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AAPS Journal

Haoxun Wang, Jinghui Zhang, Guofeng You
Organic anion transporter 3 (OAT3) plays a vital role in removing a broad variety of anionic drugs from kidney, thus avoiding their possible toxicity in the body. We earlier established that activation of protein kinase C (PKC) enhances OAT3 ubiquitination, which promotes OAT3 internalization from the cell plasma membrane to intracellular endosomes and consequent degradation. As a result, OAT3 expression and transport activity are reduced. In the current study, we discovered that protein kinase A (PKA) had an opposite effect to PKC on the regulation of OAT3...
February 13, 2019: AAPS Journal
Tycho Heimbach, Sandra Suarez-Sharp, Maziar Kakhi, Nico Holmstock, Andrés Olivares-Morales, Xavier Pepin, Erik Sjögren, Eleftheria Tsakalozou, Paul Seo, Min Li, Xinyuan Zhang, Ho-Pi Lin, Timothy Montague, Amitava Mitra, Denise Morris, Nikunjkumar Patel, Filippos Kesisoglou
This publication summarizes the proceedings of day 2 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Patient-centric drug product development from a drug product quality perspective necessitates the establishment of clinically relevant drug product specifications via an in vitro-in vivo link. Modeling and simulation offer a path to establish this link; in this regard, physiologically based modeling has been implemented successfully to support regulatory decision-making and drug product labeling...
February 11, 2019: AAPS Journal
Piotr J Rudzki, Przemysław Biecek, Michał Kaza
Reliable results of pharmacokinetic and toxicokinetic studies are vital for correct decision making during drug discovery and development. Thus, ensuring high quality of bioanalytical methods is of critical importance. Incurred sample reanalysis (ISR)-one of the tools used to validate a method-is included in the bioanalytical regulatory recommendations. The methodology of this test is well established, but the estimation of the sample size is still commented on and contested. We have applied the hypergeometric distribution to evaluate ISR test passing rates in different clinical study sizes...
February 11, 2019: AAPS Journal
Katherine Kay, Keith Dolcy, Robert Bies, Dhaval K Shah
Tumor doubling time can significantly affect the outcome of anticancer therapy, but it is very challenging to determine. Here, we present a statistical approach that extracts doubling times from progression-free survival (PFS) plots, which inherently contains information regarding the growth of solid tumors. Twelve cancers were investigated and multiple PFS plots were evaluated for each type. The PFS plot showing fastest tumor growth was deemed to best represent the inherent growth kinetics of the solid tumor, and selected for further analysis...
February 8, 2019: AAPS Journal
Eduardo F Mufarrege, Lydia A Haile, Marina Etcheverrigaray, Daniela I Verthelyi
Recombinant human interferon-β (rhIFN-β) therapy is the first-line treatment in relapsing-remitting forms of multiple sclerosis (MS). The mechanism of action underlying its therapeutic activity is only partially understood as IFN-βs induce the expression of over 1000 genes modifying multiple immune pathways. Currently, assessment of potency for IFN-β products is based on their antiviral effect, which is not linked to its therapeutic effect. Here, we explore the use of a multiplexed gene expression system to more broadly characterize IFN-β bioactivity...
February 8, 2019: AAPS Journal
Worth Longest, Dale Farkas
Computational fluid dynamics (CFD) modeling offers a powerful tool for the development of drug delivery devices using a first principles approach but has been underutilized in the development of pharmaceutical inhalers. The objective of this study was to develop quantitative correlations for predicting the aerosolization behavior of a newly proposed dry powder inhaler (DPI). The dose aerosolization and containment (DAC) unit DPI utilizes inlet and outlet air orifices designed to maximize the dispersion of spray-dried powders, typically with low air volumes (~ 10 mL) and relatively low airflow rates (~ 3 L/min)...
February 7, 2019: AAPS Journal
Jessie L-S Au, Ze Lu, Roberto A Abbiati, M Guillaume Wientjes
Approval of generic drugs by the US Food and Drug Administration (FDA) requires the product to be pharmaceutically equivalent to the reference listed drug (RLD) and demonstrate bioequivalence (BE) in effectiveness when administered to patients under the conditions in the RLD product labeling. Effectiveness is determined by drug exposure at the target sites. However, since such measurement is usually unavailable, systemic exposure is assumed to equal target site exposure and systemic BE to equal target site BE...
February 1, 2019: AAPS Journal
Maria Garcia-Cremades, Celine Pitou, Philip W Iversen, Iñaki F Troconiz
The aim of this evaluation was to predict tumour response to gemcitabine in patients with advanced pancreas or ovarian cancer using pre-clinical data obtained from xenograft tumour-bearing mice. The approach consisted of building a translational model combining pre-clinical pharmacokinetic-pharmacodynamic (PKPD) models and parameters, with dosing paradigms used in the clinics along with clinical PK models to derive tumour profiles in humans driving overall survival. Tumour growth inhibition simulations were performed using drug effect parameters obtained from mice, system parameters obtained from mice after appropriate scaling, patient PK models for gemcitabine and carboplatin, and the standard dosing schedules given in the clinical scenario for both types of cancers...
January 31, 2019: AAPS Journal
Hyeong-Seok Lim, Wan Sun, Kourosh Parivar, Diane Wang
Prediction of survival endpoints, e.g., overall survival (OS) and progression-free survival (PFS), based on early observations, i.e., tumor size, may facilitate early decision making in oncology drug development. In this paper, using data from six randomized trials for first- or second-line advanced breast cancer (ABC) treatments with various mechanisms of action, tumor size change from baseline at different observation time points was evaluated as a predictor for survival endpoints using different modeling approaches...
January 30, 2019: AAPS Journal
Andreas Abend, David Curran, Jesse Kuiper, Xujin Lu, Hanlin Li, Andre Hermans, Pramod Kotwal, Dorys A Diaz, Michael J Cohen, Limin Zhang, Erika Stippler, German Drazer, Yiqing Lin, Kimberly Raines, Lawrence Yu, Carrie A Coutant, Haiyan Grady, Johannes Krämer, Sarah Pope-Miksinski, Sandra Suarez-Sharp
This publication summarizes the proceedings and key outcomes of the first day ("Day 1") of the 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." The overall aims of the workshop were to foster a productive dialog between industry and regulatory agencies and to discuss current strategies toward the development and implementation of clinically relevant dissolution specifications as an integral part of enhanced drug product understanding and effective drug product life-cycle management...
January 28, 2019: AAPS Journal
Haruka Nishimuta, Takao Watanabe, Kiyoko Bando
Accurate prediction of human pharmacokinetics for drugs remains challenging, especially for non-cytochrome P450 (P450) substrates. Hepatocytes might be suitable for predicting hepatic intrinsic clearance (CLint ) of new chemical entities, because they can be applied to various compounds regardless of the metabolic enzymes. However, it was reported that hepatic CLint is underestimated in hepatocytes. The purpose of the present study was to confirm the predictability of human hepatic clearance for P450 and non-P450 substrates in hepatocytes and the utility of animal scaling factors for the prediction using hepatocytes...
January 23, 2019: AAPS Journal
Cordula Stillhart, Xavier Pepin, Christophe Tistaert, David Good, An Van Den Bergh, Neil Parrott, Filippos Kesisoglou
The establishment of an in vitro-in vivo correlation (IVIVC) is considered the gold standard to establish in vivo relevance of a dissolution method and to utilize dissolution data in the context of regulatory bioequivalence questions, including the development of dissolution specifications. However, several recent publications, including industry surveys and reviews from regulatory agencies, have indicated a low success rate for IVIVCs, especially for immediate-release formulations. In recent years, the use of physiologically based pharmacokinetics (PBPK) and absorption modeling, as a tool to facilitate formulation development, has been attracting increased attention...
January 23, 2019: AAPS Journal
Man Li, Yuting Yang, Chaoqun Xu, Jiaojie Wei, Yingke Liu, Xingli Cun, Qianwen Yu, Xian Tang, Sheng Yin, Zhirong Zhang, Qin He
Chemoimmunotherapy with chemotherapeutics and immunoadjuvant inhibits tumor growth by activating cytotoxic T cells. However, this process also upregulates the expression of PD-1/PD-L1 and consequently leads to immune suppression. To maximize the anti-tumor immune responses and alleviate immunosuppression, PD-L1 antibody was combined with paclitaxel (PTX) and the immunoadjuvant α-galactosylceramide (αGC), which were coencapsulated into pH-sensitive TH peptide-modified liposomes (PTX/αGC/TH-Lip) to treat melanoma and lung metastasis...
January 11, 2019: AAPS Journal
Thomas M Polasek, Amin Rostami-Hodjegan, Dong-Seok Yim, Masoud Jamei, Howard Lee, Holly Kimko, Jae Kyoung Kim, Phuong Thi Thu Nguyen, Adam S Darwich, Jae-Gook Shin
Model-informed precision dosing (MIPD) is modeling and simulation in healthcare to predict the drug dose for a given patient based on their individual characteristics that is most likely to improve efficacy and/or lower toxicity in comparison to traditional dosing. This paper describes the background and status of MIPD and the activities at the 1st Asian Symposium of Precision Dosing. The theme of the meeting was the question, "What does it take to make MIPD common practice?" Formal presentations highlighted the distinction between genetic and non-genetic sources of variability in drug exposure and response, the use of modeling and simulation as decision support tools, and the facilitators to MIPD implementation...
January 9, 2019: AAPS Journal
Fiona Chandra, Lihi Zaks, Andy Zhu
A single efficacy metric quantifying anti-tumor activity in xenograft models is useful in evaluating different tumors' drug sensitivity and dose-response of an anti-tumor agent. Commonly used metrics include the ratio of tumor volume in treated vs. control mice (T/C), tumor growth inhibition (TGI), ratio of area under the curve (AUC), and growth rate inhibition (GRI). However, these metrics have some limitations. In particular, for biologics with long half-lives, tumor volume (TV) of treated xenografts displays a delay in volume reduction (and in some cases, complete regression) followed by a growth rebound...
January 9, 2019: AAPS Journal
Sussan Ghassabian, Tina B Gillani, Tristan Rawling, Severine Crettol, Pramod C Nair, Michael Murray
The multi-kinase inhibitor sorafenib (SOR) is clinically important in the treatment of hepatocellular and renal cancers and undergoes CYP3A4-dependent oxidation in liver to the pharmacologically active N-oxide metabolite (SNO). There have been reports that kinase inhibitors such as SOR may precipitate pharmacokinetic interactions with coadministered drugs that compete for CYP3A4-mediated biotransformation, but these occur non-uniformly in patients. Clinical evidence also indicates that SNO accumulates in serum of some patients during prolonged SOR therapy...
January 9, 2019: AAPS Journal
Xiaowen Guan, Vivian Rodriguez-Cruz, Marilyn E Morris
AR-C155858 and AZD3965, pyrrole pyrimidine derivatives, represent potent monocarboxylate transporter 1 (MCT1) inhibitors, with potential immunomodulatory and chemotherapeutic properties. Currently, there is limited information on the inhibitory properties of this new class of MCT1 inhibitors. The purpose of this study was to characterize the concentration- and time-dependent inhibition of L-lactate transport and the membrane permeability properties of AR-C155858 and AZD3965 in the murine 4T1 breast tumor cells that express MCT1...
January 7, 2019: AAPS Journal
Qing Liu, Mohammad Absar, Bhawana Saluja, Changning Guo, Badrul Chowdhury, Robert Lionberger, Dale P Conner, Bing V Li
In 2016, the US Food and Drug Administration (FDA) approved the first Abbreviated New Drug Application for Mometasone Furoate Nasal Suspension Spray. To establish the bioequivalence of this generic nasal suspension spray with the reference listed drug product (RLD), Nasonex®, a "weight-of-evidence" approach was utilized by the applicant that included formulation and device similarities, equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition to these testing for comprehensive evaluation of the drug product, FDA also considered supportive data generated by a novel in vitro method, Morphologically-Directed Raman Spectroscopy (MDRS), to characterize the particle size distribution (PSD) of active pharmaceutical ingredient (API) in the drug product...
January 7, 2019: AAPS Journal
Lipika Chablani, Suprita A Tawde, Archana Akalkotkar, Martin J D'Souza
Breast cancer impacts female population globally and is the second most common cancer for females. With various limitations and adverse effects of current therapies, several immunotherapies are being explored. Development of an effective breast cancer vaccine can be a groundbreaking immunotherapeutic approach. Such approaches are being evaluated by several clinical trials currently. On similar lines, our research study aims to evaluate a particulate breast cancer vaccine delivered via skin. This particulate breast cancer vaccine was prepared by spray drying technique and utilized murine breast cancer whole cell lysate as a source of tumor-associated antigens...
January 2, 2019: AAPS Journal
Sebastiaan C Goulooze, Elke H J Krekels, Thomas Hankemeier, Catherijne A J Knibbe
During covariate modeling in pharmacometrics, computational time can be reduced by using a fast preselection tool to identify a subset of promising covariates that are to be tested with the more computationally demanding likelihood ratio test (LRT), which is considered to be the standard for covariate selection. There is however a lack of knowledge on best practices for covariate (pre)selection in pharmacometric repeated time-to-event (RTTE) models. Therefore, we aimed to systematically evaluate the performance of three covariate (pre)selection tools for RTTE models: the likelihood ratio test (LRT), the empirical Bayes estimates (EBE) test, and a novel Schoenfeld-like residual test...
December 18, 2018: AAPS Journal
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