TY  - JOUR
A1  - Zhang, Jin
A1  - Heimbach, Tycho
A1  - Scheer, Nico
A1  - Barve, Avantika
A1  - Li, Wenkui
A1  - Lin, Wen
A1  - He, Handan
T1  - Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4–Humanized Mouse Studies With PBPK Modeling
JF  - Journal of Pharmaceutical Sciences
N2  - NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (ƒₘCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate ƒₘCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human ƒₘCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir.
Y1  - 2016
U6  - https://doi.org/doi.org/10.1016/j.xphs.2016.01.021
SN  - 0022-3549
VL  - Volume 105
IS  - Issue 4
SP  - 1398
EP  - 1404
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Wilson, Ian D.
A1  - Wilson, Claire E.
A1  - Scheer, Nico
A1  - Dickie, A.P.
A1  - Schreiter, K.
A1  - Wilson, E. M.
A1  - Riley, R. J.
A1  - Wehr, R.
A1  - Bial, J.
T1  - The Pharmacokinetics and Metabolism of Lumiracoxib in Chimeric Humanized and Murinized FRG Mice
JF  - Biochemical pharmacology
Y1  - 2017
U6  - https://doi.org/10.1016/j.bcp.2017.03.015
SN  - 1873-2968
VL  - Volume 135
SP  - 139
EP  - 150
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - CHAP
A1  - Mataré, Victor
A1  - Schiffer, Stefan
A1  - Ferrein, Alexander
ED  - Steinbauer, Gerald
ED  - Ferrein, Alexander
T1  - golog++ : An integrative system design
T2  - CogRob 2018. Cognitive Robotics Workshop : Proceedings of the 11th Cognitive Robotics Workshop 2018 co-located with 16th International Conference on Principles of Knowledge Representation and Reasoning (KR 2018) Tempe, AZ, USA, October 27th, 2018
Y1  - 2019
SN  - 1613-0073
SP  - 29
EP  - 35
ER  - 
TY  - CHAP
A1  - Rütters, René
A1  - Weinheimer, Marius
A1  - Bragard, Michael
T1  - Teaching Control Theory with a Simplified Helicopter Model and a Classroom Fitting Hardware Test-Bench
T2  - 2018 IEEE 59th International Scientific Conference on Power and Electrical Engineering of Riga Technical University (RTUCON)
Y1  - 2018
SN  - 978-1-5386-6903-7
U6  - https://doi.org/10.1109/RTUCON.2018.8659871
ER  - 
TY  - CHAP
A1  - Bragard, Michael
A1  - Hoek, Hauke van
A1  - Hoegen, Anne von
A1  - Doncker, Rik W. De
T1  - Motivation-based Learning: Teaching Fundamentals of Electrical Engineering with an LED Spinning Top
T2  - 2018 IEEE 59th International Scientific Conference on Power and Electrical Engineering of Riga Technical University (RTUCON)
Y1  - 2018
SN  - 978-1-5386-6903-7
U6  - https://doi.org/10.1109/RTUCON.2018.8659810
SP  - 1
EP  - 6
ER  - 
TY  - CHAP
A1  - Bindzus, Manuel
A1  - Bragard, Michael
T1  - Motivating Intuitive Understanding of the Switched Reluctance Machine in the Education of Undergraduate Students
T2  - 2018 IEEE 59th International Scientific Conference on Power and Electrical Engineering of Riga Technical University (RTUCON)
Y1  - 2018
SN  - 978-1-5386-6903-7
U6  - https://doi.org/10.1109/RTUCON.2018.8659870
SP  - 1
EP  - 6
ER  - 
TY  - JOUR
A1  - Leschinger, Tim
A1  - Birgel, Stefan
A1  - Hackl, Michael
A1  - Staat, Manfred
A1  - Müller, Lars Peter
A1  - Wegmann, Kilian
T1  - A musculoskeletal shoulder simulation of moment arms and joint reaction forces after medialization of the supraspinatus footprint in rotator cuff repair
JF  - Computer Methods in Biomechanics and Biomedical Engineering
Y1  - 2019
U6  - https://doi.org/10.1080/10255842.2019.1572749
IS  - Early view
PB  - Taylor & Francis
CY  - London
ER  - 
TY  - JOUR
A1  - Wilson, C. E.
A1  - Dickie, A. P.
A1  - Schreiter, K.
A1  - Wehr, R.
A1  - Wilson, E. M.
A1  - Bial, J.
A1  - Scheer, Nico
A1  - Wilson, I. D.
A1  - Riley, R. J.
T1  - The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice
JF  - Archives of Toxicology
N2  - The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans.
Y1  - 2018
U6  - https://doi.org/10.1007/s00204-018-2212-1
SN  - 1432-0738
VL  - 92
IS  - 6
SP  - 1953
EP  - 1967
PB  - Springer
ER  - 
TY  - CHAP
A1  - Kazuki, Yasuhiro
A1  - Kobayashi, Kaoru
A1  - Hirabayashi, Masumi
A1  - Abe, Satoshi
A1  - Kajitani, Naoyo
A1  - Kazuki, Kanoko
A1  - Takehara, Shoko
A1  - Takiguchi, Masato
A1  - Satoh, Daisuke
A1  - Kuze, Jiro
A1  - Sakuma, Tetsushi
A1  - Kaneko, Takehito
A1  - Mashimo, Tomoji
A1  - Osamura, Minori
A1  - Hashimoto, Mari
A1  - Wakatsuki, Riko
A1  - Hirashima, Rika
A1  - Fujiwara, Ryoichi
A1  - Deguchi, Tsuneo
A1  - Kurihara, Atsushi
A1  - Tsukazaki, Yasuko
A1  - Senda, Naoto
A1  - Yamamoto, Takashi
A1  - Scheer, Nico
A1  - Oshimura, Mitsuo
T1  - Humanized UGT2 and CYP3A transchromosomic rats for improved prediction of human drug metabolism
T2  - PNAS Proceedings of the National Academy of Sciences of the United States of America
Y1  - 2019
U6  - https://doi.org/10.1073/pnas.1808255116
SN  - 1091-6490
VL  - 116
IS  - 8
SP  - 3072
EP  - 3081
ER  - 
TY  - CHAP
A1  - Baader, Fabian
A1  - Reiswich, M.
A1  - Bartsch, M.
A1  - Keller, D.
A1  - Tiede, E.
A1  - Keck, G.
A1  - Demircian, A.
A1  - Friedrich, M.
A1  - Dachwald, Bernd
A1  - Schüller, K.
A1  - Lehmann, Raphael
A1  - Chojetzki, R.
A1  - Durand, C.
A1  - Rapp, L.
A1  - Kowalski, Julia
A1  - Förstner, R.
T1  - VIPER - Student research on extraterrestrical ice penetration technology
T2  - Proceedings of the 2nd Symposium on Space Educational Activities
N2  - Recent analysis of scientific data from Cassini and earth-based observations gave evidence for a global ocean under a surrounding solid ice shell on Saturn's moon Enceladus. Images of Enceladus' South Pole showed several fissures in the ice shell with plumes constantly exhausting frozen water particles, building up the E-Ring, one of the outer rings of Saturn. In this southern region of Enceladus, the ice shell is considered to be as thin as 2 km, about an order of magnitude thinner than on the rest of the moon. Under the ice shell, there is a global ocean consisting of liquid water. Scientists are discussing different approaches the possibilities of taking samples of water, i.e. by melting through the ice using a melting probe. FH Aachen UAS developed a prototype of maneuverable melting probe which can navigate through the ice that has already been tested successfully in a terrestrial environment. This means no atmosphere and or ambient pressure, low ice temperatures of around 100 to 150K (near the South Pole) and a very low gravity of 0,114 m/s^2 or 1100 μg. Two of these influencing measures are about to be investigated at FH Aachen UAS in 2017, low ice temperature and low ambient pressure below the triple point of water. Low gravity cannot be easily simulated inside a large experiment chamber, though. Numerical simulations of the melting process at RWTH Aachen however are showing a gravity dependence of melting behavior. Considering this aspect, VIPER provides a link between large-scale experimental simulations at FH Aachen UAS and numerical simulations at RWTH Aachen. To analyze the melting process, about 90 seconds of experiment time in reduced gravity and low ambient pressure is provided by the REXUS rocket. In this time frame, the melting speed and contact force between ice and probes are measured, as well as heating power and a two-dimensional array of ice temperatures. Additionally, visual and infrared cameras are used to observe the melting process.
Y1  - 2018
SP  - 1
EP  - 6
ER  -