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AAPS Journal

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https://www.readbyqxmd.com/read/28646408/a-mechanism-based-pk-pd-model-for-hematological-toxicities-induced-by-antibody-drug-conjugates
#1
Sihem Ait-Oudhia, Weiyan Zhang, Donald E Mager
Antibody-drug conjugates (ADCs) are complex drug platforms composed of monoclonal antibodies (mAbs) conjugated to potent cytotoxic drugs (payloads) via chemical linkers, enabling selective payload delivery to neoplastic cells, resulting in improved efficacy and reduced toxicity. Brentuximab vedotin (Adcetris®, SGN-35) and adotrastuzumab emtansine (Kadcyla®, T-DM1) are the two FDA-approved and commercially available ADCs, and both drugs exhibit ADC-related thrombocytopenia and neutropenia. A pharmacokinetic/pharmacodynamic (PK/PD) model for ADCs was developed to identify the analyte from each ADC that is most associated with the observed hematopoietic toxicities and to determine the role of the apparent in vivo payload release rate on the severity of thrombocytopenia and neutropenia...
June 23, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28634883/a-minimal-continuous-time-markov-pharmacometric-model
#2
Emilie Schindler, Mats O Karlsson
In this work, an alternative model to discrete-time Markov model (DTMM) or standard continuous-time Markov model (CTMM) for analyzing ordered categorical data with Markov properties is presented: the minimal CTMM (mCTMM). Through a CTMM reparameterization and under the assumption that the transition rate between two consecutive states is independent on the state, the Markov property is expressed through a single parameter, the mean equilibration time, and the steady-state probabilities are described by a proportional odds (PO) model...
June 20, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28620884/kinetic-pharmacodynamic-model-of-chemotherapy-induced-peripheral-neuropathy-in-patients-with-metastatic-breast-cancer-treated-with-paclitaxel-nab-paclitaxel-or-ixabepilone-calgb-40502-alliance
#3
Shailly Mehrotra, Manish R Sharma, Elizabeth Gray, Kehua Wu, William T Barry, Clifford Hudis, Eric P Winer, Alan P Lyss, Deborah L Toppmeyer, Alvaro Moreno-Aspitia, Thomas E Lad, Mario Valasco, Beth Overmoyer, Hope Rugo, Mark J Ratain, Jogarao V Gobburu
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity caused by several chemotherapeutic agents. Currently, CIPN is managed by empirical dose modifications at the discretion of the treating physician. The goal of this research is to quantitate the dose-CIPN relationship to inform the optimal strategies for dose modification. Data were obtained from the Cancer and Leukemia Group B (CALGB) 40502 trial, a randomized phase III trial of paclitaxel vs. nab-paclitaxel vs. ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer...
June 15, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28608238/the-impact-of-disintegrant-type-surfactant-and-api-properties-on-the-processability-and-performance-of-roller-compacted-formulations-of-acetaminophen-and-aspirin
#4
Junshu Zhao, Otilia Koo, Duohai Pan, Yongmei Wu, Dinesh Morkhade, Sandeep Rana, Partha Saha, Arturo Marin
In formulation development, certain excipients, even though used in small quantities, can have a significant impact on the processability and performance of the dosage form. In this study, three common disintegrants, croscarmellose sodium (CCS), crospovidone (xPVP), and sodium starch glycolate (SSG) as well as the surfactant sodium lauryl sulfate (SLS) were evaluated for their impact on the processability and performance of a typical dry granulation formulation. Two model compounds, the mechanically brittle and chemically inert acetaminophen and the mechanically ductile carboxylic acid aspirin, were used for the evaluation...
June 12, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28593514/influence-of-formulation-factors-on-the-aerosol-performance-of-suspension-and-solution-metered-dose-inhalers-a-systematic-approach
#5
Poonam Sheth, Dennis Sandell, Denise S Conti, Jay T Holt, Anthony J Hickey, Bhawana Saluja
Metered dose inhalers (MDIs) are complex drug-device combination products widely used to treat pulmonary disorders. The efficacy, driven by aerosol performance of the products, depends on a multitude of factors including, but not limited to, the physicochemical properties of drug and nature and amount of excipient(s). Under the quality by design (QbD) paradigm, systematic investigations are necessary to understand how changes in critical quality attributes (CQAs) of formulation, device, and manufacturing process influence key product performance parameters, such as delivered dose (DD) and fine particle dose (FPD)...
June 7, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28589510/singlicate-ligand-binding-assay-using-an-automated-microfluidic-system-a-clinical-case-study
#6
Hao Jiang, Alex Kozhich, Jennifer Cummings, Janice Gambardella, Frank Zambito, Craig Titsch, Jonathan Haulenbeek, Kelli Phillips, Ross Fergus, Heather Myler
The bioanalytical strategy for monoclonal antibody therapeutics, intended for multiple oncology indications, includes multiple integrated measurements of pharmacologically relevant therapeutics from discovery through development. Three ligand binding assays were cohesively developed and validated, as applicable, using the Gyrolab microfluidic system for the measurement of a free monoclonal antibody BMS-986207. Accuracy and precision demonstrate %bias from -6.3 to 4.4%, percent coefficient of variation (%CV) from 2...
June 6, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28589509/strategies-of-drug-transporter-quantitation-by-lc-ms-importance-of-peptide-selection-and-digestion-efficiency
#7
Buyun Chen, Liling Liu, Hoangdung Ho, Yuan Chen, Ze Yang, Xiaorong Liang, Jian Payandeh, Brian Dean, Cornelis E C A Hop, Yuzhong Deng
Huge variation of drug transporter abundance was seen in the literature, making PBPK prediction difficult when transporters play a major role. Among multiple factors such as membrane fraction, digestion, and peptide selection that contributed to such variation, peptide selection is the least discussed. Herein, a strategy was established by using a small amount of purified protein standard to select a peptide with near 100% digestion efficiency for quantitation of a transporter protein MDR1. The impact of native membrane protein's tertiary structure on the digestion efficiency of surrogate peptides of MDR1 was investigated...
June 6, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28584908/the-ep3-receptor-gz-signaling-axis-as-a-therapeutic-target-for-diabetes-and-cardiovascular-disease
#8
Michael D Schaid, Jaclyn A Wisinski, Michelle E Kimple
Cardiovascular disease is a common co-morbidity found with obesity-linked type 2 diabetes. Current pharmaceuticals for these two diseases treat each of them separately. Yet, diabetes and cardiovascular disease share molecular signaling pathways that are increasingly being understood to contribute to disease pathophysiology, particularly in pre-clinical models. This review will focus on one such signaling pathway: that mediated by the G protein-coupled receptor, Prostaglandin E2 Receptor 3 (EP3), and its associated G protein in the insulin-secreting beta-cell and potentially the platelet, Gz...
June 5, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28577121/recent-advances-in-musculoskeletal-tissue-regeneration
#9
EDITORIAL
Aliasger K Salem
No abstract text is available yet for this article.
June 2, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28577120/large-scale-prediction-of-drug-target-interaction-a-data-centric-review
#10
Tiejun Cheng, Ming Hao, Takako Takeda, Stephen H Bryant, Yanli Wang
The prediction of drug-target interactions (DTIs) is of extraordinary significance to modern drug discovery in terms of suggesting new drug candidates and repositioning old drugs. Despite technological advances, large-scale experimental determination of DTIs is still expensive and laborious. Effective and low-cost computational alternatives remain in strong need. Meanwhile, open-access resources have been rapidly growing with massive amount of bioactivity data becoming available, creating unprecedented opportunities for the development of novel in silico models for large-scale DTI prediction...
June 2, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28560482/integrated-in-silico-fragment-based-drug-design-case-study-with-allosteric-modulators-on-metabotropic-glutamate-receptor-5
#11
Yuemin Bian, Zhiwei Feng, Peng Yang, Xiang-Qun Xie
GPCR allosteric modulators target at the allosteric binding pockets of G protein-coupled receptors (GPCRs) with indirect influence on the effects of an orthosteric ligand. Such modulators exhibit significant advantages compared to the corresponding orthosteric ligands, including better chemical tractability or physicochemical properties, improved selectivity, and reduced risk of oversensitization towards their receptors. Metabotropic glutamate receptor 5 (mGlu5), a member of class C GPCRs, is a promising therapeutic target for treating many central nervous system diseases...
May 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28550637/breaking-bad-the-structure-and-function-of-the-blood-brain-barrier-in-epilepsy
#12
Hadas Han, Aniv Mann, Dana Ekstein, Sara Eyal
Epilepsy is a neurological disease with variable etiology and clinical manifestation, affecting more than 50 million people worldwide. Although the ultimate precipitators of seizures are neurons, it is becoming evident that epileptic activity is associated with changes in the function of other cell types, including those consisting the blood-brain barrier (BBB) and regulating its permeability. The interrelationships between impaired BBB function and epilepsy are complex, as BBB dysfunction may both lead to seizures and be induced by epileptic activity...
May 26, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28540623/qsp-toolbox-computational-implementation-of-integrated-workflow-components-for-deploying-multi-scale-mechanistic-models
#13
Yougan Cheng, Craig J Thalhauser, Shepard Smithline, Jyotsna Pagidala, Marko Miladinov, Heather E Vezina, Manish Gupta, Tarek A Leil, Brian J Schmidt
Quantitative systems pharmacology (QSP) modeling has become increasingly important in pharmaceutical research and development, and is a powerful tool to gain mechanistic insights into the complex dynamics of biological systems in response to drug treatment. However, even once a suitable mathematical framework to describe the pathophysiology and mechanisms of interest is established, final model calibration and the exploration of variability can be challenging and time consuming. QSP models are often formulated as multi-scale, multi-compartment nonlinear systems of ordinary differential equations...
May 24, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28534292/development-and-characterization-of-a-neutralizing-anti-idiotype-antibody-against-mirvetuximab-for-analysis-of-clinical-samples
#14
Sven Loebrich, Mingfang Shen, Erika Cohen, Gillian Payne, Ying Chen, Megan Bogalhas, Yiwei Zhao
Antibody-drug-conjugates (ADCs) are an emerging class of biological therapeutics. Mirvetuximab soravtansine is a novel folate receptor alpha (FRα)-targeting ADC which represents a potential new treatment for patients with ovarian and other FRα-positive cancers. Since patient immune responses to biological therapeutics may negatively affect drug efficacy and patient safety, regulatory authorities require rigorous monitoring of patient samples. Taking advantage of the immune system's ability to generate highly specific antibodies, the field has turned to anti-idiotype antibodies as powerful tools for the development of sensitive and specific bioassays...
May 22, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28534291/ultra-sensitive-measurement-of-il-17a-and-il-17f-in-psoriasis-patient-serum-and-skin
#15
Catherine Soderstrom, Gabriel Berstein, Weidong Zhang, Hernan Valdez, Lori Fitz, Max Kuhn, Stephanie Fraser
Interleukin 17 is a family of cytokines that play a central role in many autoimmune and inflammatory diseases. IL-17A has been implicated as a key driver of psoriasis, mediating a chronic cycle of T-cell activation, keratinocyte proliferation and angiogenesis. It has been hypothesized that expression of IL-17A and the related cytokine IL-17F could be used as predictive biomarkers for therapeutic response, though they have been difficult to measure locally or in circulation because of their low abundance. We developed ultrasensitive methods for measuring IL-17A and IL-17F in human serum samples and found that serum from psoriasis patients had higher and a broader range of concentrations of both IL-17 proteins compared to healthy volunteers...
May 22, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28526963/incorporation-of-the-time-varying-postprandial-increase-in-splanchnic-blood-flow-into-a-pbpk-model-to-predict-the-effect-of-food-on-the-pharmacokinetics-of-orally-administered-high-extraction-drugs
#16
Rachel H Rose, David B Turner, Sibylle Neuhoff, Masoud Jamei
Following a meal, a transient increase in splanchnic blood flow occurs that can result in increased exposure to orally administered high-extraction drugs. Typically, physiologically based pharmacokinetic (PBPK) models have incorporated this increase in blood flow as a time-invariant fed/fasted ratio, but this approach is unable to explain the extent of increased drug exposure. A model for the time-varying increase in splanchnic blood flow following a moderate- to high-calorie meal (TV-Q Splanch) was developed to describe the observed data for healthy individuals...
May 19, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28516359/evolution-of-choice-of-solubility-and-dissolution-media-after-two-decades-of-biopharmaceutical-classification-system
#17
Nadia Bou-Chacra, Katherine Jasmine Curo Melo, Ivan Andrés Cordova Morales, Erika S Stippler, Filippos Kesisoglou, Mehran Yazdanian, Raimar Löbenberg
The introduction of the biopharmaceutics drug classification system (Biopharmaceutics Classification System (BCS)), in 1995, provided a simple way to describe the biopharmaceutics behavior of a drug. Solubility and permeability are among the major parameters, which determine the fraction dose absorbed of a drug substance and consequently its chances to be bioavailable. The purpose of this review is to summarize the evolution of the media used for determining solubility and dissolution and how this can be used in modern drug development...
May 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28516358/mechanistic-modeling-of-the-pharmacodynamic-and-pharmacokinetic-relationship-of-tissue-factor-pathway-inhibitor-neutralizing-antibody-bay-1093884-in-cynomolgus-monkeys
#18
Jian-Ming Gu, Xiao-Yan Zhao, Thomas Schwarz, Joachim Schuhmacher, Andreas Baumann, Elena Ho, Babu Subramanyan, Kathy Tran, Timothy Myles, Chandra Patel, Maria Koellnberger
BAY 1093884 is a fully human monoclonal antibody against the tissue factor pathway inhibitor (TFPI) in development as prophylaxis in patients with hemophilia with or without inhibitors. In vitro, BAY 1093884 binds to human, mouse, and monkey TFPI. The objective of this study was to find a pharmacodynamic (PD) biomarker after administration of BAY 1093884 to normal monkeys. In monkey plasma, BAY 1093884 exhibited an IC50 (concentration that inhibits 50%) of 4.65 and 6.19 nM for free TFPI and diluted prothrombin time (dPT), respectively...
May 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28497318/controlled-ion-release-from-novel-polyester-ceramic-composites-enhances-osteoinductivity
#19
Soheila Ali Akbari Ghavimi, Rama Rao Tata, Andrew J Greenwald, Brittany N Allen, David A Grant, Sheila A Grant, Mark W Lee, Bret D Ulery
Due to the growing number of patients suffering from musculoskeletal defects and the limited supply of and sub-optimal outcomes associated with biological graft materials, novel biomaterials must be created that can function as graft substitutes. For bone regeneration, composite materials that mimic the organic and inorganic phases of natural bone can provide cues which expedite and enhance endogenous repair. Specifically, recent research has shown that calcium and phosphate ions are inherently osteoinductive, so controllably delivering their release holds significant promise for this field...
May 11, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28488175/erratum-to-microdialysis-the-key-to-physiologically-based-model-prediction-of-human-cns-target-site-concentrations
#20
Yumi Yamamoto, Meindert Danhof, Elizabeth C M de Lange
No abstract text is available yet for this article.
May 9, 2017: AAPS Journal
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