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Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.KEY WORDS: absorption modeling, PBPK, pharmacokinetics, Quality by Design (QbD), quality target product profile (QTPP) 相似文献
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Brandon N. Nicolay Paul S. Danielian Filippos Kottakis John D. Lapek Jr Ioannis Sanidas Wayne O. Miles Mantre Dehnad Katrin Tsch?p Jessica J. Gierut Amity L. Manning Robert Morris Kevin Haigis Nabeel Bardeesy Jacqueline A. Lees Wilhelm Haas Nicholas J. Dyson 《Genes & development》2015,29(17):1875-1889
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Increased transduction of human intestinal epithelial cells by adenoviral vectors in inflammatory bowel disease 总被引:2,自引:0,他引:2
Schmiedlin-Ren P Kesisoglou F Mapili JA Sabek SE Barnett JL Chey WD Roessler B Zimmermann EM 《Inflammatory bowel diseases》2005,11(5):464-472
BACKGROUND: Delivery of genes encoding anti-inflammatory proteins has been proposed as a strategy for the treatment of inflammatory bowel disease (IBD). The goal of this study was to assess the ability of a standard adenoviral vector to transfect epithelial cells in intestinal explants from patients with IBD compared with controls. METHODS: Endoscopic colon biopsies obtained from patients with no history of IBD and endoscopically normal colon (n = 4), patients with a history of ulcerative colitis (UC; n = 5), and patients with a history of Crohn's disease (CD; n = 3) were placed in explant culture and exposed to an adenoviral vector carrying the nuclear targeted beta-galactosidase reporter gene. RESULTS: X-Gal staining showed that the total number of transduced cells per square millimeter was greater in UC explants than in controls (mean, 11.3 versus 0.9 blue nuclei/mm, respectively; P < 0.02) and that the frequency of epithelial cell transduction was greater in UC explants than in controls (86% versus 47% of explants, respectively; P = 0.01). Transduction of mature columnar surface epithelial cells occurred exclusively in UC and CD explants and was not seen in controls. Attenuated epithelial cells at sites of tissue damage or ulceration showed increased transduction compared with mature columnar epithelial cells (62% versus 19% of occurrences, respectively; P < 0.0001). CONCLUSIONS: We conclude that intestinal epithelial cells from IBD patients are more readily transfected by standard adenoviral vectors than are those from control patients. These results suggest that targeting genes to inflamed intestine through the luminal route may be possible. 相似文献
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Andreas Abend Tycho Heimbach Michael Cohen Filippos Kesisoglou Xavier Pepin Sandra Suarez-Sharp 《The AAPS journal》2018,20(3):60
On May 15th–17th, 2017, the US FDA and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) held a workshop at the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI), to discuss the role of dissolution testing and translational modeling and simulation in enabling patient-centric solid oral drug product development. This 3-day event was attended by scientists from regulatory agencies, pharmaceutical companies, and academia. The workshop included podium presentations followed by breakout session discussions. The first day of the meeting focused on the challenges in dissolution method development and the role of dissolution testing throughout drug product development. On the second day, approaches to establish a link between in vitro testing and in vivo drug product performance (e.g., systemic exposure) were presented. Overall success rates and challenges in establishing IVIVCs via traditional and modern physiologically based pharmacokinetic (PBPK) modeling and simulation approaches were discussed. Day 3 provided an opportunity to discuss the expectations for establishing clinically relevant drug product specifications (CRDPS). It was recognized that understanding the impact of formulation and process variations on dissolution and in vivo performance is critical for most drug products formulated with poorly soluble drugs to ensure consistent product performance. The breakout sessions served as platforms for discussing controversial topics such as the clarification of dissolution terminology, PBPK model development and validation expectations, and approaches to set CRDPS. The meeting concluded with a commitment to continue the dialog between regulators, industry, and academia to advance overall product quality understanding. 相似文献