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AAPS Journal

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https://www.readbyqxmd.com/read/29327295/common-deficiencies-of-in-vitro-binding-bioequivalence-be-studies-submitted-in-abbreviated-new-drug-applications-andas
#1
Dongmei Lu, Diana Vivian, Ping Ren, Yongsheng Yang, Hongling Zhang, Xiaojian Jiang, Ethan Stier
There are several drug products that bind phosphate or bile acid in the gastrointestinal (GI) tract to exert their therapeutic efficacy. In vitro binding studies are used to assess bioequivalence (BE) of these products. The objective of this study is to identify the common deficiencies in Abbreviated New Drug Applications (ANDAs) for these products. Deficiencies were compiled from ANDAs containing in vitro binding BE studies. The deficiencies were classified into eight categories: Pre-Study Method Validation, During-Study Sample Analysis, Study Design, Study Procedure, Dissolution/Disintegration, Analytical Site Inspection, Data Submission, and Formulations...
January 11, 2018: AAPS Journal
https://www.readbyqxmd.com/read/29285735/recommendations-for-the-development-and-validation-of-neutralizing-antibody-assays-in-support-of-biosimilar-assessment
#2
D Gouty, C C Cai, X Y Cai, A Kasinath, V Kumar, S Alvandkouhi, J Yang, S Pederson, B Babbitt, D Peritt, A Rudy, V Koppenburg, A Dasilva, M Ullmann, S Liu, C Satterwhite
The American Association of Pharmaceutical Scientists (AAPS) biosimilar focus group on nonclinical and clinical assays has developed this manuscript to guide the industry on best practices and testing strategies when developing neutralizing antibody (NAb) assays for biosimilar programs. The immunogenicity assessment to biosimilar and originator drug products is one of the key aspects of clinical programs for biosimilars to demonstrate biosimilarity. Establishing that there are no clinically meaningful differences in immune response between a proposed product and the originator product is a key element in the demonstration of biosimilarity...
December 28, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29285730/adaptive-optimal-designs-for-dose-finding-studies-with-time-to-event-outcomes
#3
Yevgen Ryeznik, Oleksandr Sverdlov, Andrew C Hooker
We consider optimal design problems for dose-finding studies with censored Weibull time-to-event outcomes. Locally D-optimal designs are investigated for a quadratic dose-response model for log-transformed data subject to right censoring. Two-stage adaptive D-optimal designs using maximum likelihood estimation (MLE) model updating are explored through simulation for a range of different dose-response scenarios and different amounts of censoring in the model. The adaptive optimal designs are found to be nearly as efficient as the locally D-optimal designs...
December 28, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29282611/calibration-curves-in-quantitative-ligand-binding-assays-recommendations-and-best-practices-for-preparation-design-and-editing-of-calibration-curves
#4
Mitra Azadeh, Boris Gorovits, John Kamerud, Stephen MacMannis, Afshin Safavi, Jeffrey Sailstad, Perceval Sondag
The accuracy of reported sample results is contingent upon the quality of the assay calibration curve, and as such, calibration curves are critical components of ligand binding and other quantitative methods. Regulatory guidance and lead publications have defined many of the requirements for calibration curves which encompass design, acceptance criteria, and selection of a regression model. However, other important aspects such as preparation and editing guidelines have not been addressed by health authorities...
December 27, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29282567/demonstration-of-direct-nose-to-brain-transport-of-unbound-hiv-1-replication-inhibitor-db213-via-intranasal-administration-by-pharmacokinetic-modeling
#5
Qianwen Wang, Yufeng Zhang, Chun-Ho Wong, H Y Edwin Chan, Zhong Zuo
Intranasal administration could be an attractive alternative route of administration for the delivery of drugs to the central nervous system (CNS). However, there are always doubts about the direct transport of therapeutics from nasal cavity to the CNS since there are only limited studies on the understanding of direct nose-to-brain transport. Therefore, this study aimed to (1) investigate the existence of nose-to-brain transport of intranasally administered HIV-1 replication inhibitor DB213 and (2) assess the direct nose-to-brain transport of unbound HIV-1 replication inhibitor DB213 quantitatively by a pharmacokinetic approach...
December 27, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29280004/the-drug-of-abuse-gamma-hydroxybutyric-acid-exhibits-tissue-specific-nonlinear-distribution
#6
Melanie A Felmlee, Bridget L Morse, Kristin E Follman, Marilyn E Morris
The drug of abuse γ-hydroxybutyric acid (GHB) demonstrates complex toxicokinetics with dose-dependent metabolic and renal clearance. GHB is a substrate of monocarboxylate transporters (MCTs) which are responsible for the saturable renal reabsorption of GHB. MCT expression is observed in many tissues and therefore may impact the tissue distribution of GHB. The objective of the present study was to evaluate the tissue distribution kinetics of GHB at supratherapeutic doses. GHB (400, 600, and 800 mg/kg iv) or GHB 600 mg/kg plus L-lactate (330 mg/kg iv bolus followed by 121 mg/kg/h infusion) was administered to rats and blood and tissues were collected for up to 330 min post-dose...
December 26, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29270863/pluripotent-stem-cell-derived-human-tissue-platforms-to-evaluate-drug-metabolism-and-safety
#7
REVIEW
Jose Meseguer-Ripolles, Salman R Khetani, Javier G Blanco, Miari Iredale, David C Hay
Despite the improvements in drug screening, high levels of drug attrition persist. Although high-throughput screening platforms permit the testing of compound libraries, poor compound efficacy or unexpected organ toxicity are major causes of attrition. Part of the reason for drug failure resides in the models employed, most of which are not representative of normal organ biology. This same problem affects all the major organs during drug development. Hepatotoxicity and cardiotoxicity are two interesting examples of organ disease and can present in the late stages of drug development, resulting in major cost and increased risk to the patient...
December 21, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29264822/in-vitro-in-vivo-dose-response-of-ursolic-acid-sulforaphane-peitc-and-curcumin-in-cancer-prevention
#8
Christina N Ramirez, Wenji Li, Chengyue Zhang, Renyi Wu, Shan Su, Chao Wang, Linbo Gao, Ran Yin, Ah-Ng Tony Kong
According to the National Center of Health Statistics, cancer was the culprit of nearly 600,000 deaths in 2016 in the USA. It is by far one of the most heterogeneous diseases to treat. Treatment for metastasized cancers remains a challenge despite modern diagnostics and treatment regimens. For this reason, alternative approaches are needed. Chemoprevention using dietary phytochemicals such as triterpenoids, isothiocyanates, and curcumin in the prevention of initiation and/or progression of cancer poses a promising alternative strategy...
December 20, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29243172/therapeutic-delivery-of-simvastatin-loaded-in-pla-peg-polymersomes-resulted-in-amplification-of-anti-inflammatory-effects-in-activated-microglia
#9
Dharani Manickavasagam, Kimberly Novak, Moses O Oyewumi
Simvastatin (Sim), a lipid-lowering drug has been studied in chronic neuroinflammation associated with degenerative brain disorders due to its potential protective properties against inflammatory reaction, oxidative damage, neuronal dysfunction, and death. Meanwhile, potential application of Sim in neuroinflammation will require a suitable delivery system that can overcome notable challenges pertaining to poor blood-brain barrier (BBB) permeability and side/off-target effects. Herein, we engineered and characterized nano-sized polymersomes loaded with Sim (Sim-Ps) using PEG-PdLLA (methoxy polyethylene glycol-poly(D,L) lactic acid) diblock co-polymers...
December 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29234895/intestinal-stem-cells-to-advance-drug-development-precision-and-regenerative-medicine-a-paradigm-shift-in-translational-research
#10
Jonathan P Mochel, Albert E Jergens, Dawn Kingsbury, Hyun Jung Kim, Martín G Martín, Karin Allenspach
Recent advances in our understanding of the intestinal stem cell niche and the role of key signaling pathways on cell growth and maintenance have allowed the development of fully differentiated epithelial cells in 3D organoids. Stem cell-derived organoids carry significant levels of proteins that are natively expressed in the gut and have important roles in drug transport and metabolism. They are, therefore, particularly relevant to study the gastrointestinal (GI) absorption of oral medications. In addition, organoids have the potential to serve as a robust preclinical model for demonstrating the effectiveness of new drugs more rapidly, with more certainty, and at lower costs compared with live animal studies...
December 12, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29218445/demonstration-of-nucleoside-transporter-activity-in-the-nose-to-brain-distribution-of-18f-fluorothymidine-using-pet-imaging
#11
Laura L Boles Ponto, Jiangeng Huang, Susan A Walsh, Michael R Acevedo, Christine Mundt, John Sunderland, Maureen Donovan
To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [18F]fluorothymidine (FLT), an equilibrative nucleoside transporter (ENT1,2) and concentrative nucleoside transporter (CNT1-3) substrate, using PET to measure local tissue concentrations. Anesthetized Sprague-Dawley rats were administered FLT by intranasal (IN) instillation or tail-vein injection (IV). NBMPR (nitrobenzylmercaptopurine riboside), an ENT1 inhibitor, was administered either IN or intraperitoneally (IP). Dynamic PET imaging was performed for up to 40 min...
December 7, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29218424/pharmacoimaging-of-blood-brain-barrier-permeable-fdg-and-impermeable-flt-substrates-after-intranasal-in-administration
#12
Laura L Boles Ponto, Susan Walsh, Jiangeng Huang, Christine Mundt, Katherine Thede-Reynolds, G Leonard Watkins, John Sunderland, Michael Acevedo, Maureen Donovan
To illustrate the use of imaging to quantify the transfer of materials from the nasal cavity to other anatomical compartments, specifically, transfer to the brain using the thymidine analogue, [18F]fluorothymidine (FLT), and the glucose analogue, [18F]fluorodeoxyglucose (FDG). Anesthetized rats were administered FLT or FDG by intranasal instillation (IN) or tail-vein injection (IV). PET/CT imaging was performed for up to 60 min. Volumes-of-interest (VOIs) for the olfactory bulb (OB) and the remaining brain were created on the CT and transferred to the co-registered dynamic PET...
December 7, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29204966/roles-of-organic-anion-transporting-polypeptide-2a1-oatp2a1-slco2a1-in-regulating-the-pathophysiological-actions-of-prostaglandins
#13
Takeo Nakanishi, Ikumi Tamai
Solute carrier organic anion transporter family member 2A1 (OATP2A1, encoded by the SLCO2A1 gene), which was initially identified as prostaglandin transporter (PGT), is expressed ubiquitously in tissues and mediates the distribution of prostanoids, such as PGE2, PGF2α, PGD2 and TxB2. It is well known to play a key role in the metabolic clearance of prostaglandins, which are taken up into the cell by OATP2A1 and then oxidatively inactivated by 15-ketoprostaglandin dehydrogenase (encoded by HPGD); indeed, OATP2A1-mediated uptake is the rate-limiting step of PGE2 catabolism...
December 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29204823/balancing-antibacterial-efficacy-and-reduction-in-renal-function-to-optimise-initial-gentamicin-dosing-in-paediatric-oncology-patients
#14
Carolina Consuelo Llanos-Paez, Christine Staatz, Stefanie Hennig
This study aimed to determine the optimal starting dose of gentamicin in paediatric oncology patients. A population pharmacokinetic model describing drug exposure, a semi-mechanistic model describing bacterial killing and an Emax model describing renal cortex accumulation were linked in a utility function using NONMEM®. The optimal gentamicin starting dose was estimated in patients aged from 0.1 to 18.2 years, by balancing the probability of efficacy on day 1 against relative renal function reduction on day 7 with continued dosing...
December 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29204754/the-na-cl-coupled-broad-specific-amino-acid-transporter-slc6a14-atb0-emerging-roles-in-multiple-diseases-and-therapeutic-potential-for-treatment-and-diagnosis
#15
Mohd Omar F Sikder, Shengping Yang, Vadivel Ganapathy, Yangzom D Bhutia
Amino acids are essential building blocks of all mammalian cells, and amino acid transporters play a vital role in transporting them into cells and their further distribution among the various cellular compartments. There are ~ 430 known transporters in the solute-linked carrier (SLC) gene family, divided into 52 distinct families. Eleven of these gene families contain one or more amino acid transporters. These transporters differ significantly from each other in terms of substrate specificity, ion dependence, and energetics...
December 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29204742/target-and-tissue-selectivity-prediction-by-integrated-mechanistic-pharmacokinetic-target-binding-and-quantitative-structure-activity-modeling
#16
Anna H C Vlot, Wilhelmus E A de Witte, Meindert Danhof, Piet H van der Graaf, Gerard J P van Westen, Elizabeth C M de Lange
Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D) and the target dissociation rate constant on target and tissue selectivity...
December 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29196830/a-multi-site-in-depth-evaluation-of-the-quanterix-simoa-from-a-user-s-perspective
#17
Allison Given Chunyk, Alison Joyce, Saloumeh K Fischer, Mark Dysinger, Alvydas Mikulskis, Andreas Jeromin, Rosemary Lawrence-Henderson, Dana Baker, David Yeung
An in-depth evaluation of the Quanterix© Simoa™ platform was undertaken by scientists from the AAPS Emerging Technologies Focus Group to determine the overall performance of the technology as well as provide guidance to future users. In order to test the platform in a non-GLP bioanalytical setting, a cross-site evaluation of the Quanterix IL-6 biomarker kit was performed. Parameters tested during this evaluation included sensitivity, accuracy and precision, and parallelism in human serum from normal individuals...
December 1, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29192381/abcb6-an-abc-transporter-impacting-drug-response-and-disease
#18
Rebba C Boswell-Casteel, Yu Fukuda, John D Schuetz
Recent findings have discovered how insufficiency of ATP-binding cassette (ABC) transporter, ABCB6, can negatively impact human health. These advances were made possible by, first, finding that ABCB6 deficiency was the genetic basis for some severe transfusion reactions and by, second, determining that functionally impaired ABCB6 variants enhanced the severity of porphyria, i.e., diseases associated with defects in heme synthesis. ABCB6 is a broad-spectrum porphyrin transporter that is capable of both exporting and importing heme and its precursors across the plasma membrane and outer mitochondrial membrane, respectively...
November 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29192345/transporter-mediated-interaction-between-platinum-drugs-and-sorafenib-at-the-cellular-level
#19
Verena Schneider, Selim Chaib, Claudia Spanier, Mandy Knapp, Violeta Moscvin, Laura Scordovillo, Alessandra Ewertz, Ulrich Jaehde, Ganna V Kalayda
Combining the multikinase inhibitor sorafenib with the platinum-based chemotherapy of solid tumors was expected to improve treatment outcome. However, in many clinical trials, no benefit from sorafenib addition to the platinum-containing regimen could be demonstrated. Moreover, in some studies, decreased survival of ovarian cancer patients as well as non-small cell lung cancer patients with squamous cell histology was observed. The aim of this study was to investigate the cellular mechanisms of the pharmacological interaction between platinum drugs and sorafenib in different cancer cell lines...
November 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29192343/a-view-on-the-importance-of-multi-attribute-method-for-measuring-purity-of-biopharmaceuticals-and-improving-overall-control-strategy
#20
Richard S Rogers, Michael Abernathy, Douglas D Richardson, Jason C Rouse, Justin B Sperry, Patrick Swann, Jette Wypych, Christopher Yu, Li Zang, Rohini Deshpande
Today, we are experiencing unprecedented growth and innovation within the pharmaceutical industry. Established protein therapeutic modalities, such as recombinant human proteins, monoclonal antibodies (mAbs), and fusion proteins, are being used to treat previously unmet medical needs. Novel therapies such as bispecific T cell engagers (BiTEs), chimeric antigen T cell receptors (CARTs), siRNA, and gene therapies are paving the path towards increasingly personalized medicine. This advancement of new indications and therapeutic modalities is paralleled by development of new analytical technologies and methods that provide enhanced information content in a more efficient manner...
November 30, 2017: AAPS Journal
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