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AAPS Journal

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https://www.readbyqxmd.com/read/30209711/michaelis-menten-from-an-in-vivo-perspective-open-versus-closed-systems
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
https://www.readbyqxmd.com/read/30167825/porcine-and-human-in-vivo-simulations-for-doxorubicin-containing-formulations-used-in-locoregional-hepatocellular-carcinoma-treatment
#7
Ilse R Dubbelboer, Erik Sjögren, Hans Lennernäs
It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles...
August 30, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30159772/time-scaling-for-in-vitro-in-vivo-correlation-the-inverse-release-function-irf-approach
#8
Jean Michel Cardot, John C Lukas, Paula Muniz
In vitro-in vivo correlations (IVIVC) are methods used to create a link between biopharmaceutical properties such as dissolution and physiological response such as plasma concentration. Level A IVIVC defines 1:1 relationship between the percent absorbed in vivo and the percent dissolved in vitro. A successful level A IVIVC provides the capacity to predict in vivo behavior based only on in vitro data with application in formulation development and support of biowaivers recognized by regulatory agencies across the world...
August 29, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30151644/emerging-cancer-therapeutic-targets-in-protein-homeostasis
#9
Prabhakar Bastola, Derek B Oien, Megan Cooley, Jeremy Chien
Genomic aberrations inside malignant cells through copy number alterations, aneuploidy, and mutations can exacerbate misfolded and unfolded protein burden resulting in increased proteotoxic stress. Increased proteotoxic stress can be deleterious to malignant cells; therefore, these cells rely heavily on the protein quality control mechanisms for survival and proliferation. Components of the protein quality control, such as the unfolded protein response, heat shock proteins, autophagy, and the ubiquitin proteasome system, orchestrate a cascade of downstream events that allow the mitigation of the proteotoxic stress...
August 27, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30151612/applications-of-clinically-relevant-dissolution-testing-workshop-summary-report
#10
Sandra Suarez-Sharp, Michael Cohen, Filippos Kesisoglou, Andreas Abend, Patrick Marroum, Poonam Delvadia, Evangelos Kotzagiorgis, Min Li, Anna Nordmark, Nagesh Bandi, Erik Sjögren, Andrew Babiskin, Tycho Heimbach, Shinichi Kijima, Haritha Mandula, Kimberly Raines, Paul Seo, Xinyuan Zhang
This publication summarizes the proceedings of day 3 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes...
August 27, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30128758/reflections-on-fda-draft-guidance-for-products-containing-nanomaterials-is-the-abbreviated-new-drug-application-anda-a-suitable-pathway-for-nanomedicines
#11
Marden Emily, Ntai Ioanna, Bass Scott, Flühmann Beat
The US Food and Drug Administration (FDA) recently released a draft guidance for industry titled "Drug Products, Including Biological Products, that Contain Nanomaterials." The FDA's attention to the unique safety and efficacy aspects of drugs containing nanomaterials is commendable. This Draft Guidance succeeds in acknowledging the complexity of these products, as well as the challenges associated with approving safe and therapeutically equivalent complex generic versions. However, the challenge posed by the manufacturing process for drugs containing nanomaterials is insufficiently addressed...
August 20, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30112626/a-population-pharmacokinetic-pharmacodynamic-model-of-pegfilgrastim
#12
Ari Brekkan, Luis Lopez-Lazaro, Gunnar Yngman, Elodie L Plan, Chayan Acharya, Andrew C Hooker, Suresh Kankanwadi, Mats O Karlsson
Neutropenia and febrile neutropenia (FN) are serious side effects of cytotoxic chemotherapy which may be alleviated with the administration of recombinant granulocyte colony-stimulating factor (GCSF) derivatives, such as pegfilgrastim (PG) which increases absolute neutrophil count (ANC). In this work, a population pharmacokinetic-pharmacodynamic (PKPD) model was developed based on data obtained from healthy volunteers receiving multiple administrations of PG. The developed model was a bidirectional PKPD model, where PG stimulated the proliferation, maturation, and margination of neutrophils and where circulating neutrophils in turn increased the elimination of PG...
August 15, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30109442/nephrotoxicity-and-kidney-transport-assessment-on-3d-perfused-proximal-tubules
#13
Marianne K Vormann, Linda Gijzen, Simon Hutter, Lisette Boot, Arnaud Nicolas, Angelique van den Heuvel, Jelle Vriend, Chee Ping Ng, Tom T G Nieskens, Vincent van Duinen, Bjorn de Wagenaar, Rosalinde Masereeuw, Laura Suter-Dick, Sebastiaan J Trietsch, Martijn Wilmer, Jos Joore, Paul Vulto, Henriette L Lanz
Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells...
August 14, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30094524/using-clinical-pk-pd-studies-to-support-no-clinically-meaningful-differences-between-a-proposed-biosimilar-and-the-reference-product
#14
Peijuan Zhu, Ping Ji, Yaning Wang
No abstract text is available yet for this article.
August 9, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30069613/exact-gradients-improve-parameter-estimation-in-nonlinear-mixed-effects-models-with-stochastic-dynamics
#15
Helga Kristin Olafsdottir, Jacob Leander, Joachim Almquist, Mats Jirstrand
Nonlinear mixed effects (NLME) modeling based on stochastic differential equations (SDEs) have evolved into a promising approach for analysis of PK/PD data. SDE-NLME models go beyond the realm of standard population modeling as they consider stochastic dynamics, thereby introducing a probabilistic perspective on the state variables. This article presents a summary of the main contributions to SDE-NLME models found in the literature. The aims of this work were to develop an exact gradient version of the first-order conditional estimation (FOCE) method for SDE-NLME models and to investigate whether it enabled faster estimation and better gradient precision/accuracy compared to the use of gradients approximated by finite differences...
August 1, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30051196/screening-of-drug-transporter-interactions-in-a-3d-microfluidic-renal-proximal-tubule-on-a-chip
#16
Jelle Vriend, Tom T G Nieskens, Marianne K Vormann, Bartholomeus T van den Berge, Angelique van den Heuvel, Frans G M Russel, Laura Suter-Dick, Henriëtte L Lanz, Paul Vulto, Rosalinde Masereeuw, Martijn J Wilmer
Drug-transporter interactions could impact renal drug clearance and should ideally be detected in early stages of drug development to avoid toxicity-related withdrawals in later stages. This requires reliable and robust assays for which current high-throughput screenings have, however, poor predictability. Kidney-on-a-chip platforms have the potential to improve predictability, but often lack compatibility with high-content detection platforms. Here, we combined conditionally immortalized proximal tubule epithelial cells overexpressing organic anion transporter 1 (ciPTEC-OAT1) with the microfluidic titer plate OrganoPlate to develop a screenings assay for renal drug-transporter interactions...
July 26, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30039346/combining-extracellular-mirna-determination-with-microfluidic-3d-cell-cultures-for-the-assessment-of-nephrotoxicity-a-proof-of-concept-study
#17
Laura Suter-Dick, L Mauch, D Ramp, M Caj, M K Vormann, S Hutter, H L Lanz, J Vriend, R Masereeuw, M J Wilmer
Drug-induced kidney injury is often observed in the clinics and can lead to long-term organ failure. In this work, we evaluated a novel in vitro system that aims at detecting whether compounds can cause renal proximal tubule damage in man. For this, we implemented organotypic cultures of human conditionally immortalized proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1) in a three-channel OrganoPlate under microfluidic conditions. Cells were exposed to four known nephrotoxicants (cisplatin, tenofovir, cyclosporine A, and tobramycin)...
July 23, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30027336/implementing-optimal-designs-for-dose-response-studies-through-adaptive-randomization-for-a-small-population-group
#18
Yevgen Ryeznik, Oleksandr Sverdlov, Andrew C Hooker
In dose-response studies with censored time-to-event outcomes, D-optimal designs depend on the true model and the amount of censored data. In practice, such designs can be implemented adaptively, by performing dose assignments according to updated knowledge of the dose-response curve at interim analysis. It is also essential that treatment allocation involves randomization-to mitigate various experimental biases and enable valid statistical inference at the end of the trial. In this work, we perform a comparison of several adaptive randomization procedures that can be used for implementing D-optimal designs for dose-response studies with time-to-event outcomes with small to moderate sample sizes...
July 19, 2018: AAPS Journal
https://www.readbyqxmd.com/read/30003443/effect-of-inhalation-flow-rate-on-mass-based-plume-geometry-of-commercially-available-suspension-pmdis
#19
Daniel F Moraga-Espinoza, Eli Eshaghian, Albert Shaver, Hugh D C Smyth
Although high-speed laser imaging is the current standard to characterize the plume angle of suspension-based pressurized metered dose inhalers (pMDIs), this method is limited by the inability to identify the drug content in a droplet and simulate inhalation flow. The Plume Induction Port Evaluator (PIPE) is a modified induction port for cascade impactors that allows for the calculation of the angle of a plume based on direct drug mass quantification rather than indirect droplet illumination under airflow conditions...
July 12, 2018: AAPS Journal
https://www.readbyqxmd.com/read/29995258/virtual-thorough-qt-tqt-trial-extrapolation-of-in-vitro-cardiac-safety-data-to-in-vivo-situation-using-multi-scale-physiologically-based-ventricular-cell-wall-model-exemplified-with-tolterodine-and-fesoterodine
#20
Nikunjkumar Patel, Barbara Wisniowska, Sebastian Polak
QT interval prolongation typically assessed with dedicated clinical trials called thorough QT/QTc (TQT) studies is used as surrogate to identify the proarrhythmic risk of drugs albeit with criticism in terms of cost-effectiveness in establishing the actual risk of torsade de pointes (TdP). Quantitative systems toxicology and safety (QSTS) models have potential to quantitatively translate the in vitro cardiac safety data to clinical level including simulation of TQT trials. Virtual TQT simulations have been exemplified with use of two related drugs tolterodine and fesoterodine...
July 11, 2018: AAPS Journal
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