TY - JOUR A1 - Schrezenmeier, E. A1 - Hoffmann, F. A1 - Jaeger, C. A1 - Schrezenmeier, J. A1 - Lisec, Jan A1 - Glander, P. A1 - Algharably, E. A1 - Kreutz, R. A1 - Budde, K. A1 - Duerr, M. A1 - Halleck, F. T1 - Pharmacokinetics of Daclatasvir, Sofosbuvir and GS-331007 in a Prospective Cohort of HCV positive Kidney Transplant Recipients JF - Therapeutic drug monitoring N2 - Limited data exist on the pharmacokinetic profile of novel direct acting antivirals in kidney transplant recipients. Daclatasvir is primarily eliminated via the biliary route and sofosbuvir via the renal route; here we report the pharmacokinetic profile of combined treatment with these compounds in a prospective study of hepatitis C virus positive kidney transplant recipients (EudraCT: 2014-004551-32). In this study plasma samples of 16 HCV positive kidney transplant recipients receiving daclatasvir and sofosbuvir were collected at 4 time points at day 1, 7, 14, 21, 56, and 84 after start of treatment. Inclusion criteria were stable graft function and an estimated GFR (eGFR) > 30mL/min/1.73m. Daclatasvir, sofosbuvir and GS-331007 (inactive metabolite of sofosbuvir) plasma concentrations were determined using ultra-performance liquid chromatography quadrupole time of flight mass spectrometry. All patients showed a rapid virological response with HCV RNA below the detection limit 21 days after the start of therapy (medium time to viral clearance). No difference of the areas under the concentration-time curve (AUC) of daclatsavir, sofosbuvir and GS-331007 was observed between patients with an eGFR below or ≥ 60mL/min. For GS-331007, no relevant changes of trough levels were observed over time. Mean GS-331007 trough levels were 339.5±174.9 ng/mL in patients with an eGFR ≥ 60mL/min and 404.3±226 ng/mL in patients with an eGFR < 60mL/min at day 7 (p=0.52). At day 84, GS-331007 trough levels were 357.8±200.8 ng/mL and 404.2±70.2 ng/mL in patients with an eGFR ≥ 60 mL/min and in patients with an eGFR < 60 mL/min, respectively (p=0.51). The accumulation ratios of renally eliminated GS-331007 for AUC and Cmax did not significantly differ between the two eGFR groups at day 7. An impaired eGFR (30-60 mL/min) does not lead to a dose accumulation of daclatasvir, sofosbuvir and GS-331007. This study provides the rationale for future studies investigating the pharmacokinetic profile of sofosbuvir based HCV treatment in kidney transplant recipients with an eGFR < 30 mL/min. KW - Mass-Spectrometry PY - 2018 DO - https://doi.org/10.1097/FTD.0000000000000567 SN - 0163-4356 VL - 41 IS - 1 SP - 53 EP - 58 PB - Wolters Kluwer AN - OPUS4-46647 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Lisec, Jan A1 - Hoffmann, F. A1 - Jaeger, C. A1 - Bhattacharya, A. A1 - Schmitt, C. A. T1 - Nontargeted Identification of Tracer Incorporation in High- Resolution Mass Spectrometry JF - Analytical Chemistry N2 - “Fluxomics” refers to the systematic analysis of metabolic fluxes in a biological system and may uncover novel dynamic properties of metabolism that remain undetected in conventional metabolomic approaches. In labeling experiments, tracer molecules are used to track changes in the isotopologue distribution of metabolites, which allows one to estimate fluxes in the metabolic network. Because unidentified compounds cannot be mapped on pathways, they are often neglected in labeling experiments. However, using recent developments in de novo annotation may allow to harvest the information present in these compounds if they can be identified. Here, we present a novel tool (HiResTEC) to detect tracer incorporation in high-resolution mass spectrometry data sets. The software automatically extracts a comprehensive, nonredundant list of all compounds showing more than 1% tracer incorporation in a nontargeted fashion. We explain and show in an example data set how mass precision and other filter heuristics, calculated on the raw data, can efficiently be used to reduce redundancy and noninformative signals by 95%. Ultimately, this allows to quickly investigate any labeling experiment for a complete set of labeled compounds (here 149) with acceptable false positive rates. We further re-evaluate a published data set from liquid chromatography-electrospray ionization (LC-ESI) to demonstrate broad applicability of our tool and emphasize importance of quality control (QC) tests. HiResTEC is provided as a package in the open source software framework R and is freely available on CRAN. KW - Fluxomics KW - R package KW - Mass-Spectrometry PY - 2018 DO - https://doi.org/10.1021/acs.analchem.8b00356 VL - 90 IS - 12 SP - 7253 EP - 7260 PB - ACS Publications AN - OPUS4-45493 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER -