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AAPS Journal

Chen Qiu, Hongbin Zhu, Connie Ruzicka, David Keire, Hongping Ye
Penicillins and some non-penicillin β-lactams may cause potentially life-threatening allergic reactions. Thus, possible cross contamination of β-lactams in food or drugs can put people at risk. Therefore, when there is a reasonable possibility that a non-penicillin product could be contaminated by penicillin, the drug products are tested for penicillin contamination. Here, a sensitive and rapid method for simultaneous determination of multiple β-lactam antibiotics using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated...
May 15, 2018: AAPS Journal
Lambertus A Peletier, Johan Gabrielsson
In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target...
May 14, 2018: AAPS Journal
Kristof Vandekerckhove, Andreas Seidl, Hiten Gutka, Manish Kumar, Gyöngyi Gratzl, David Keire, Todd Coffey, Henriette Kuehne
Leading regulatory agencies recommend biosimilar assessment to proceed in a stepwise fashion, starting with a detailed analytical comparison of the structural and functional properties of the proposed biosimilar and reference product. The degree of analytical similarity determines the degree of residual uncertainty that must be addressed through downstream in vivo studies. Substantive evidence of similarity from comprehensive analytical testing may justify a targeted clinical development plan, and thus enable a shorter path to licensing...
May 10, 2018: AAPS Journal
Scott Ferguson, Sera Kim, Christine Lee, Michael Deci, Juliane Nguyen
Exosomes are nano-sized vesicles composed of lipids, proteins, and nucleic acids. Their molecular landscape is diverse, and exosomes derived from different cell types have distinct biological activities. Since exosomes are now being utilized as delivery vehicles for exogenous therapeutic cargoes, their intrinsic properties and biological effects must be understood. We performed miRNA profiling and found substantial differences in the miRNA landscape of prostate cancer (PC3) and human embryonic kidney (HEK) 293 exosomes with little correlation in abundance of common miRNAs (R2  = 0...
April 30, 2018: AAPS Journal
Mohammad Tabrizi, Daping Zhang, Vaishnavi Ganti, Glareh Azadi
With the recent advances in cancer immunotherapy, it is now evident that the antigen-specific activation of the patients' immune responses can be utilized for achieving significant therapeutic benefits. Novel molecules have been developed and promising advances have been achieved in cancer therapy. The recent success of cancer immunotherapy clearly reflects the novelty of the approach and importance of this class of therapeutics. Due to the nature of immunotherapy, i.e., harnessing the patient's immune system, it becomes critical to evaluate the important variables that can guide preclinical development, translational strategies, patient selection, and effective clinical dosing paradigms following single and combination therapies...
April 27, 2018: AAPS Journal
Shannon D Chilewski, Julie Shields, Johanna R Mora, Heather Myler
PEGylation is a modification commonly used to increase the half-life of therapeutic proteins. The strategy for immunogenicity testing of these compounds should include methods to detect both anti-protein and anti-PEG antibodies. We previously reported a method for the detection of anti-PEG antibodies using ProterixBio's (formerly BioScale) acoustic membrane microparticle (AMMP) technology. Our initial method development work showed the assay was capable of detecting antibodies in human serum with a sensitivity of 1 μg/mL with good reproducibility (CV < 7%)...
April 24, 2018: AAPS Journal
Theodoros Papathanasiou, Anders Strathe, Andrew C Hooker, Trine Meldgaard Lund, Rune Viig Overgaard
The exposure-response relationship of combinatory drug effects can be quantitatively described using pharmacodynamic interaction models, which can be used for the selection of optimal dose combinations. The aim of this simulation study was to evaluate the reliability of parameter estimates and the probability for accurate dose identification for various underlying exposure-response profiles, under a number of different phase II designs. An efficacy variable driven by the combined exposure of two theoretical compounds was simulated and model parameters were estimated using two different models, one estimating all parameters and one assuming that adequate previous knowledge for one drug is readily available...
April 23, 2018: AAPS Journal
Weirong Wang, Jocelyn Leu, Rebecca Watson, Zhenhua Xu, Honghui Zhou
A prominent example of human therapeutic protein-drug interaction (TP-DI) is between methotrexate (MTX) and anti-TNFα mAbs. One plausible mechanism for this TP-DI is through the pharmacodynamic effect of MTX on immunogenicity. However, there is no definitive evidence to substantiate this mechanism, and other competing hypotheses, such as MTX suppressing FcγRI expression thereby affecting mAb PK, have also been proposed. In order to understand this mechanism, a cynomolgus monkey study was conducted using golimumab as a model compound...
April 17, 2018: AAPS Journal
Meng Hu, Xiaohui Jiang, Mohammad Absar, Stephanie Choi, Darby Kozak, Meiyu Shen, Yu-Ting Weng, Liang Zhao, Robert Lionberger
Particle size distribution (PSD) is an important property of particulates in drug products. In the evaluation of generic drug products formulated as suspensions, emulsions, and liposomes, the PSD comparisons between a test product and the branded product can provide useful information regarding in vitro and in vivo performance. Historically, the FDA has recommended the population bioequivalence (PBE) statistical approach to compare the PSD descriptors D50 and SPAN from test and reference products to support product equivalence...
April 12, 2018: AAPS Journal
Andreas Abend, Tycho Heimbach, Michael Cohen, Filippos Kesisoglou, Xavier Pepin, Sandra Suarez-Sharp
On May 15th-17th, 2017, the US FDA and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) held a workshop at the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI), to discuss the role of dissolution testing and translational modeling and simulation in enabling patient-centric solid oral drug product development. This 3-day event was attended by scientists from regulatory agencies, pharmaceutical companies, and academia. The workshop included podium presentations followed by breakout session discussions...
April 9, 2018: AAPS Journal
Yuemin Bian, Xiang-Qun Sean Xie
Fragment-based drug design (FBDD) has become an effective methodology for drug development for decades. Successful applications of this strategy brought both opportunities and challenges to the field of Pharmaceutical Science. Recent progress in the computational fragment-based drug design provide an additional approach for future research in a time- and labor-efficient manner. Combining multiple in silico methodologies, computational FBDD possesses flexibilities on fragment library selection, protein model generation, and fragments/compounds docking mode prediction...
April 9, 2018: AAPS Journal
Yankang Jing, Yuemin Bian, Ziheng Hu, Lirong Wang, Xiang-Qun Sean Xie
Over the last decade, deep learning (DL) methods have been extremely successful and widely used to develop artificial intelligence (AI) in almost every domain, especially after it achieved its proud record on computational Go. Compared to traditional machine learning (ML) algorithms, DL methods still have a long way to go to achieve recognition in small molecular drug discovery and development. And there is still lots of work to do for the popularization and application of DL for research purpose, e.g., for small molecule drug research and development...
March 30, 2018: AAPS Journal
Simon Buatois, Sebastian Ueckert, Nicolas Frey, Sylvie Retout, France Mentré
In drug development, pharmacometric approaches consist in identifying via a model selection (MS) process the model structure that best describes the data. However, making predictions using a selected model ignores model structure uncertainty, which could impair predictive performance. To overcome this drawback, model averaging (MA) takes into account the uncertainty across a set of candidate models by weighting them as a function of an information criterion. Our primary objective was to use clinical trial simulations (CTSs) to compare model selection (MS) with model averaging (MA) in dose finding clinical trials, based on the AIC information criterion...
March 29, 2018: AAPS Journal
Bart Hens, Arjang Talattof, Paulo Paixão, Marival Bermejo, Yasuhiro Tsume, Raimar Löbenberg, Gordon L Amidon
For the last two decades, the application of physiologically based pharmacokinetic (PBPK) models has grown exponentially in the field of oral absorption and in a regulatory context. Although these models are widely used, their predictive power should be validated and optimized in order to rely on these models and to know exactly what is going on "under the hood". In this study, an automated sensitivity analysis (ASA) was performed for 11 gastrointestinal (GI) variables that are integrated into the PBPK software program Simcyp®...
March 29, 2018: AAPS Journal
Philippe B Pierrillas, Sylvain Fouliard, Marylore Chenel, Andrew C Hooker, Lena E Friberg, Mats O Karlsson
The middle initial in the fifth author's name is incorrect in the original article. "Lena F. Friberg" should be "Lena E. Friberg". The original article was corrected.
March 27, 2018: AAPS Journal
Yaxia Yuan, Fang Zheng, Chang-Guo Zhan
Blood-brain barrier (BBB) permeability of a compound determines whether the compound can effectively enter the brain. It is an essential property which must be accounted for in drug discovery with a target in the brain. Several computational methods have been used to predict the BBB permeability. In particular, support vector machine (SVM), which is a kernel-based machine learning method, has been used popularly in this field. For SVM training and prediction, the compounds are characterized by molecular descriptors...
March 21, 2018: AAPS Journal
Xiabin Chen, Jing Deng, Wenpeng Cui, Shurong Hou, Jinling Zhang, Xirong Zheng, Xin Ding, Huimei Wei, Ziyuan Zhou, Kyungbo Kim, Chang-Guo Zhan, Fang Zheng
Cocaine abuse is a worldwide public health and social problem without a US Food and Drug Administration (FDA)-approved medication. Accelerating cocaine metabolism that produces biologically inactive metabolites by administration of an efficient cocaine hydrolase (CocH) has been recognized as a promising strategy for cocaine abuse treatment. However, the therapeutic effects of CocH are limited by its short biological half-life (e.g., 8 h or shorter in rats). In this study, we designed and prepared a set of Fc-fusion proteins constructed by fusing Fc(M3) with CocH3 at the N-terminus of CocH3...
March 19, 2018: AAPS Journal
Karen Liao, Stacy Derbyshire, Kai-Fen Wang, Cherilyn Caucci, Shuo Tang, Claire Holland, Amy Loercher, George R Gunn
Bridging immunoassays commonly used to detect and characterize immunogenicity during biologic development do not provide direct information on the presence or development of a memory anti-drug antibody (ADA) response. In this study, a B cell ELISPOT assay method was used to evaluate pre-existing ADA for anti-TNFR1 domain antibody, GSK1995057, an experimental biologic in treatment naive subjects. This assay utilized a 7-day activation of PBMCs by a combination of GSK1995057 (antigen) and polyclonal stimulator followed by GSK1995057-specific ELISPOT for the enumeration of memory B cells that have differentiated into antibody secreting cells (ASC) in vitro...
March 16, 2018: AAPS Journal
Christian Hove Rasmussen, Mike K Smith, Kaori Ito, Vijayakumar Sundararajan, Mats O Magnusson, E Niclas Jonsson, Luke Fostvedt, Paula Burger, Lynn McFadyen, Thomas G Tensfeldt, Timothy Nicholas
Every year, the pharmaceutical industry generates a large number of scientific reports related to drug research, development, and regulatory submissions. Many of these reports are created using text processing tools such as Microsoft Word. Given the large number of figures, tables, references, and other elements, this is often a tedious task involving hours of copying and pasting and substantial efforts in quality control (QC). In the present article, we present the LaTeX-based open-source reporting platform, PharmTeX, a community-based effort to make reporting simple, reproducible, and user-friendly...
March 16, 2018: AAPS Journal
Kyle I Mentkowski, Jonathan D Snitzer, Sarah Rusnak, Jennifer K Lang
Extracellular vesicles (EVs) comprise a heterogeneous group of small membrane vesicles, including exosomes, which play a critical role in intracellular communication and regulation of numerous physiological processes in health and disease. Naturally released from virtually all cells, these vesicles contain an array of nucleic acids, lipids and proteins which they transfer to target cells within their local milieu and systemically. They have been proposed as a means of "cell-free, cell therapy" for cancer, immune disorders, and more recently cardiovascular disease...
March 15, 2018: AAPS Journal
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