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Binfeng Xia Zhen Yang Haiying Zhou Viera Lukacova Wei Zhu Mikolaj Milewski Filippos Kesisoglou 《The AAPS journal》2015,17(3):631-642
Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms. The purpose of this work was to develop and evaluate a novel, physiologically based oral cavity model for projection and mechanistic analysis of the clinical pharmacokinetics of intraoral formulations. The GastroPlus™ Oral Cavity Compartmental Absorption and Transit (OCCAT™) model was used to simulate the plasma concentration versus time profiles and the fraction and rate of intraoral drug transit/absorption for Intermezzo® sublingual tablets (zolpidem tartrate). The model was evaluated by the goodness-of-fit between simulated and observed concentrations and the deviation of key PK parameters (e.g., Cmax, Tmax, and AUC). In addition, a sensitivity analysis was conducted to demonstrate the interplay and impact of key modeling parameters on the fraction absorbed via oral mucosa (Fa_IO). The OCCAT™ model captured the observed pharmacokinetics for Intermezzo® sublingual tablets (R2 > 0.9). The predicted deviations (%) for Cmax, AUC0–inf, AUC0–20 min, and Tmax were 5.7, 28.0, 11.8, and 28.6%, respectively, indicating good prediction accuracy. The model also estimated ~18% of total drug was absorbed via the IO route. Furthermore, the sensitivity analysis indicated that the Fa_IO was not only associated with drug diffusivity and unbound fraction in epithelium tissue (fut) but also depended on the physicochemical properties of compounds for IO delivery (e.g., solubility and logDpH = 7.4). The novel physiologically based IO absorption OCCAT™ model showed satisfactory performance and will be helpful to guide development of future intraoral formulations.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-015-9727-7) contains supplementary material, which is available to authorized users.KEY WORDS: diffusivity, intraoral delivery, oral cavity compartmental absorption and transit (OCCAT™) model, unbound fraction in epithelium tissue, zolpidem 相似文献94.
Papavramidis TS Laskou S Michalopoulos N Pliakos I Kesisoglou I Papavramidis S 《Tropical doctor》2012,42(2):118-119
This is a typical case of a splenic hydatid cysts. We present the clinical features, the diagnostic work-up and the management of the disease. 相似文献
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Isaak Quast Christian W. Keller Michael A. Maurer John P. Giddens Bj?rn Tackenberg Lai-Xi Wang Christian Münz Falk Nimmerjahn Marinos C. Dalakas Jan D. Lünemann 《The Journal of clinical investigation》2015,125(11):4160-4170
IgG molecules exert both pro- and antiinflammatory effector functions based on the composition of the fragment crystallizable (Fc) domain glycan. Sialylated IgG Fc domains have antiinflammatory properties that are attributed to their ability to increase the activation threshold of innate effector cells to immune complexes by stimulating the upregulation of the inhibitory Fcγ receptor IIB (FcγRIIB). Here, we report that IgG Fc sialylation of human monoclonal IgG1 molecules impairs their efficacy to induce complement-mediated cytotoxicity (CDC). Fc sialylation of a CD20-targeting antibody had no impact on antibody-dependent cellular cytotoxicity and did not change the affinity of the antibody for activating Fcγ receptors. In contrast, the presence of sialic acid abrogated the increased binding of C1q to Fc-galactosylated IgG1 and resulted in decreased levels of C3b deposition on the cell surface. Similar to monoclonal antibodies, sialic acid inhibited the increased C1q binding to galactosylated Fc fragments in human polyclonal IgG. In sera derived from patients with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system in which humoral immune responses mediate tissue damage, induction of IgG Fc sialylation was associated with clinical disease remission. Thus, impairment of CDC represents an FcγR-independent mechanism by which Fc-sialylated glycovariants might limit proinflammatory IgG effector functions. 相似文献
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The opportunistic fungi Trichophyton rubrum and T. mentagrophytes, are responsible for relatively non-inflammatory chronic dermatophytes infections in immunocompromised patients but also in healthy individuals. This chronic infection is associated with immunosuppressive effects of the cell wall components particularly the polysaccharides secreted by these organisms. We have studied glycosylphosphatidylinositol (GPI) anchor biosynthesis in the pathogenic fungus T. rubrum and could demonstrate that T. rubrum is able to synthesize GPI structures. Glycolipids synthesized in a cell-free system prepared from the dermatophyte T. rubrum and labeled with [3H]mannose, and [3H]galactose using GDP-[3H]mannose and UDP-[3H]galactose, respectively, were identified and structurally characterized as GPIs. The evolutionary conserved backbone of T. rubrum GPIs incorporates galactose. Further, all glycolipids lack the acyl group on the inositol which was shown for Saccharomyces cerevisiae and mammalian GPIs. Our data suggest significant differences in the GPI biosynthetic pathway between mammalian and T. rubrum cells that could perhaps be exploited for the development of an antimycotic for Trichophyton infection. 相似文献
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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 《The AAPS journal》2018,20(6):93
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. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product. 相似文献