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https://www.readbyqxmd.com/read/28321831/the-impact-of-gastric-ph-volume-and-emptying-on-the-food-effect-of-ziprasidone-oral-absorption
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/28247191/a-lc-ms-all-in-one-workflow-for-site-specific-location-identification-and-quantification-of-n-o-glycosylation-in-human-chorionic-gonadotropin-drug-products
#12
Hongbin Zhu, Chen Qiu, Ashley C Ruth, David A Keire, Hongping Ye
Site-specific characterization of the N- and O-linked glycosylation on a set of different human chorionic gonadotropin (hCG) drug products was performed by a LC-MS method combining high resolution (120K at m/z 200) mass spectrometry, multiple dissociation methods, tandem mass tag (TMT 10plex) labeling, and partial least squares-discriminant analysis (PLS-DA). In total, the data provided identification, relative quantification, and comparison of site-specific glycosylation of protein therapeutics with a single experiment...
February 28, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28236228/characterising-drug-release-from-immediate-release-formulations-of-a-poorly-soluble-compound-basmisanil-through-absorption-modelling-and-dissolution-testing
#13
Cordula Stillhart, Neil J Parrott, Marc Lindenberg, Pascal Chalus, Darren Bentley, Anikó Szepes
The study aimed to characterise the mechanism of release and absorption of Basmisanil, a biopharmaceutics classification system (BCS) class 2 compound, from immediate-release formulations via mechanistic absorption modelling, dissolution testing, and Raman imaging. An oral absorption model was developed in GastroPlus® and verified with single-dose pharmacokinetic data in humans. The properties and drug release behaviour of different oral Basmisanil formulations were characterised via biorelevant dissolution and Raman imaging studies...
February 24, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28233244/aptamer-conjugated-chitosan-anchored-liposomal-complexes-for-targeted-delivery-of-erlotinib-to-egfr-mutated-lung-cancer-cells
#14
Fengqiao Li, Hao Mei, Xiaodong Xie, Huijuan Zhang, Jian Liu, Tingting Lv, Huifang Nie, Yu Gao, Lee Jia
Lung cancer is the leading cancer and has the highest death rate. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has had a promising response in lung cancer therapy. Unfortunately, individuals with TKI-resistant EGFR mutations often develop acquired resistance against erlotinib. To overcome this resistance, in the present study, we developed liposomes anchored with anti-EGFR aptamer (Apt)-conjugated chitosan (Apt-Cs) as stable carriers to deliver erlotinib to the target...
February 23, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28233243/erratum-to-reliable-rate-measurements-for-active-and-passive-hepatic-uptake-using-plated-human-hepatocytes
#15
Yi-An Bi, Renato J Scialis, Sarah Lazzaro, Sumathy Mathialagan, Emi Kimoto, Julie Keefer, Hui Zhang, Anna M Vildhede, Chester Costales, A David Rodrigues, Larry M Tremaine, Manthena V S Varma
No abstract text is available yet for this article.
February 23, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28224402/assessment-of-correlation-between-early-and-late-efficacy-endpoints-to-identify-potential-surrogacy-relationships-in-non-hodgkin-lymphoma-a-literature-based-meta-analysis-of-108-phase-ii-and-phase-iii-studies
#16
Rui Zhu, Dan Lu, Yu-Waye Chu, Akiko Chai, Michelle Green, Nancy Zhang, Jin Yan Jin
Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II-III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson's coefficient of determination (R (2))...
February 21, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28204967/advantageous-solubility-permeability-interplay-when-using-amorphous-solid-dispersion-asd-formulation-for-the-bcs-class-iv-p-gp-substrate-rifaximin-simultaneous-increase-of-both-the-solubility-and-the-permeability
#17
Avital Beig, Noa Fine-Shamir, David Lindley, Jonathan M Miller, Arik Dahan
Rifaximin is a BCS class IV (low-solubility, low-permeability) drug and also a P-gp substrate. The aims of this work were to assess the efficiency of different rifaximin amorphous solid dispersion (ASDs) formulations in achieving and maintaining supersaturation and to investigate the consequent solubility-permeability interplay. Spray-dried rifaximin ASDs were prepared with different hydrophilic polymers and their ability to achieve and maintain supersaturation was assessed. Then, rifaximin's apparent intestinal permeability was investigated as a function of increasing supersaturation both in vitro using the parallel artificial membrane permeability assay (PAMPA) and in vivo using the single-pass rat intestinal perfusion (SPIP) model...
February 15, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28197827/phloretin-prevents-high-fat-diet-induced-obesity-and-improves-metabolic-homeostasis
#18
Sary Alsanea, Mingming Gao, Dexi Liu
Reactive oxygen species generated as a by-product in metabolism play a central role in the development of obesity and obesity-related metabolic complications. The objective of the current study is to explore the possibility to block obesity and improve metabolic homeostasis via phloretin, a natural antioxidant product from apple tree leaves and Manchurian apricot. Both preventive and therapeutic activities of phloretin were assessed using a high-fat diet-induced obesity mouse model. Phloretin was injected intraperitoneally twice weekly into regular and obese mice fed a high-fat diet...
February 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28194704/challenges-and-future-prospects-for-the-delivery-of-biologics-oral-mucosal-pulmonary-and-transdermal-routes
#19
Javier O Morales, Kristin R Fathe, Ashlee Brunaugh, Silvia Ferrati, Song Li, Miguel Montenegro-Nicolini, Zeynab Mousavikhamene, Jason T McConville, Mark R Prausnitz, Hugh D C Smyth
Biologic products are large molecules such as proteins, peptides, nucleic acids, etc., which have already produced many new drugs for clinical use in the last decades. Due to the inherent challenges faced by biologics after oral administration (e.g., acidic stomach pH, digestive enzymes, and limited permeation through the gastrointestinal tract), several alternative routes of administration have been investigated to enable sufficient drug absorption into systemic circulation. This review describes the buccal, sublingual, pulmonary, and transdermal routes of administration for biologics with relevant details of the respective barriers...
February 13, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28188574/reliable-rate-measurements-for-active-and-passive-hepatic-uptake-using-plated-human-hepatocytes
#20
Yi-An Bi, Renato J Scialis, Sarah Lazzaro, Sumathy Mathialagan, Emi Kimoto, Julie Keefer, Hui Zhang, Anna M Vildhede, Chester Costales, A David Rodrigues, Larry M Tremaine, Manthena V S Varma
Transporter-mediated hepatic uptake is proven to be the rate-determining step in the systemic clearance of several drugs. Therefore, accurate measurement of active and passive uptake clearances in vitro is critical to facilitate pharmacokinetics and drug-drug interaction predictions. Here, we evaluated the plated human hepatocytes (PHH) and studied the effect of incubation temperature and inhibitor concentration on uptake measurements, in order to reliably estimate hepatic uptake components. Uptake rates measured using PHH, at 37°C without and with rifamycin SV, were comparable with those obtained from suspension hepatocytes and sandwich-cultured hepatocytes for a set of 10-13 compounds...
February 10, 2017: AAPS Journal
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