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Thomas Wagener untersuchte die Wechseslwirkung von Einsamkeit und psychischen Erkrankungen in einer Psychiatrie. Hierzu befragte er 15 Patient:innen, mit 10 von ihnen führte er längere Interviews, wobei davon vier verschriftlicht und veröffentlicht wurden. Die nicht verschriftlichten Interviews dienten als ein Erfahrungsbericht, der den abgedruckten Interviews vorangestellt wurde. Ein besonderes Augenmerk lag auf den sozialen Interaktionen zwischen den Patient:innen und der sie umgebenen Gesellschaft, wie Familie, Freunde und Bekannte. Auch wurde die Rolle der modernen Psychiatrie und ihr Bezug zum gesellschaftlichen Umfeld ausgeleuchtet. Abschließend erfolgte eine Schlußfolgerung des Verfassers, in dem verschiedene Aussagen der Interviewten nocheinmal gegenüber gestellt wurden.

Introduction: Many patients do not benefit from immunotherapies targeting immune checkpoints such as PD(L)-1 due to a variety of resistance mechanisms. The AhR pathway is downstream of the Trp-IDO/TDO-Kyn axis. High levels of immune-suppressive AhR-activating ligands, such as kynurenine derived from IDO1/TDO2-expressing tumors, have been implicated as a potential resistance mechanism and are associated with poor responses to PD-1 therapies. Compared with inhibition of IDO1/TDO2 alone, direct AhR inhibition can block the activation of this transcription factor and may better counteract immune suppression. BAY2416964 is a novel, oral AhR inhibitor currently in a Phase I clinical trial in patients with solid tumors. Preclinically, BAY2416964 can block the activation of AhR by kynurenine and relieve its immune-suppressive effects, thereby restoring anti-tumor T-cell activity, reducing the level of inhibitory myeloid-derived suppressor cells and regulatory T cells, and improving the effectiveness of PD-1 blockade. We have analyzed PK and biomarker data from the ongoing monotherapy dose-escalation study to explore a potential optimal dose and schedule for effective AhR inhibition. Methods: PK data were intensely sampled from patients in 10 different groups with different dosing regimens (once and twice daily) and various food-intake scenarios. AhR downstream target gene expression after ex vivo kynurenic acid stimulation of patients’ peripheral blood mononuclear cells (PBMCs) was assessed. A population PK (popPK) model was developed and calibrated to characterize the PK of BAY2416964 across treatment groups. This model accounts for the non-linear relationship between dose and bioavailability as well as the effect of food intake. Results: The preliminary popPK model identified a non-linear relationship between the BAY2416964 dose and its (relative) bioavailability which was dependent on the respective food condition. The popPK model was able to describe the clinical BAY2416964 plasma exposures from all dose groups, including the effect of food intake. Ex vivo analysis of PBMCs showed inhibition of kynurenic acid-induced AhR downstream gene expression (such as CYP1A1, CYP1B1), suggesting effective in vivo target engagement in the doses tested. Conclusion: This modeling-based PK analysis along with target engagement in peripheral blood informed the posology to be tested in the dose-expansion part of the ongoing clinical trial. Citation Format: Kyriakos Papadopoulos, Michael Cecchini, Juanita S. Lopez, Dirk Jäger, Ki Young Chung, Michael Platten, Florian Prinz, Yuko Ishii, David Schaer, Ilona Gutcher, Gabriele Leder, Radost Pencheva, Thomas Wagener, Christian Scheerans, Carsten Zieschang, Andrea Wagner, Spyros Stamatelos, Ecaterina Dumbrava. Preliminary analysis of pharmacokinetic (PK) and target engagement biomarkers from a first in human phase 1 study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT276.