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https://www.readbyqxmd.com/read/29110222/recommendations-for-the-assessment-and-management-of-pre-existing-drug-reactive-antibodies-during-biotherapeutic-development
#1
Li Xue, Adrienne Clements-Egan, Lakshmi Amaravadi, Mary Birchler, Boris Gorovits, Meina Liang, Heather Myler, Shobha Purushothama, Marta Starcevic Manning, Crystal Sung
Anti-drug antibodies (ADA) pose a potential risk to patient safety and efficacy and are routinely monitored during clinical trials. Pre-existing drug-reactive antibodies are present in patients without prior drug exposure and are defined by their ability to bind to a component of the drug. These pre-existing drug-reactive antibodies are frequently observed and could represent an adaptive immune response of an individual who has been previously exposed to antigens with structural similarities to the biotherapeutic...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/29063411/drug-target-interference-in-immunogenicity-assays-recommendations-and-mitigation-strategies
#2
Zhandong Don Zhong, Adrienne Clements-Egan, Boris Gorovits, Mauricio Maia, Giane Sumner, Valerie Theobald, Yuling Wu, Manoj Rajadhyaksha
Sensitive and specific methodology is required for the detection and characterization of anti-drug antibodies (ADAs). High-quality ADA data enables the evaluation of potential impact of ADAs on the drug pharmacokinetic profile, patient safety, and efficacious response to the drug. Immunogenicity assessments are typically initiated at early stages in preclinical studies and continue throughout the drug development program. One of the potential bioanalytical challenges encountered with ADA testing is the need to identify and mitigate the interference mediated by the presence of soluble drug target...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/29047044/exosomes-for-the-enhanced-tissue-bioavailability-and-efficacy-of-curcumin
#3
Farrukh Aqil, Radha Munagala, Jeyaprakash Jeyabalan, Ashish Kumar Agrawal, Ramesh Gupta
Exosomes are extracellular microvesicles with a particle size of 30-100 nm and carry a cargo of proteins, lipids, RNA, and DNA. Their properties of shuttling in-and-out of the cells suggest that these particles can be exploited as a nano drug carrier. In this manuscript, we show that curcumin can be delivered effectively using milk-derived exosomes. Curcumin when mixed with exosomes in the presence of 10% ethanol:acetonitrile (1:1) provided a drug load of 18-24%, and the formulation stored at - 80°C was stable for 6 months as determined by particle size analysis, drug load, and antiproliferative activity...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/29019117/physiologically-based-pharmacokinetic-modeling-of-transporter-mediated-hepatic-clearance-and-liver-partitioning-of-oatp-and-oct-substrates-in-cynomolgus-monkeys
#4
Bridget L Morse, Jamus G MacGuire, Anthony M Marino, Yue Zhao, Maxine Fox, Yueping Zhang, Hong Shen, W Griffith Humphreys, Punit Marathe, Yurong Lai
In the present investigations, we evaluate in vitro hepatocyte uptake and partitioning for the prediction of in vivo clearance and liver partitioning. Monkeys were intravenously co-dosed with rosuvastatin and bosentan, substrates of the organic anion transporting polypeptides (OATPs), and metformin, a substrate of organic cation transporter 1 (OCT1). Serial plasma and liver samples were collected over time. Liver and plasma unbound fraction was determined using equilibrium dialysis. In vivo unbound partitioning (Kpu,u) for rosuvastatin, bosentan, and metformin, calculated from total concentrations in the liver and plasma, were 243, 553, and 15, respectively...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/29019032/nanotechnology-as-a-delivery-tool-for-precision-cancer-therapies
#5
Bhawna Sharma, Rachael M Crist, Pavan P Adiseshaiah
Genomic analyses from patients with cancer have improved the understanding of the genetic elements that drive the disease, provided new targets for treating this relentless disease, and offered criteria for stratifying patient populations that will benefit most from treatments. In the last decade, several new targeted therapies have been approved by the FDA based on these omics findings, leading to significantly improved survival and quality of life for select patient populations. However, many of these precision medicines, e...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28980204/mechanistic-fluid-transport-model-to-estimate-gastrointestinal-fluid-volume-and-its-dynamic-change-over-time
#6
Alex Yu, Trachette Jackson, Yasuhiro Tsume, Mark Koenigsknecht, Jeffrey Wysocki, Luca Marciani, Gordon L Amidon, Ann Frances, Jason R Baker, William Hasler, Bo Wen, Amit Pai, Duxin Sun
Gastrointestinal (GI) fluid volume and its dynamic change are integral to study drug disintegration, dissolution, transit, and absorption. However, key questions regarding the local volume and its absorption, secretion, and transit remain unanswered. The dynamic fluid compartment absorption and transit (DFCAT) model is proposed to estimate in vivo GI volume and GI fluid transport based on magnetic resonance imaging (MRI) quantified fluid volume. The model was validated using GI local concentration of phenol red in human GI tract, which was directly measured by human GI intubation study after oral dosing of non-absorbable phenol red...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28971365/investigating-oral-absorption-of-carbamazepine-in-pediatric-populations
#7
Philip Kohlmann, Cordula Stillhart, Martin Kuentz, Neil Parrott
Prediction of the pharmacokinetics of orally administered drugs in children is of importance to optimize the efficacy and safety of pediatric medicines. Physiologically based pharmacokinetic (PBPK) models can be helpful for this purpose. However, application of these tools is limited by significant knowledge gaps regarding the physiological and anatomical changes which occur with age. This study aimed at investigating the age-dependent differences in oral absorption of a poorly soluble model compound, carbamazepine (CBZ) in children, infants, and neonates...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28971363/recommendations-for-selection-and-characterization-of-protein-biomarker-assay-calibrator-material
#8
Kyra J Cowan, Lakshmi Amaravadi, Mark J Cameron, Damien Fink, Darshana Jani, Medha Kamat, Lindsay King, Robert J Neely, Yan Ni, Paul Rhyne, Renee Riffon, Yuda Zhu
As biomarkers continue to become an integral part of drug development and decision-making, there are increased expectations for reliable and quantitative assays. Protein biomarker assay results are directly influenced by the calibrator material. The selection of calibrator material presents many challenges that impact the relative accuracy and performance of the assay. There is an industry-wide challenge finding reliable and well-characterized calibrator material with good documentation. Several case studies are presented that demonstrate some of the challenges involved in selecting appropriate calibrators along with the resolutions that were ultimately applied...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28971357/alternative-splicing-expanding-diversity-in-major-abc-and-slc-drug-transporters
#9
Ji Eun Park, Gongmi Ryoo, Wooin Lee
Alternative splicing is an important mechanism of genetic regulation enhancing diversity and complexity of the transcriptome and proteome from the finite number of genes. Many reported cases demonstrate that alternative splicing events can lead to changes in the expression/function of proteins during disease development and progression. For pharmacogenes that can influence drug disposition and response, the role of alternative splicing has begun to receive increasing attention as an under-explored source of variable drug response...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28971356/how-close-are-we-to-profiling-immunogenicity-risk-using-in-silico-algorithms-and-in-vitro-methods-an-industry-perspective
#10
Jochem Gokemeijer, Vibha Jawa, Shibani Mitra-Kaushik
In silico HLA-binding algorithms and in vitro T cell-based assays as predictive tools for human immunogenicity risk have made inroads in the biotherapeutic drug discovery and development process. Currently, these tools are being used only for candidate selection or characterization and not for making a go/no-go decision for further development. A clear limitation for a broader implementation is the lack of correlation between the predicted T cell epitope content/immune reactivity potential of a biotherapeutic and the subsequent ADA-related clinical immunogenicity outcome...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28924630/role-of-in-vitro-release-methods-in-liposomal-formulation-development-challenges-and-regulatory-perspective
#11
Deepak Solomon, Nilesh Gupta, Nihal S Mulla, Snehal Shukla, Yadir A Guerrero, Vivek Gupta
In the past few years, measurement of drug release from pharmaceutical dosage forms has been a focus of extensive research because the release profile obtained in vitro can give an indication of the drug's performance in vivo. Currently, there are no compendial in vitro release methods designed for liposomes owing to a range of experimental challenges, which has created a major hurdle for both development and regulatory acceptance of liposome-based drug products. In this paper, we review the current techniques that are most often used to assess in vitro drug release from liposomal products; these include the membrane diffusion techniques (dialysis, reverse dialysis, fractional dialysis, and microdialysis), the sample-and-separate approach, the in situ method, the continuous flow, and the modified United States Pharmacopeia methods (USP I and USP IV)...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28905273/early-to-long-term-alterations-of-cns-barriers-after-traumatic-brain-injury-considerations-for-drug-development
#12
Beatriz Rodriguez-Grande, Aleksandra Ichkova, Sighild Lemarchant, Jerome Badaut
Traumatic brain injury (TBI) is one of the leading causes of death and disability, particularly amongst the young and the elderly. The functions of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are strongly impaired after TBI, thus affecting brain homeostasis. Following the primary mechanical injury that characterizes TBI, a secondary injury develops over time, including events such as edema formation, oxidative stress, neuroinflammation, and alterations in paracelullar and transcellular transport...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28895093/sirna-mediated-rna-interference-in-precision-cut-tissue-slices-prepared-from-mouse-lung-and-kidney
#13
Mitchel J R Ruigrok, Nalinie Maggan, Delphine Willaert, Henderik W Frijlink, Barbro N Melgert, Peter Olinga, Wouter L J Hinrichs
Small interfering RNA (siRNA)-mediated RNAi interference (RNAi) is a powerful post-transcriptional gene silencing mechanism which can be used to study the function of genes in vitro (cell cultures) and in vivo (animal models). However, there is a translational gap between these models. Hence, there is a need for novel experimental models that combine the advantages of in vitro and in vivo models (e.g., simplicity, flexibility, throughput, and representability) to study the effects of siRNA. This need may be addressed by precision-cut tissue slices (PCTS), which represent an ex vivo model that mimics the structural and functional characteristics of a whole organ...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28895080/population-pharmacokinetic-and-pharmacodynamic-modeling-of-artemisinin-resistance-in-southeast-asia
#14
Jesmin Lohy Das, Arjen M Dondorp, Francois Nosten, Aung Pyae Phyo, Warunee Hanpithakpong, Pascal Ringwald, Pharath Lim, Nicholas J White, Mats O Karlsson, Martin Bergstrand, Joel Tarning
Orally administered artemisinin-based combination therapy is the first-line treatment against uncomplicated P. falciparum malaria worldwide. However, the increasing prevalence of artemisinin resistance is threatening efforts to treat and eliminate malaria in Southeast Asia. This study aimed to characterize the exposure-response relationship of artesunate in patients with artemisinin sensitive and resistant malaria infections. Patients were recruited in Pailin, Cambodia (n = 39), and Wang Pha, Thailand (n = 40), and received either 2 mg/kg/day of artesunate mono-therapy for 7 consecutive days or 4 mg/kg/day of artesunate monotherapy for 3 consecutive days followed by mefloquine 15 and 10 mg/kg for 2 consecutive days...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28895076/new-botanical-anxiolytics-for-use-in-companion-animals-and-humans
#15
Rui Liu, Fida Ahmed, Christian Cayer, Martha Mullally, Ana Francis Carballo, Marco Otarola Rojas, Mario Garcia, John Baker, Aleksandar Masic, Pablo E Sanchez, Luis Poveda, Zul Merali, Tony Durst, John T Arnason
As part of our ongoing research into botanical therapies for anxiety disorders, the neotropical vine Souroubea sympetala was chosen for study as a phytochemical discovery strategy focusing on rare Central American plant families. When orally administered to male Sprague-Dawley rats, the crude plant extract, its ethyl acetate fraction, supercritical carbon dioxide fraction, or its isolated triterpenes reduced anxiety and/or fear-related behavior in standardized behavioral models. Pharmacological studies showed that the extracts acted at the benzodiazepine GABAA receptor and reduced corticosterone levels...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28879628/in-vitro-approaches-to-support-bioequivalence-and-substitutability-of-generic-proton-pump-inhibitors-via-nasogastric-tube-administration
#16
Ping Ren, Minglei Cui, Om Anand, Li Xia, Zhuojun J Zhao, Dajun Sun, Trueman Sharp, Dale P Conner, John Peters, Wenlei Jiang, Ethan Stier, Xiaojian Jiang
Administration of proton pump inhibitors (PPIs) through nasogastric tubes may present risks. If the PPI drug products are not prepared properly, clogging or obstruction of nasogastric tubes can pose a safety concern. In addition, the integrity of the enteric coating of the drug product may be damaged resulting in reduced bioavailability of the active moiety. From the perspective of administration of generic PPIs when compared to the reference drug product, differences in formulation can potentially result in a greater relative risk for the generic drug product...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28875479/development-of-an-enantioselective-and-biomarker-informed-translational-population-pharmacokinetic-pharmacodynamic-model-for-etodolac
#17
Carolina de Miranda Silva, Adriana Rocha, Eduardo Tozatto, Lucienir Maria da Silva, Eduardo Antônio Donadi, Teresa Dalla Costa, Vera Lucia Lanchote, Stephan Schmidt, Jürgen B Bulitta
Cyclooxygenase-2 (COX-2) isoform has a critical role in the development of pain. Inhibition of COX-2 in vitro serves as a biomarker for nonsteroidal anti-inflammatory drugs (NSAIDs). The NSAID concentrations yielding 80% COX-2 inhibition (IC80) correlate with therapeutic doses to achieve analgesia across multiple COX-2 inhibitors. However, there are no time-course models relating COX-2 inhibition with decreased pain. This study aimed to characterize the relationship between NSAID concentrations, in vitro COX-2 inhibition, and acute pain decrease in humans over time by a translational approach using clinical pharmacokinetic and literature reported in vitro and clinical pharmacodynamic data...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28875358/determination-of-critical-quality-attributes-for-a-biotherapeutic-in-the-qbd-paradigm-gcsf-as-a-case-study
#18
Sumit K Singh, Deepak Kumar, Anurag S Rathore
Estimating impact of the various product-related variants and impurities on a biotherapeutic's safety and efficacy is an essential requirement in the quality by design paradigm. In view of the limited role that clinical studies offer in this regard, we demonstrate a preclinical approach to achieve this for granulocyte colony-stimulating factor (GCSF). While our repeated-dose toxicity data suggest that these variants do not elicit any adverse effects or histopathological changes, aggregated GCSF impurity caused sluggishness in animal behavior manifested by a possible muscular injury...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28853055/quantification-of-the-pharmacodynamic-interaction-of-morphine-and-gabapentin-using-a-response-surface-approach
#19
Theodoros Papathanasiou, Rasmus Vestergaard Juul, Charlotte Gabel-Jensen, Mads Kreilgaard, Anne-Marie Heegaard, Trine Meldgaard Lund
The combination of morphine and gabapentin has shown to be promising for managing postoperative pain but finding the right dose for the combination has proven to be a challenge. The purpose of this study was to quantitatively characterize the pharmacodynamic interaction between the two drugs and to identify the optimal concentration-effect relationship of the combination. Information regarding plasma concentrations and von Frey withdrawal thresholds following incisional surgery on Sprague Dawley rats, after administration of morphine, gabapentin, or their combination was available from published studies...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28849396/investigation-of-the-influence-of-protein-losing-enteropathy-on-monoclonal-antibody-pharmacokinetics-in-mice
#20
Yujie Yang, Tommy R Li, Joseph P Balthasar
Protein losing enteropathy (PLE), which is characterized by substantial loss of plasma proteins into the gastrointestinal (GI) tract, is a complication of a variety of GI diseases, including inflammatory bowel disease. Clinical studies have found that the clearance of monoclonal antibodies (mAb) is often increased in subjects with diseases known to cause PLE; however, direct relationships between PLE and mAb pharmacokinetics have not been demonstrated. This study employed a murine model of colitis to examine the influence of PLE on mAb pharmacokinetics...
November 2017: AAPS Journal
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