TY - JOUR A1 - Shah, Nirav R. A1 - Bulitta, Jürgen B. A1 - Kinzig, Martina A1 - Landersdorfer, Cornelia B. A1 - Jiao, Yuanyuan A1 - Sutaria, Dhruvitkumar S. A1 - Tao, Xun A1 - Höhl, Rainer A1 - Holzgrabe, Ulrike A1 - Kees, Frieder A1 - Stephan, Ulrich A1 - Sörgel, Fritz T1 - Novel population pharmacokinetic approach to explain the differences between cystic fibrosis patients and healthy volunteers via protein binding JF - Pharmaceutics N2 - The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding. KW - cystic fibrosis patients KW - healthy volunteers KW - cefotiam KW - beta-lactam antibiotics KW - population pharmacokinetics KW - protein binding KW - allometric scaling KW - body size KW - body composition KW - S-ADAPT Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196934 SN - 1999-4923 VL - 11 IS - 6 ER - TY - JOUR A1 - Ma, Eric Yue A1 - Calvo, M. Reyes A1 - Wang, Jing A1 - Lian, Biao A1 - Mühlbauer, Mathias A1 - Brüne, Christoph A1 - Cui, Yong-Tao A1 - Lai, Keji A1 - Kundhikanjana, Worasom A1 - Yang, Yongliang A1 - Baenninger, Matthias A1 - König, Markus A1 - Ames, Christopher A1 - Buhmann, Hartmut A1 - Leubner, Philipp A1 - Molenkamp, Laurens W. A1 - Zhang, Shou-Cheng A1 - Goldhaber-Gordon, David A1 - Kelly, Michael A. A1 - Shen, Zhi-Xun T1 - Unexpected edge conduction in mercury telluride quantum wells under broken time-reversal symmetry JF - Nature Communications N2 - The realization of quantum spin Hall effect in HgTe quantum wells is considered a milestone in the discovery of topological insulators. Quantum spin Hall states are predicted to allow current flow at the edges of an insulating bulk, as demonstrated in various experiments. A key prediction yet to be experimentally verified is the breakdown of the edge conduction under broken time-reversal symmetry. Here we first establish a systematic framework for the magnetic field dependence of electrostatically gated quantum spin Hall devices. We then study edge conduction of an inverted quantum well device under broken time-reversal symmetry using microwave impedance microscopy, and compare our findings to a noninverted device. At zero magnetic field, only the inverted device shows clear edge conduction in its local conductivity profile, consistent with theory. Surprisingly, the edge conduction persists up to 9 T with little change. This indicates physics beyond simple quantum spin Hall model, including material-specific properties and possibly many-body effects. KW - topological insulators KW - surface states KW - HgTe KW - Hg1-xCdxTe KW - vacancies Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143185 VL - 6 IS - 7252 ER - TY - JOUR A1 - Bulitta, Jürgen B. A1 - Jiao, Yuanyuan A1 - Landersdorfer, Cornelia B. A1 - Sutaria, Dhruvitkumar S. A1 - Tao, Xun A1 - Shin, Eunjeong A1 - Höhl, Rainer A1 - Holzgrabe, Ulrike A1 - Stephan, Ulrich A1 - Sörgel, Fritz T1 - Comparable Bioavailability and Disposition of Pefloxacin in Patients with Cystic Fibrosis and Healthy Volunteers Assessed via Population Pharmacokinetics JF - Pharmaceutics N2 - Quinolone antibiotics present an attractive oral treatment option in patients with cystic fibrosis (CF). Prior studies have reported comparable clearances and volumes of distribution in patients with CF and healthy volunteers for primarily renally cleared quinolones. We aimed to provide the first pharmacokinetic comparison for pefloxacin as a predominantly nonrenally cleared quinolone and its two metabolites between both subject groups. Eight patients with CF (fat-free mass [FFM]: 36.3 ± 6.9 kg, average ± SD) and ten healthy volunteers (FFM: 51.7 ± 9.9 kg) received 400 mg pefloxacin as a 30 min intravenous infusion and orally in a randomized, two-way crossover study. All plasma and urine data were simultaneously modelled. Bioavailability was complete in both subject groups. Pefloxacin excretion into urine was approximately 74% higher in patients with CF compared to that in healthy volunteers, whereas the urinary excretion of metabolites was only slightly higher in patients with CF. After accounting for body size and composition via allometric scaling by FFM, pharmacokinetic parameter estimates in patients with CF divided by those in healthy volunteers were 0.912 for total clearance, 0.861 for nonrenal clearance, 1.53 for renal clearance, and 0.916 for volume of distribution. Nonrenal clearance accounted for approximately 90% of total pefloxacin clearance. Overall, bioavailability and disposition were comparable between both subject groups. KW - cystic fibrosis patients KW - healthy volunteers KW - fluoroquinolone KW - pefloxacin KW - absolute bioavailability KW - population pharmacokinetics KW - allometric scaling KW - body size KW - body composition KW - S-ADAPT Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197221 SN - 1999-4923 VL - 11 IS - 7 ER -