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https://www.readbyqxmd.com/read/28808917/development-of-a-translational-physiologically-based-pharmacokinetic-model-for-antibody-drug-conjugates-a-case-study-with-t-dm1
#1
Antari Khot, Jay Tibbitts, Dan Rock, Dhaval K Shah
Systems pharmacokinetic (PK) models that can characterize and predict whole body disposition of antibody-drug conjugates (ADCs) are needed to support (i) development of reliable exposure-response relationships for ADCs and (ii) selection of ADC targets with optimal tumor and tissue expression profiles. Towards this goal, we have developed a translational physiologically based PK (PBPK) model for ADCs, using T-DM1 as a tool compound. The preclinical PBPK model was developed using rat data. Biodistribution of DM1 in rats was used to develop the small molecule PBPK model, and the PK of conjugated trastuzumab (i...
August 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28795351/advancements-in-understanding-immunogenicity-of-biotherapeutics-in-the-intraocular-space
#2
Eric Wakshull, Valerie Quarmby, Hanns-Christian Mahler, Hongwen Rivers, Dhananjay Jere, Meg Ramos, Piotr Szczesny, Karoline Bechtold-Peters, Sharmila Masli, Swati Gupta
Therapeutic breakthroughs in a number of retinal degenerative diseases have come about through the development of biotherapeutics administered directly into the eye. As a consequence of their use, we have gained more insight into the immune privileged status of the eye and the various considerations that development, manufacturing, and use of these drugs require. It has been observed that therapeutic proteins injected into the vitreous can elicit an immune response resulting in the production of anti-drug antibodies (ADAs) which can have clinical consequences...
August 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28791599/comparison-of-nmr-and-dynamic-light-scattering-for-measuring-diffusion-coefficients-of-formulated-insulin-implications-for-particle-size-distribution%C3%A2-measurements-in-drug-products
#3
Sharadrao M Patil, David A Keire, Kang Chen
Particle size distribution, a measurable physicochemical quantity, is a critical quality attribute of drug products that needs to be controlled in drug manufacturing. The non-invasive methods of dynamic light scattering (DLS) and Diffusion Ordered SpectroscopY (DOSY) NMR can be used to measure diffusion coefficient and derive the corresponding hydrodynamic radius. However, little is known about their use and sensitivity as analytical tools for particle size measurement of formulated protein therapeutics. Here, DLS and DOSY-NMR methods are shown to be orthogonal and yield identical diffusion coefficient results for a homogenous monomeric protein standard, ribonuclease A...
August 8, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28779380/peripheral-nerve-nanoimaging-monitoring-treatment-and-regeneration
#4
Jelena M Janjic, Vijay S Gorantla
Accidental and iatrogenic trauma are major causes of peripheral nerve injury. Healing after nerve injury is complex and often incomplete, which can lead to acute or chronic pain and functional impairment. Current assessment methods for nerve regeneration lack sensitivity and objectivity. There is a need for reliable and reproducible, noninvasive strategies with adequate spatial and temporal resolution for longitudinal evaluation of degeneration or regeneration after injury/treatment. Methods for noninvasive monitoring of the efficacy and effectiveness of neurotherapeutics in nerve regeneration or of neuropathic pain are needed to ensure adequacy and responsiveness to management, especially given the large variability in the patient populations, etiologies, and complexity of nerve injuries...
August 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28779379/submicron-matrices-embedded-in-a-polymeric-caplet-for-extended-intravaginal-delivery-of-zidovudine
#5
Felix Mashingaidze, Yahya E Choonara, Pradeep Kumar, Lisa C du Toit, Vinesh Maharaj, Eckhart Buchmann, Viness Pillay
In this study, an intravaginal delivery system able to deliver an anti-HIV-1 agent for the purpose of potentially reducing HIV-1 transmission acting over an extended duration was successfully formulated. This delivery system was a composite polymeric caplet comprising zidovudine-loaded polyethylene glycol enclatherated pectin-mucin submicron matrices embedded within a poly (D,L-lactide), magnesium stearate, Kollidon® SR, and Carbopol® 974P NF-based polymeric caplet matrix. A three-factor and three-level Box-Behnken statistical design was utilized to optimize the polymeric caplet...
August 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28779378/blood-brain-barrier-driven-pharmacoresistance-in-amyotrophic-lateral-sclerosis-and-challenges-for-effective-drug-therapies
#6
Loqman A Mohamed, Shashirekha Markandaiah, Silvia Bonanno, Piera Pasinelli, Davide Trotti
The blood-brain barrier (BBB) is essential for proper neuronal function, homeostasis, and protection of the central nervous system (CNS) microenvironment from blood-borne pathogens and neurotoxins. The BBB is also an impediment for CNS penetration of drugs. In some neurologic conditions, such as epilepsy and brain tumors, overexpression of P-glycoprotein, an efflux transporter whose physiological function is to expel catabolites and xenobiotics from the CNS into the blood stream, has been reported. Recent studies reported that overexpression of P-glycoprotein and increase in its activity at the BBB drives a progressive resistance to CNS penetration and persistence of riluzole, the only drug approved thus far for treatment of amyotrophic lateral sclerosis (ALS), rapidly progressive and mostly fatal neurologic disease...
August 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28770387/data-to-decisions-creating-a-culture-of-model-driven-drug-discovery
#7
Frank K Brown, Farida Kopti, Charlie Zhenyu Chang, Scott A Johnson, Meir Glick, Chris L Waller
Merck & Co., Inc., Kenilworth, NJ, USA, is undergoing a transformation in the way that it prosecutes R&D programs. Through the adoption of a "model-driven" culture, enhanced R&D productivity is anticipated, both in the form of decreased attrition at each stage of the process and by providing a rational framework for understanding and learning from the data generated along the way. This new approach focuses on the concept of a "Design Cycle" that makes use of all the data possible, internally and externally, to drive decision-making...
August 2, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28762128/physicochemical-characterization-of-iron-carbohydrate-colloid-drug-products
#8
Peng Zou, Katherine Tyner, Andre Raw, Sau Lee
Iron carbohydrate colloid drug products are intravenously administered to patients with chronic kidney disease for the treatment of iron deficiency anemia. Physicochemical characterization of iron colloids is critical to establish pharmaceutical equivalence between an innovator iron colloid product and generic version. The purpose of this review is to summarize literature-reported techniques for physicochemical characterization of iron carbohydrate colloid drug products. The mechanisms, reported testing results, and common technical pitfalls for individual characterization test are discussed...
July 31, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28762127/microdialysis-as-an-important-technique-in-systems-pharmacology-a-historical-and-methodological-review
#9
Margareta Hammarlund-Udenaes
Microdialysis has contributed with very important knowledge to the understanding of target-specific concentrations and their relationship to pharmacodynamic effects from a systems pharmacology perspective, aiding in the global understanding of drug effects. This review focuses on the historical development of microdialysis as a method to quantify the pharmacologically very important unbound tissue concentrations and of recent findings relating to modeling microdialysis data to extrapolate from rodents to humans, understanding distribution of drugs in different tissues and disease conditions...
July 31, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28752430/integrated-gut-and-liver-microphysiological-systems-for-quantitative-in-vitro-pharmacokinetic-studies
#10
Nikolaos Tsamandouras, Wen Li Kelly Chen, Collin D Edington, Cynthia L Stokes, Linda G Griffith, Murat Cirit
Investigation of the pharmacokinetics (PK) of a compound is of significant importance during the early stages of drug development, and therefore several in vitro systems are routinely employed for this purpose. However, the need for more physiologically realistic in vitro models has recently fueled the emerging field of tissue-engineered 3D cultures, also referred to as organs-on-chips, or microphysiological systems (MPSs). We have developed a novel fluidic platform that interconnects multiple MPSs, allowing PK studies in multi-organ in vitro systems along with the collection of high-content quantitative data...
July 27, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28741221/optimization-and-application-of-a-biotinylation-method-for-quantification-of-plasma-membrane-expression-of-transporters-in-cells
#11
Vineet Kumar, Tot Bui Nguyen, Beáta Tóth, Viktoria Juhasz, Jashvant D Unadkat
Quantitative proteomics, using LC-MS/MS, is increasingly used to quantify drug transporters present in tissues and cells. Most of these investigations quantify total transporter expression in the cells by utilizing a total membrane fraction, not only the plasma membrane. Here, we report development and optimization of a biotinylation method to quantify protein expression of transporters in the plasma membrane of cells. The Pierce cell surface isolation protocol was optimized for plasma membrane isolation. Incubation of OATP1B1-expressing CHO cells with 0...
July 24, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28733862/recommendations-for-systematic-statistical-computation-of-immunogenicity-cut-points
#12
Viswanath Devanarayan, Wendell C Smith, Rocco L Brunelle, Mary E Seger, Kim Krug, Ronald R Bowsher
Today, the assessment of immunogenicity is integral in nonclinical and clinical testing of new biotherapeutics and biosimilars. A key component in the risk-based evaluation of immunogenicity involves the detection and characterization of anti-drug antibodies (ADA). Over the past couple of decades, much progress has been made in standardizing the generalized approach for ADA testing with a three-tiered testing paradigm involving screening, confirmation, and quasi-quantitative titer assessment representing the typical harmonized scheme...
July 21, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28717926/clinical-evaluation-of-modified-release-and-immediate-release-tacrolimus-formulations
#13
Simon Tremblay, Rita R Alloway
The science of drug delivery has evolved considerably and has led to the development of multiple sustained release formulations. Each of these formulations can present particular challenges in terms of clinical evaluation and necessitate careful study to identify their optimal use in practice. Tacrolimus is an immunosuppressive agent that is widely used in organ transplant recipients. However, it is poorly soluble, has an unpredictable pharmacokinetic profile subject to important genetic polymorphisms and drug-drug interactions, and has a narrow therapeutic index...
July 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28710684/utility-of-physiologically-based-pharmacokinetic-absorption-modeling-to-predict-the-impact-of-salt-to-base-conversion-on-prasugrel-hcl-product-bioequivalence-in-the-presence-of-proton-pump-inhibitors
#14
Jianghong Fan, Xinyuan Zhang, Liang Zhao
Prasugrel HCl may convert to prasugrel base during manufacturing or storage. It was reported that formulations with different ratios of salt to base were bioequivalent in healthy subjects, but formulations with a higher extent of conversion were not bioequivalent in subjects taking proton pump inhibitor (PPI) whose stomach pH is elevated. The objective of this study was to assess the magnitude of impact of salt-to-base conversion on prasugrel HCl products BE evaluation in healthy subjects on PPI. A physiologically based pharmacokinetic (PBPK) absorption model was constructed to predict pharmacokinetic (PK) profiles of active metabolite after oral administration of prasugrel HCl products containing various fractions of base based on the prasugrel salt and base intrinsic solubility...
July 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28685397/application-of-exposure-response-analyses-to-establish-the-pharmacodynamic-similarity-of-a-once-daily-regimen-to-an-approved-twice-daily-dosing-regimen-for-the-treatment-of-hcv-infection
#15
Akshanth R Polepally, Haoyu Wang, Patrick J Marroum, Mukul Minocha, Balakrishna Hosmane, Amit Khatri, Sven Mensing, Thomas J Podsadecki, Daniel E Cohen, Walid M Awni, Rajeev M Menon
The triple direct-acting antiviral (3-DAA) regimen (two co-formulated tablets of ombitasvir/paritaprevir/ritonavir once daily and one tablet of dasabuvir twice daily) for patients with hepatitis C virus (HCV) genotype 1 infection has been reformulated for once-daily administration containing all three active DAAs (3QD regimen). Two bioequivalence studies compared the 3-DAA and 3QD regimens. In study 1, fed, single-, and multiple-dose crossover comparisons revealed exposures for drug components that were slightly outside the bioequivalence criteria, i...
July 6, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28685396/pharmacokinetics-and-pharmacogenomics-of-bupropion-in-three-different-formulations-with-different-release-kinetics-in-healthy-human-volunteers
#16
Jamie N Connarn, Stephanie Flowers, Marisa Kelly, Ruijuan Luo, Kristen M Ward, Gloria Harrington, Ila Moncion, Masoud Kamali, Melivin McInnis, Meihua R Feng, Vicki Ellingrod, Andrew Babiskin, Xinyuan Zhang, Duxin Sun
The purpose of this pharmacokinetics (PK) study was to investigate whether different release kinetics from bupropion hydrochloride (HCl) immediate release (IR), sustained release (SR), and extended release (ER) formulations alter its metabolism and to test the hypothesis that the unsuccessful bioequivalence (BE) study of the higher strength (300 mg) of bupropion HCl ER tablets based on the successful BE study of the lower strength (150 mg) was due to metabolic saturation in the gastrointestinal (GI) lumen...
July 6, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28681160/biopharmaceutical-evaluation-and-cmc-aspects-of-oral-modified-release-formulations
#17
Rong-Kun Chang, Neil Mathias, Munir A Hussain
This article discusses the range of outcomes from biopharmaceutical studies of specific modified release (MR) product examples in preclinical models and humans. It touches upon five major biopharmaceutical areas for MR drug products: (1) evidence for regional permeability throughout the GI tract, (2) susceptibility to food-effect, (3) susceptibility to pH-effect, (4) impact of chronopharmacology in designing MR products, and (5) implications to narrow therapeutic index products. Robust bioperformance requires that product quality is met through a thorough understanding of the appropriate critical quality attributes that ensure reliable and robust manufacture of a MR dosage form...
July 5, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28664465/slc-and-abc-transporters-expression-localization-and-species-differences-at-the-blood-brain-and-the-blood-cerebrospinal-fluid-barriers
#18
Marilyn E Morris, Vivian Rodriguez-Cruz, Melanie A Felmlee
The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) separate the brain and cerebrospinal fluid (CSF) from the systemic circulation and represent a barrier to the uptake of both endogenous compounds and xenobiotics into the brain. For compounds whose passive diffusion is limited due to their ionization or hydrophilicity, membrane transporters can facilitate their uptake across the BBB or BCSFB. Members of the solute carrier (SLC) and ATP-binding case (ABC) families are present on these barriers...
June 29, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28660399/microdialysis-coupled-with-lc-ms-ms-for-in-vivo-neurochemical-monitoring
#19
Alexander G Zestos, Robert T Kennedy
Microdialysis is a powerful sampling technique used to monitor small molecules in vivo. Despite the many applications of microdialysis sampling, it is limited by the method of analyzing the resulting samples. An emerging technique for analysis of microdialysis samples is liquid chromatography-tandem mass spectrometry (LC-MS/MS). This technique is highly versatile, allowing multiplexed analysis of neurotransmitters, metabolites, and neuropeptides. Using LC-MS/MS for polar neurotransmitters is hampered by weak retention reverse phase LC columns...
June 28, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28653244/%C3%AE-hydroxybutyric-acid-ghb-pharmacokinetics-and-pharmacodynamics-semi-mechanistic-and-physiologically-relevant-pk-pd-model
#20
Rutwij A Dave, Kristin E Follman, Marilyn E Morris
An overdose of γ-hydroxybutyric acid (GHB), a drug of abuse, results in fatality caused by severe respiratory depression. In this study, a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize monocarboxylate transporter 1 (MCT1)-mediated transport of GHB, as well as effects of GHB on respiration frequency, for IV doses of 200, 600, and 1500 mg/kg in rats. The proposed PK/PD model for GHB consists of nonlinear metabolism of GHB in the liver, MCT1-mediated renal reabsorption with physiologically relevant concurrent fluid reabsorption, MCT1-mediated uptake into the brain, and direct effects of binding of GHB to GABAB receptors on the PD parameter, respiration frequency...
June 26, 2017: AAPS Journal
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