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AAPS Journal

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https://www.readbyqxmd.com/read/30446887/effect-of-the-plasticizer-dehp-in-blood-collection-bags-on-human-plasma-fraction-unbound-determination-for-alpha-1-acid-glycoprotein-aag-binding-drugs
#1
Nicholas Ingram, Christopher Dishinger, Jennifer Wood, J Matthew Hutzler, Sherri Smith, Michael Huskin
Fraction unbound (fu ) is a critical drug distribution parameter commonly utilized for modeling efficacious dosage and safety margin predictions. An over-estimation of fu for 13 chemically diverse small molecule drugs primarily bound to alpha-1-acid glycoprotein (AAG) in human plasma was discovered when in vitro results from our screening lab were compared to literature values. Di-(2-ethylhexyl) phthalate (DEHP), a plasticizer known to be used in the manufacture of blood collection bags, was extracted from plasma obtained through three common techniques that allowed contact with DEHP, and drug fu values in plasma from each collection method were estimated using the HTDialysis protein binding methodology...
November 16, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30402825/approaches-to-resolve-false-reporting-in-neutralizing-antibody-assays-caused-by-reagent-leaching-from-affinity-capture-elution-solid-phase
#2
Yuhong Xiang, John Kamerud, Jean Donley, Katrina Olson, Teresa Caiazzo, Dave Yeung, Chuenlei Parng, Boris Gorovits
Insufficient drug tolerance presents a major challenge in the development of neutralizing antibody (NAb) assays for biotherapeutics. Sample pre-treatment using solid-phase extraction with acid dissociation (SPEAD) is widely reported to improve drug tolerance. In this paper, a case study is presented in which SPEAD was used in conjunction with a competitive ligand binding NAb assay format. A significant degree of biotin-drug conjugate leaching was observed resulting in the reporting of both false positive and false negative results in NAb assay...
November 6, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30397860/in-vitro-and-in-vivo-efficacy-of-the-monocarboxylate-transporter-1-inhibitor-ar-c155858-in-the-murine-4t1-breast-cancer-tumor-model
#3
Xiaowen Guan, Mark A Bryniarski, Marilyn E Morris
Monocarboxylate transporter 1 (MCT1), also known as a L-lactate transporter, is a potential therapeutic target in cancer. The objectives of this study were to evaluate efficacy and assess concentration-effect relationships of AR-C155858 (a selective and potent MCT1 inhibitor) in murine 4T1 breast cancer cells and in the 4T1 tumor xenograft model. Western blotting of 4T1 cells demonstrated triple negative breast cancer (TNBC) characteristics and overexpression of MCT1 and CD147 (a MCT1 accessory protein), but absence of MCT4 expression...
November 5, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30392015/the-journey-to-aaps-2020-a-reflection-from-strategic-planning-to-pharmsci-360
#4
EDITORIAL
Joseph W Polli, Christopher R McCurdy, Dale Eric Wurster, Binodh S DeSilva, Annette Bak, Reina Bendayan, Bernd Meibohm, Allen C Templeton, William Weiser
No abstract text is available yet for this article.
November 3, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30377854/population-pharmacokinetics-of-al-335-and-its-two-main-metabolites-als-022399-als-022227-in-monotherapy-and-in-combination-with-odalasvir-and-or-simeprevir
#5
Elodie Valade, Thomas N Kakuda, Matthew W McClure, Christopher Westland, Belén Valenzuela, Sivi Ouwerkerk-Mahadevan, Juan José Perez-Ruixo, Oliver Ackaert
The aim of the current study was to characterize the time course of plasma concentrations of AL-335 and its main metabolites (ALS-022399 and ALS-022227) after oral administration in healthy and hepatitis C virus (HCV)-infected subjects, in monotherapy as well as in combination with simeprevir and/or odalasvir. AL-335, ALS-022399, and ALS-022227 plasma concentrations from subjects receiving 800 mg of AL-335 orally once daily (qd) as monotherapy or in combination were pooled and analyzed using a nonlinear mixed effect modeling approach...
October 24, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30350297/characterizing-the-pharmacokinetic-interaction-between-simeprevir-and-odalasvir-in-healthy-volunteers-using-a-population-modeling-approach
#6
Elodie Valade, Belén Valenzuela, Thomas N Kakuda, Christopher Westland, Matthew W McClure, Sivi Ouwerkerk-Mahadevan, Juan José Perez-Ruixo, Oliver Ackaert
The aim of this study was to characterize the pharmacokinetic drug-drug interaction (DDI) between simeprevir (NS3/4A protease inhibitor) and odalasvir (NS5A inhibitor) after oral administration to support the design and dose selection of clinical studies with this combination for the treatment of chronic hepatitis C infection (HCV). Simeprevir and odalasvir plasma concentrations from 30 healthy subjects receiving these drugs in monotherapy as well as in combination were pooled and analyzed using a population pharmacokinetic modeling approach...
October 22, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30350232/conjugation-to-ascorbic-acid-enhances-brain-availability-of-losartan-carboxylic-acid-and-protects-against-parkinsonism-in-rats
#7
Bharat Bhusan Subudhi, Pratap Kumar Sahu, Vijay Kumar Singh, Shaktiketan Prusty
Identification of renin-angiotensin system in the interplay of hypertension and neurodegeneration has paved the way for the repurposing of antihypertensive drugs against Parkinsonism. Losartan carboxylic acid (LCA), the potent AT1 blocker metabolite of losartan, suffers from poor bioavailability and brain access. Since ascorbate transporters have earlier shown enough flexibility as carriers, we have conjugated losartan carboxylic acid to ascorbic acid with the aim of achieving higher oral/brain availability...
October 22, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30324224/risk-based-comparability-assessment-for-monoclonal-antibodies-during-drug-development-a-clinical-pharmacology-perspective
#8
Yanli Zhuang, Di Chen, Amarnath Sharma, Zhenhua Xu
Due to complexities in the structure, function, and manufacturing process of antibody-based therapeutic proteins, comparability assessment for supporting manufacturing changes can sometimes be a challenging task. Regulatory guidance recommends a hierarchical risk-based approach, starting with Chemistry, Manufacturing, and Controls (CMC) analytical characterizations, followed by non-clinical and/or clinical studies to ensure that any potential changes in quality attributes have no adverse impact on efficacy and safety of the product...
October 15, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30306365/nanoparticle-based-delivery-of-crispr-cas9-genome-editing-therapeutics
#9
Brittany E Givens, Youssef W Naguib, Sean M Geary, Eric J Devor, Aliasger K Salem
The recent progress in harnessing the efficient and precise method of DNA editing provided by CRISPR/Cas9 is one of the most promising major advances in the field of gene therapy. However, the development of safe and optimally efficient delivery systems for CRISPR/Cas9 elements capable of achieving specific targeting of gene therapy to the location of interest without off-target effects is a primary challenge for clinical therapeutics. Nanoparticles (NPs) provide a promising means to meet such challenges. In this review, we present the most recent advances in developing innovative NP-based delivery systems that efficiently deliver CRISPR/Cas9 constructs and maximize their effectiveness...
October 10, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30298434/tissue-physiology-of-cynomolgus-monkeys-cross-species-comparison-and-implications-for-translational-pharmacology
#10
Danielle Mandikian, Isabel Figueroa, Amy Oldendorp, Hanine Rafidi, Sheila Ulufatu, Michelle G Schweiger, Jessica A Couch, Noel Dybdal, Sean B Joseph, Saileta Prabhu, Gregory Z Ferl, C Andrew Boswell
We previously performed a comparative assessment of tissue-level vascular physiological parameters in mice and rats, two of the most commonly utilized species in translational drug development. The present work extends this effort to non-human primates by measuring tissue- and organ-level vascular volumes (Vv ), interstitial volumes (Vi ), and blood flow rates (Q) in cynomolgus monkeys. These measurements were accomplished by red blood cell labeling, extracellular marker infusion, and rubidium chloride bolus distribution, respectively, the same methods used in previous rodent measurements...
October 8, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30280294/reverse-engineering-the-1-month-lupron-depot%C3%A2
#11
Jia Zhou, Keiji Hirota, Rose Ackermann, Jennifer Walker, Yan Wang, Stephanie Choi, Anna Schwendeman, Steven P Schwendeman
The 1-month Lupron Depot® (LD) encapsulating water-soluble leuprolide in poly(lactic-co-glycolic acid) (PLGA) microspheres is a benchmark product upon which modern long-acting release products are often compared. Despite expiration of patent coverage, no generic product for the LD has been approved in the USA, likely due to the complexity of components and manufacturing processes involved in the product. Here, we describe the reverse engineering of the LD composition and important product attributes. Specific attributes analyzed for microspheres were as follows: leuprolide content by three methods; gelatin content, type, and molecular weight distribution; PLGA content, lactic acid/glycolic acid ratio, and molecular weight distribution; mannitol content; in vitro drug release; residual solvent and moisture content; particle size distribution and morphology; and glass transition temperature...
October 2, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30280286/a-gyrolab-assay-for-the-quantitation-of-free-complement-protein-c5a-in-human-plasma
#12
Mark Dysinger, Mark Ma
Complement protein C5a is recognized as an important component of the alternative complement pathway. Its role is prominent enough to garner interest not only as a biomarker, but also as a potential therapeutic target. Bioanalytical challenges have been posed in proper quantitation of free C5a due to interference from its precursor, C5. Additionally, free therapeutic target quantitation can be difficult due to effects of sample dilution and prolonged sample incubation when therapeutic is used as capture reagent...
October 2, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30255312/correction-to-reflections-on-fda-draft-guidance-for-products-containing-nanomaterials-is-the-abbreviated-new-drug-application-anda-a-suitable-pathway-for-nanomedicines
#13
Emily Marden, Ioanna Ntai, Scott Bass, Beat Flühmann
In the published article the given name and the family name for each author is listed in the incorrect order and therefore cited incorrectly. The correct order (given name followed by family name) of names is listed above.
September 25, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30255287/the-properties-of-cysteine-conjugated-antibody-drug-conjugates-are-impacted-by-the-igg-subclass
#14
Amita Datta-Mannan, Hiuwan Choi, David Stokell, Jason Tang, Anthony Murphy, Aaron Wrobleski, Yiqing Feng
Among the numerous antibody-drug conjugate (ADC) clinical candidates, one of the most prevalent types utilizes the interchain cysteines in antibodies to conjugate auristatin via a maleimide-containing linker. In this class of ADCs, there are a paucity of systematic studies characterizing how IgG subclass influences the biophysical properties and in vivo pharmacokinetics of the ADC molecules. In the current investigation, we studied cysteine-conjugated ADCs using a model system consisting of human IgG1, IgG2, and IgG4 antibodies with the same variable region...
September 25, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30209711/michaelis-menten-from-an-in-vivo-perspective-open-versus-closed-systems
#15
Johan Gabrielsson, Lambertus A Peletier
After a century of applications of the seminal Michaelis-Menten equation since its advent it is timely to scrutinise its principal parts from an in vivo point of view. Thus, the Michaelis-Menten system was revisited in which enzymatic turnover, i.e. synthesis and elimination was incorporated. To the best of our knowledge, previous studies of the Michaelis-Menten system have been mainly based on the assumption that the total pool of enzyme, free and bound, is constant. However, in fact this may not always be the case, particularly for chronic indications...
September 12, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30209693/additive-manufacturing-with-3d-printing-progress-from-bench-to-bedside
#16
Ziyaur Rahman, Sogra F Barakh Ali, Tanil Ozkan, Naseem A Charoo, Indra K Reddy, Mansoor A Khan
Three-dimensional (3D) printing was discovered in the 1980s, and many industries have embraced it, but the pharmaceutical industry is slow or reluctant to adopt it. Spiritam® is the first and only 3D-printed drug product approved by FDA in 2015. Since then, the FDA has not approved any 3D-printed drug product due to technical and regulatory issues. The 3D printing process cannot compete with well-established and understood conventional processes for making solid dosage forms. However, pharmaceutical companies can utilize it where mass production is not required; rather, consistency, precision, and accuracy in quality are paramount...
September 12, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30191341/in-vivo-predictive-dissolution-and-simulation-workshop-report-facilitating-the-development-of-oral-drug-formulation-and-the-prediction-of-oral-bioperformance
#17
Yasuhiro Tsume, Sanjaykumar Patel, Nikoletta Fotaki, Christel Bergstrӧm, Gordon L Amidon, James G Brasseur, Deanna M Mudie, Duxin Sun, Marival Bermejo, Ping Gao, Wei Zhu, David C Sperry, Maria Vertzoni, Neil Parrott, Robert Lionberger, Atsushi Kambayashi, Andre Hermans, Xujin Lu, Gregory E Amidon
No abstract text is available yet for this article.
September 6, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30187254/adding-the-t-to-adme-predictive-toxicity-in-renal-drug-development
#18
EDITORIAL
Raymond E Lai, Rosalinde Masereeuw
No abstract text is available yet for this article.
September 5, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30187172/imaging-techniques-in-the-diagnosis-and-management-of-ocular-tumors-prospects-and-challenges
#19
Rabin Neupane, Ripal Gaudana, Sai H S Boddu
Different types of imaging modalities are used in the diagnosis of ocular cancer. Selection of an imaging modality is based on the features of a tumor as well as the inherent characteristics of the imaging technique. It is vital to select an appropriate imaging modality in diagnosis of ocular tumor with confidence. This review focuses on five most commonly used imaging modalities, i.e., positron emission tomography-computed tomography (PET/CT), single photon emission computed tomography (SPECT), optical coherence tomography (OCT), ultrasound (US), and magnetic resonance imaging (MRI)...
September 5, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30187153/individualized-dosing-of-therapeutic-monoclonal-antibodies-a-changing-treatment-paradigm
#20
Anne S Strik, Yow-Ming C Wang, Laura E Ruff, William Yashar, Bradley T Messmer, Diane R Mould
The introduction of monoclonal antibodies (mAbs) to the treatment of inflammatory bowel disease (IBD) was an important medical milestone. MAbs have been demonstrated as safe and efficacious treatments of IBD. However, a large percentage of patients either fail to respond initially or lose response to therapy after a period of treatment. Although there are factors associated with poor treatment outcomes in IBD, one cause for treatment failure may be low mAb exposure. Consequently, gastroenterologists have begun using therapeutic drug monitoring (TDM) to guide dose adjustment...
September 5, 2018: AAPS Journal
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