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1دورية أكاديمية
المؤلفون: Birk Poller, Felix Huth, Gáborik Zsuzsanna, Hanna Imad, Huth Felix, Imad Hanna, Imola Juhász, Juhász Imola, Patrick Schweigler, Poller Birk, Péter Tátrai, Sakata Takeshi, Schweigler Patrick, Takeshi Sakata, Tátrai Péter, Zsuzsanna Gáborik
المصدر: Proceedings for Annual Meeting of The Japanese Pharmacological Society. 2019, :1-112
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2دورية أكاديمية
المؤلفون: Loesche, Christian, Picard, Damien, Van Hoorick, Benjamin, Schuhmann, Imelda, Jäger, Petra, Klein, Kai, Schuhler, Carole, Thoma, Gebhard, Markert, Christian, Poller, Birk, Zamurovic, Natasa, Weiss, H. Markus, Otto, Heike, Fink, Martin, Röhn, Till A.
المصدر: Clinical and Translational Science ; volume 17, issue 2 ; ISSN 1752-8054 1752-8062
الوصف: LYS006 is a novel, highly potent and selective, new‐generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil‐driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006‐treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re‐distribution from target expressing cells resulted in a long terminal half‐life and a long‐lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well‐tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose‐limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil‐driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.
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3دورية أكاديمية
المؤلفون: Keuper-Navis, Marit, Walles, Markus, Poller, Birk, Myszczyszyn, Adam, van der Made, Thomas K, Donkers, Joanne, Amirabadi, Hossein Eslami, Wilmer, Martijn J, Aan, Saskia, Spee, Bart, Masereeuw, Rosalinde, van de Steeg, Evita
المساهمون: Afd Pharmacology, Interne geneeskunde GD, CS_STEM, Pharmacology
مصطلحات موضوعية: Organ-on-chip, Drug development, Pharmacokinetics, ADME
الوصف: Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential of OoC models to improve the prediction of human oral bioavailability and intrinsic clearance is discussed, with a focus on the functionality of the models and the application in current drug development practice. Multi-OoC models demonstrating the application for pharmacokinetic (PK) studies are summarized and existing challenges are identified. Physiological parameters for a minimal viable platform of a multi-OoC model to study PK are provided, together with PK specific read-outs and recommendations for relevant reference compounds to validate the model. Finally, the translation to in vivo PK profiles is discussed, which will be required to routinely apply OoC models during drug development.
وصف الملف: application/pdf
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4دورية أكاديمية
المؤلفون: Trunzer, Markus, Teigao, Joana, Huth, Felix, Poller, Birk, Rodriguez Perez, Raquel, Desrayaud, Sandrine, Faller, Bernard
الوصف: It is common practice in drug discovery and development to predict in vivo hepatic clearance from in vitro incubations with liver microsomes or hepatocytes using the well-stirred model (WSM). When applying the WSM to a set of approximately 3000 Novartis research compounds, 73% of neutral and basic compounds (extended clearance classification system [ECCS] class 2) were well-predicted within 3-fold. In contrast, only 44% (ECCS class 1A) or 34% (ECCS class 1B) of acids were predicted within 3-fold. To explore the hypothesis whether the higher degree of plasma protein binding for acids contributes to the in vitro-in vivo correlation (IVIVC) disconnect, 68 proprietary compounds were incubated with rat liver microsomes in the presence and absence of 5% plasma. A minor impact of plasma on clearance IVIVC was found for moderately bound compounds (fraction unbound in plasma [fup] ≥1%). However, addition of plasma significantly improved the IVIVC for highly bound compounds (fup <1%) as indicated by an increase of the average fold error from 0.10 to 0.36. Correlating fup with the scaled unbound intrinsic clearance ratio in the presence or absence of plasma allowed the establishment of an empirical, nonlinear correction equation that depends on fup Taken together, estimation of the metabolic clearance of highly bound compounds was enhanced by the addition of plasma to microsomal incubations. For standard incubations in buffer only, application of an empirical correction provided improved clearance predictions. SIGNIFICANCE STATEMENT: Application of the well-stirred liver model for clearance in vitro-in vivo extrapolation (IVIVE) in rat generally underpredicts the clearance of acids and the strong protein binding of acids is suspected to be one responsible factor. Unbound intrinsic in vitro clearance (CLint,u) determinations using rat liver microsomes supplemented with 5% plasma resulted in an improved IVIVE. An empirical equation was derived that can be applied to correct CLint,u-values in dependance of fraction unbound ...
العلاقة: Trunzer, Markus, Teigao, Joana, Huth, Felix, Poller, Birk, Rodriguez Perez, Raquel, Desrayaud, Sandrine and Faller, Bernard (2024) Improving In Vitro-In Vivo Extrapolation of Clearance Using Rat Liver Microsomes for Highly Plasma Protein-Bound Molecules. Drug metabolism and disposition: the biological fate of chemicals, 52 (5). pp. 345-354. ISSN 1521-009X
الإتاحة: https://doi.org/10.1124/dmd.123.001597Test
https://oak.novartis.com/52137Test/
https://dmd.aspetjournals.org/content/52/5/345Test -
5دورية أكاديمية
المؤلفون: Huth, Felix, Schiller, Hilmar, Jin, Yi, Poller, Birk, Schuhler, Carole, Weis, Wendy, Woessner, Ralph, Drollmann, Anton, End, Peter
المصدر: Clinical and Translational Science ; volume 15, issue 1, page 118-129 ; ISSN 1752-8054 1752-8062
الوصف: Remibrutinib, a novel oral Bruton’s Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first‐pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady‐state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27‐fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically‐based pharmacokinetic (PBPK) model, which well‐described the therapeutic dose range of 25–100 mg. Simulations of untested scenarios revealed an absence of drug‐drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration‐time curve ratio [AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%. Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks.
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6دورية أكاديمية
المؤلفون: Huth, Felix, Domange, Norbert, Poller, Birk, Vapurcuyan, Arpine, Durrwell, Alexandre, Hanna, Imad D., Faller, Bernard
المصدر: Journal of Pharmaceutical Sciences ; ISSN 0022-3549
مصطلحات موضوعية: Pharmaceutical Science
الإتاحة: https://doi.org/10.1016/j.xphs.2021.01.029Test
https://api.elsevier.com/content/article/PII:S002235492100071X?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S002235492100071X?httpAccept=text/plainTest -
7دورية أكاديمية
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8دورية أكاديمية
المؤلفون: James, Alexander David, Kulmatycki, Ken, Poller, Birk, Romeo, Andrea, Van Lier, Jan Jaap, Klein, Kai, Pearson, David
الوصف: Iptacopan (LNP023) is an oral, small-molecule, first-in-class, highly potent proximal complement inhibitor that specifically binds factor B and inhibits the alternative complement pathway. Iptacopan is currently in development as a targeted treatment of paroxysmal nocturnal hemoglobinuria and multiple other complement-mediated diseases. In this study, the absorption, distribution, metabolism, and excretion (ADME) of iptacopan was characterized in six healthy volunteers after a single 100 mg oral dose of [14C]iptacopan. This was supplemented with an in vivo rat ADME study and metabolite exposure comparisons between human, rat, and dog, in addition to in vitro assays, to better understand the clearance pathways and enzymes involved in the metabolism of iptacopan. The fraction of [14C]iptacopan absorbed was estimated to be about 71%, with a time to maximum concentration of 1.5 hours and elimination half-life from plasma of 12.3 hours. Following a single dose of [14C]iptacopan, 71.5% of the radioactivity was recovered in feces and 24.8% in urine. [14C]iptacopan was primarily eliminated by hepatic metabolism. The main biotransformation pathways were oxidative metabolism via CYP2C8, with M2 being the major oxidative metabolite, and acyl glucuronidation via UGT1A1. The two acyl glucuronide metabolites in human plasma, M8 and M9, each accounted for ≤ 10% of the total circulating drug-related material; systemic exposure was also observed in toxicology studies in rat and dog, suggesting a low risk associated with these metabolites. Binding of iptacopan to its target, factor B, in the bloodstream led to a concentration-dependent blood:plasma distribution and plasma protein binding of [14C]iptacopan. SIGNIFICANCE STATEMENT: We characterized the pharmacokinetics, excretion, metabolism and elimination of [14C]iptacopan (an oral, selective small-molecule inhibitor of factor B) in healthy human subjects. [14C]iptacopan was primarily eliminated by metabolism. The primary biotransformation pathways were oxidative metabolism via ...
العلاقة: James, Alexander David, Kulmatycki, Ken, Poller, Birk, Romeo, Andrea, Van Lier, Jan Jaap, Klein, Kai and Pearson, David (2023) Absorption, Distribution, Metabolism, and Excretion of [14C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies. Drug metabolism and disposition: the biological fate of chemicals, 51 (7). pp. 873-883. ISSN 1521-009X
الإتاحة: https://doi.org/10.1124/dmd.123.001290Test
https://oak.novartis.com/49443Test/
https://dmd.aspetjournals.org/content/51/7/873Test -
9دورية أكاديمية
المؤلفون: Patel, Mitesh, Riede, Julia, Bednarczyk, Dallas, Poller, Birk, Deshmukh, Sujal
الوصف: The Extended Clearance Concept Classification System was established as a development-stage tool to provide a framework for identifying fundamental mechanism(s) governing drug disposition in humans. In the present study, the applicability of the EC3S in drug discovery has been investigated. In its current format, the EC3S relies on low-throughput hepatocyte uptake data, which are not frequently generated in a discovery setting.A relationship between hepatocyte uptake clearance and MDCK permeability was first established along with intrinsic clearance from human liver microsomes. The performance of this approach was examined by categorizing 64 drugs into EC3S classes and comparing the predicted major elimination pathway(s) to that observed in humans. As an extension of the work, the ability of the simplified EC3S to predict human systemic clearance based on intrinsic clearance generated using in-vitro metabolic systems was evaluated.The assessment enabled the use of MDCK permeability and unscaled unbound intrinsic clearance to generate cut-off criteria to categorize compounds into four EC3S classes: Class 12ab, 2cd, 34ab, and 34cd, with major elimination mechanism(s) assigned to each class. The predictivity analysis suggested that systemic clearance could generally be predicted within threefold for EC3S class 12ab and 34ab compounds. For classes 2cd and 34cd, systemic clearance was poorly predicted using in-vitro systems explored in this study.Collectively, our simplified classification approach is expected to facilitate the identification of mechanism(s) involved in drug elimination, faster resolution of in-vitro to in-vivo disconnects, and better design of mechanistic pharmacokinetic studies in drug discovery.
العلاقة: Patel, Mitesh, Riede, Julia, Bednarczyk, Dallas, Poller, Birk and Deshmukh, Sujal (2023) Simplifying the Extended Clearance Concept Classification System (EC3S) to Guide Clearance Prediction in Drug Discovery. Pharmaceutical research. ISSN 1573-904X
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10دورية أكاديمية
المؤلفون: Riede, Julia, Camenisch, Gian, Huwyler, Jörg, Poller, Birk
المصدر: Journal of Pharmaceutical Sciences ; volume 106, issue 9, page 2805-2814 ; ISSN 0022-3549
مصطلحات موضوعية: Pharmaceutical Science
الإتاحة: https://doi.org/10.1016/j.xphs.2017.03.025Test
https://api.elsevier.com/content/article/PII:S0022354917302113?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0022354917302113?httpAccept=text/plainTest
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