review practices and regulatory guidance are capable of detecting and managing the potential risks to quality, safety, and efficacy when a drug product incorporates a nanomaterial...
April 18, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28397097/blood-brain-barriers-in-obesity
#2
Elizabeth M Rhea, Therese S Salameh, Aric F Logsdon, Angela J Hanson, Michelle A Erickson, William A Banks
After decades of rapid increase, the rate of obesity in adults in the USA is beginning to slow and the rate of childhood obesity is stabilizing. Despite these improvements, the obesity epidemic continues to be a major health and financial burden. Obesity is associated with serious negative health outcomes such as cardiovascular disease, type II diabetes, and, more recently, cognitive decline and various neurodegenerative dementias such as Alzheimer's disease. In the past decade, major advancements have contributed to the understanding of the role of the central nervous system (CNS) in the development of obesity and how peripheral hormonal signals modulate CNS regulation of energy homeostasis...
April 10, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28382544/in-vitro-and-in-vivo-metabolite-identification-studies-for-the-new-synthetic-opioids-acetylfentanyl-acrylfentanyl-furanylfentanyl-and-4-fluoro-isobutyrylfentanyl
#3
Shimpei Watanabe, Svante Vikingsson, Markus Roman, Henrik Green, Robert Kronstrand, Ariane Wohlfarth
New fentanyl analogs have recently emerged as new psychoactive substances and have caused numerous fatalities worldwide. To determine if the new analogs follow the same metabolic pathways elucidated for fentanyl and known fentanyl analogs, we performed in vitro and in vivo metabolite identification studies for acetylfentanyl, acrylfentanyl, 4-fluoro-isobutyrylfentanyl, and furanylfentanyl. All compounds were incubated at 10 μM with pooled human hepatocytes for up to 5 h. For each compound, four or five authentic human urine samples from autopsy cases with and without enzymatic hydrolysis were analyzed...
April 5, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28374319/application-of-a-pk-pd-modeling-and-simulation-based-strategy-for-clinical-translation-of-antibody-drug-conjugates-a-case-study-with-trastuzumab-emtansine-t-dm1
#4
Aman P Singh, Dhaval K Shah
Successful clinical translation of antibody-drug conjugates (ADCs) can be challenging due to complex pharmacokinetics and differences between preclinical and clinical tumors. To facilitate this translation, we have developed a general pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation (M&S)-based strategy for ADCs. Here we present the validation of this strategy using T-DM1 as a case study. A previously developed preclinical tumor disposition model for T-DM1 (Singh and Shah, AAPSJ. 2015; 18(4):861-875) was used to develop a PK-PD model that can characterize in vivo efficacy of T-DM1 in preclinical tumor models...
April 3, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28374318/erratum-to-systematic-verification-of-bioanalytical-similarity-between-a-biosimilar-and-a-reference-biotherapeutic-committee-recommendations-for-the-development-and-validation-of-a-single-ligand-binding-assay-to-support-pharmacokinetic-assessments
#5
Joseph C Marini, Michael Anderson, Xiao-Yan Cai, John Chappell, Todd Coffey, Dominique Gouty, Aparna Kasinath, Vera Koppenburg, Philip Oldfield, Shannon Rebarchak, Ronald R Bowsher
No abstract text is available yet for this article.
April 3, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28357656/physiologically-based-pharmacokinetic-and-absorption-modeling-for-osmotic-pump-products
#6
Zhanglin Ni, Arjang Talattof, Jianghong Fan, Eleftheria Tsakalozou, Satish Sharan, Dajun Sun, Hong Wen, Liang Zhao, Xinyuan Zhang
Physiologically based pharmacokinetic (PBPK) and absorption modeling approaches were employed for oral extended-release (ER) drug products based on an osmotic drug delivery system (osmotic pumps). The purpose was to systemically evaluate the in vivo relevance of in vitro dissolution for this type of formulation. As expected, in vitro dissolution appeared to be generally predictive of in vivo PK profiles, because of the unique feature of this delivery system that the in vitro and in vivo release of osmotic pump drug products is less susceptible to surrounding environment in the gastrointestinal (GI) tract such as pH, hydrodynamic, and food effects...
March 29, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28353217/hypoxic-stress-and-inflammatory-pain-disrupt-blood-brain-barrier-tight-junctions-implications-for-drug-delivery-to-the-central-nervous-system
#7
Jeffrey J Lochhead, Patrick T Ronaldson, Thomas P Davis
A functional blood-brain barrier (BBB) is necessary to maintain central nervous system (CNS) homeostasis. Many diseases affecting the CNS, however, alter the functional integrity of the BBB. It has been shown that various diseases and physiological stressors can impact the BBB's ability to selectively restrict passage of substances from the blood to the brain. Modifications of the BBB's permeability properties can potentially contribute to the pathophysiology of CNS diseases and result in altered brain delivery of therapeutic agents...
March 28, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28353216/dissolution-comparisons-using-a-multivariate-statistical-distance-msd-test-and-a-comparison-of-various-approaches-for-calculating-the-measurements-of-dissolution-profile-comparison
#8
J-M Cardot, B Roudier, H Schütz
The f 2 test is generally used for comparing dissolution profiles. In cases of high variability, the f 2 test is not applicable, and the Multivariate Statistical Distance (MSD) test is frequently proposed as an alternative by the FDA and EMA. The guidelines provide only general recommendations. MSD tests can be performed either on raw data with or without time as a variable or on parameters of models. In addition, data can be limited-as in the case of the f 2 test-to dissolutions of up to 85% or to all available data...
March 28, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28332167/controlled-release-of-vanadium-from-a-composite-scaffold-stimulates-mesenchymal-stem-cell-osteochondrogenesis
#9
S D Schussler, K Uske, P Marwah, F W Kemp, J D Bogden, S S Lin, Treena Livingston Arinzeh
Large bone defects often require the use of autograft, allograft, or synthetic bone graft augmentation; however, these treatments can result in delayed osseous integration. A tissue engineering strategy would be the use of a scaffold that could promote the normal fracture healing process of endochondral ossification, where an intermediate cartilage phase is later transformed to bone. This study investigated vanadyl acetylacetonate (VAC), an insulin mimetic, combined with a fibrous composite scaffold, consisting of polycaprolactone with nanoparticles of hydroxyapatite and beta-tricalcium phosphate, as a potential bone tissue engineering scaffold...
March 22, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28321831/the-impact-of-gastric-ph-volume-and-emptying-on-the-food-effect-of-ziprasidone-oral-absorption
#10
Steven C Sutton, Richard Nause, Kuan Gandelman
In a recent food effect clinical study, the authors concluded that a meal consisting of ≥500 kcal, regardless of fat content, produced the maximal bioavailability for ziprasidone. Using GastroPlus™, a commercially available pharmacokinetic simulation software, a semiphysiological model-a kind of physiologically based pharmacokinetic (PBPK) absorption model-was developed that could predict the concentration-time profiles when ziprasidone was administered with any one of the five test meals or fasting. Ziprasidone intravenous pharmacokinetics and oral absorption permeability were determined from clinical studies following the intravenous and duodenal infusion of ziprasidone to volunteers...
March 20, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28321830/current-trends-in-ligand-binding-real-time-measurement-technologies
#11
Stephanie Fraser, Judy Y Shih, Mark Ware, Edward O'Connor, Mark J Cameron, Martin Schwickart, Xuemei Zhao, Karin Regnstrom
Numerous advances in ligand binding assay (LBA) real-time measurement technologies have been made within the last several years, ranging from the development of novel platforms to drive technology expansion to the adaptation of existing platforms to optimize performance and throughput. In this review, we have chosen to focus on technologies that provide increased value to two distinct segments of the LBA community. First, experimentally, by measuring real-time binding events, these technologies provide data that can be used to interrogate receptor/ligand binding interactions...
March 20, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28283948/evaluation-of-the-potency-neutralizing-antibody-response-and-stability-of-a-recombinant-fusion-protein-vaccine-for-streptococcus-pyogenes
#12
E Burlet, H HogenEsch, A Dunham, G Morefield
Streptococcus pyogenes or group A streptococcus (GAS) is a Gram-positive bacterium that can cause a wide range of diseases, including pharyngitis, impetigo, scarlet fever, necrotizing fasciitis, rheumatic fever, and streptococcal toxic shock syndrome. Despite the increasing burden on global health caused by GAS, there is currently no licensed vaccine available. In this study, we evaluated immunogenicity, induction of neutralizing antibodies, and stability of a new recombinant fusion protein vaccine that targets infections from GAS...
March 10, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28281196/pharmacokinetics-of-the-inhaled-selective-glucocorticoid-receptor-modulator-azd5423-following-inhalation-using-different-devices
#13
Johanna Melin, Susanne Prothon, Charlotte Kloft, Adriaan Cleton, Carl Amilon, Carin Jorup, Per Bäckman, Bo Olsson, Ulrika Wählby Hamrén
AZD5423 is a non-steroidal glucocorticoid receptor modulator, with low aqueous solubility, developed for treatment of asthma and COPD. In this work, we aim to evaluate and compare the absorption pharmacokinetics (PK) of AZD5423 after inhalation via four devices, (Spira®, I-neb®, Turbuhaler® and a new dry powder inhaler (new DPI)) with two formulations using differently sized primary particles, and to compare the pulmonary bioavailability with the predicted lung deposited dose. Plasma concentration-time data after intravenous, oral and inhaled administration via four devices were available from two clinical studies in healthy and asthmatic subjects...
March 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28281195/microdialysis-the-key-to-physiologically-based-model-prediction-of-human-cns-target-site-concentrations
#14
Yumi Yamamoto, Meindert Danhof, Elizabeth C M de Lange
Despite the enormous research efforts that have been put into the development of central nervous system (CNS) drugs, the success rate in this area is still disappointing. To increase the successful rate in the clinical trials, first the problem of predicting human CNS drug distribution should be solved. As it is the unbound drug that equilibrates over membranes and is able to interact with targets, especially knowledge on unbound extracellular drug concentration-time profiles in different CNS compartments is important...
March 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28281194/development-considerations-for-nanocrystal-drug-products
#15
Mei-Ling Chen, Mathew John, Sau L Lee, Katherine M Tyner
Nanocrystal technology has emerged as a valuable tool for facilitating the delivery of poorly water-soluble active pharmaceutical ingredients (APIs) and enhancing API bioavailability. To date, the US Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals. These products can be delivered by different routes of administration and are used in a variety of therapeutic areas. To aid in identifying key developmental considerations for these products, a retrospective analysis was performed on the submissions received by the FDA to date...
March 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28265983/global-harmonization-of-comparator-products-for-bioequivalence-studies
#16
Luther Gwaza, John Gordon, Hubert Leufkens, Matthias Stahl, Alfredo García-Arieta
Comparator products should be the products that were shown to be safe and efficacious in pivotal clinical trials to ensure prescribability of generics. The use of a common comparator ensures switchability between generics. The selection of the comparator is a national responsibility and may be different between countries. This paper discusses the current recommendations on selection of comparators, the associated problems, and the possibility of harmonization. Most countries follow the World Health Organization (WHO) recommendations for selecting comparator products and require the comparator product to be obtained from their national markets to ensure switchability between the local comparator and their generics...
March 6, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28265982/structure-promiscuity-relationship-puzzles-extensively-assayed-analogs-with-large-differences-in-target-annotations
#17
Ye Hu, Swarit Jasial, Erik Gilberg, Jürgen Bajorath
Publicly available screening data were systematically searched for extensively assayed structural analogs with large differences in the number of targets they were active against. Screening compounds with potential chemical liabilities that may give rise to assay artifacts were identified and excluded from the analysis. "Promiscuity cliffs" were frequently identified, defined here as pairs of structural analogs with a difference of at least 20 target annotations across all assays they were tested in. New assay indices were introduced to prioritize cliffs formed by screening compounds that were extensively tested in comparably large numbers of assays including many shared assays...
March 6, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28265981/exploring-canine-human-differences-in-product-performance-part-ii-use-of-modeling-and-simulation-to-explore-the-impact-of-formulation-on-ciprofloxacin-in-vivo-absorption-and-dissolution-in-dogs
#18
M N Martinez, B Mistry, V Lukacova, K A Lentz, J E Polli, S W Hoag, T Dowling, R Kona, R M Fahmy
This study explored the in vivo performance of three oral ciprofloxacin formulations (oral solution, fast, or slow dissolving tablets) in beagle dogs. The in vivo absorption and dissolution behaviors, estimated with in silico mechanistic models, were compared to the results previously published in human volunteers. Six normal healthy male beagle dogs (five to completion) received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by tandem mass spectrometry detection...
March 6, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28247193/modeling-a-composite-score-in-parkinson-s-disease-using-item-response-theory
#19
Gopichand Gottipati, Mats O Karlsson, Elodie L Plan
In the current work, we present the methodology for development of an Item Response Theory model within a non-linear mixed effects framework to characterize the longitudinal changes of the Movement Disorder Society (sponsored revision) of Unified Parkinson's Disease Rating Scale (MDS-UPDRS) endpoint in Parkinson's disease (PD). The data were obtained from Parkinson's Progression Markers Initiative database and included 163,070 observations up to 48 months from 430 subjects belonging to De Novo PD cohort. The probability of obtaining a score, reported for each of the items in the questionnaire, was modeled as a function of the subject's disability...
February 28, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28247192/a-proposal-to-redefine-clinical-immunogenicity-assessment
#20
Daniel T Mytych, M Benjamin Hock, Mark Kroenke, Vibha Jawa, Arunan Kaliyaperumal, Yanchen Zhou
With more than 100 therapeutic proteins (TP) approved since the first EMA guidance on immunogenicity in 2007, a vast amount of clinical experience with a variety of therapeutic proteins has been gained. This has provided data on anti-drug antibodies (ADA) and their observed clinical impact, or lack thereof. It has become evident that not all ADA responses are clinically relevant. The current "standard practice" is to test for ADA in all patients on every study. It is essential that we acknowledge the immunogenicity data gained from marketed TPs and that options for immunogenicity testing reflect this information...
February 28, 2017: AAPS Journal
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