Suivi thérapeutique pharmacologique

Résumé

Le Suivi Thérapeutique Pharmacologique (STP) (en anglais Therapeutic drug monitoring (TDM)), ou « suivi thérapeutique des médicaments », (ou encore « pharmacovigilance thérapeutique ») est une branche « clinique » de la chimie et surtout de la pharmacologie, spécialisée dans la détermination des taux sanguins de médicaments. Son intérêt est de permettre une surveillance précise des substances pharmacologiquement actives ayant un index thérapeutique étroit, c'est-à-dire des médicaments pour lesquels un sous-dosage ou surtout un sur-dosage peuvent s'avérer délétères. Le STP vise à adapter les posologies d'un médicament pour un patient donné, sur la base de l'expérience clinique ou d'essais thérapeutiques ayant démontré son utilité chez tous les patients recevant ce médicament ou chez un sous-groupe d'entre eux. Un tel ajustement de posologie peut être effectué a priori, en référence à des données pharmacogénétiques, démographiques ou cliniques, ou a posteriori en référence à la mesure de

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https://fr.wikipedia.org/wiki/Suivi_th%C3%A9rapeutique_pharmacologique

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Microdevice-integrated immunoassays for Point-of-Care Therapeutic Drug Monitoring

Elena-Diana Bojescu

A significant number of drugs exhibit narrow therapeutic windows and high inter-individual pharmacokinetic variability. In such cases, Therapeutic Drug Monitoring (TDM) is compulsory in order to optimize the efficacy of the drug while avoiding adverse effects. Concentration measurements required for dose-adjustments are however complex and are therefore only performed at specialized facilities. The development of a device for accurate whole-blood quantification of critical drugs at the Point-of-Care (POC) would enable fast time-to-result and provide a more convenient solution to patients. This thesis aimed at the design of sample-to-result devices comprising microstructures that allowed for the quantification of small molecules in blood. The designs were based on the development and use of miniaturized fluorescence polarization immunoassays (FPIA). The main feature offered by the FP assay format was the ability to perform homogeneous measurements with no separation or washing steps required. An important result of this thesis is the demonstration that the concentration of small drugs can be quantified in whole blood within paper-like membranes using Fluorescence Polarization Immunoassay (FPIA). Different types of paper-like materials such as glass microfibers, cellulose and filter paper were screened for artefacts such as scattering or autofluorescence. Accurate determination of the fluorescence polarization of red-emitting fluorophores at sub-nanomolar concentrations was found possible within glass fiber membranes. This enabled the development of a competitive immunoassay for the quantification of the antibiotic tobramycin using only 1 ïL of plasma in glass fiber micro-chambers. Furthermore, the same membrane was used for transversal separation of blood cells followed by accurate FPIA read-out at the bottom part of the micro-chamber. Within the therapeutic window, coefficients of variation were around 20% and recoveries between 80-105%, demonstrating the ability to run quantitatively both clinical chemistry and sample preparation by incorporating FPIA in glass fiber membranes. Another important step towards a POC device was the design of a compact, bench-top FP-based analyzer. In this case, glass capillaries were used as detection chambers as they cause little light scattering and for reasons of convenience. Furthermore, the new optical system was employed for tobramycin quantification previously spiked in plasma samples showing good analytical performance in terms of coefficients of variation and recoveries within the therapeutic range of the drug. A more challenging class of drugs are the immunosuppressants, administered in cases of organ transplantation. Here, several fluorescent derivatives of tacrolimus at different wavelengths were synthesized. Their affinity for various biorecognition molecules were tested allowing the choice of a ligand-receptor pair for the development of a FPIA for tacrolimus quantification in buffer. Next, attempts were undertaken to adapt the immunoassay for analysis in whole blood samples. Considerable challenges due to the complexity of the matrix were revealed and initiated efforts to improve the whole blood preparation techniques with the aim of quantifying tacrolimus within its therapeutic range. With the aim of paving the way towards personalized therapies, this thesis makes the realisation of a POC for TDM a realistic goal.

EPFL2018

Chargement

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Breast cancer is a highly heterogeneous disease. The efficacy of tailored therapeutic strategies relies on the precise detection of diagnostic biomarkers by immunohistochemistry (IHC). Therefore, considering the increasing incidence of breast cancer cases, a concomitantly time-efficient and accurate diagnosis is clinically highly relevant. Microfluidics is a promising innovative technology in the field of tissue diagnostic, enabling for rapid, reliable, and automated immunostaining. We previously reported the microfluidic-based HER2 (human epidermal growth factor receptor 2) detection in breast carcinomas to greatly correlate with the HER2 gene amplification level. Here, we aimed to develop a panel of microfluidic-based IHC protocols for prognostic and therapeutic markers routinely assessed for breast cancer diagnosis, namely HER2, estrogen/progesterone receptor (ER/PR), and Ki67 proliferation factor. The microfluidic IHC protocol for each marker was optimized to reach high staining quality comparable to the standard procedure, while concomitantly shortening the staining time to 16 min-excluding deparaffinization and antigen retrieval step-with a turnaround time reduction up to 7 folds. Comparison of the diagnostic score on 50 formaldehyde-fixed paraffin-embedded breast tumor resections by microfluidic versus standard staining showed high concordance (overall agreement: HER2 94%, ER 95.9%, PR 93.6%, Ki67 93.7%) and strong correlation (rho coefficient: ER 0.89, PR 0.88, Ki67 0.87; p < 0.0001) for all the analyzed markers. Importantly, HER2 genetic reflex test for all discordant cases confirmed the scores obtained by the microfluidic technique. Overall, the microfluidic-based IHC represents a clinically validated equivalent approach to the standard chromogenic staining for rapid, accurate, and automated breast cancer diagnosis.

2019

Chargement

Hematopoietic Stem and Progenitor Cells (HSPCs) reside in their niche, a structure that regulates the balance of cellular quiescence, self-renewal and commitment towards differentiated cells. This highly plastic niche is formed by several cellular players, mainly endothelial cells, osteoblasts, adipocytes, and a variety of stromal progenitor cells of which CXCL12-abundant reticular (CAR) cells have been best characterized. Adipocytes have been shown to inhibit hematopoietic progenitor proliferation, but pre-adipocytes can efficiently support the growth of hematopoietic cells in culture. This suggests that the same cellular lineage contains populations with divergent hematopoietic-supportive capacity.In the first part of this thesis, we hypothesized that pharmacological modulation of the adipocytic differentiation axis could inhibit bone marrow (BM)-derived adipocyte maturation and improve hematopoietic progenitor support. Using a phenotypic screen, we identified calcipotriol, a vitamin D derivative, as a strong inhibitor of adipocyte differentiation. In vivo administration of calcipotriol decreased BM adipocyte size at day 18 post BM transplantation, increased total number of colony-forming units (CFUs) per leg and improved the survival of Cxcl12 haploinsufficient mice. Thus, we identified this vitamin D derivative as our top candidate to accelerate hematopoietic recovery in radio/chemotherapy-induced aplasia by targeting the maturation of adipocytes in the BM.Then, we took advantage of a prospective cohort of patients to assess the association between bone health and hematopoietic output in the context of osteoporosis. Osteoporosis is characterized by reduced bone mineral density (BMD), microarchitectural deterioration and increased BM adipocytic content. We studied the association between BMD and differential blood counts. We found that significant associations between blood counts and BMD exist, but none was consistent across bone parameters or timepoints. This suggests that, for steady-state hematopoiesis, there is no clinically significant effect of the deteriorated bone microenvironment on blood production.In the last part, to further investigate the composition of the HSPC-supportive microenvironment, we explored the simpler, albeit functional, extramedullary niche. We showed that the adrenal gland can be transformed into a hematopoietic supportive environment and used as a model to study the minimal components of a de novo niche. This induced adrenal niche supports HSPCs, including serially transplantable hematopoietic stem cells. Circulating HSPCs home into the adrenal cortex, where they are in proximity to CAR cells. These findings are supported by the presence of CXCL12+ cells in human adrenal myelolipoma, a benign tumor that contains extramedullary hematopoietic tissue. We envision our model as a novel tool to study the minimal components needed for hematopoietic support.Thus, using a combination of clinical, translational and basic research, we discovered a new therapeutic candidate approach to improve hematopoietic support by using a vitamin D analog to modify the BM adiposity. We showed the resilience of the BM niche by observing no measurable effect of the osteoporotic niche on hematopoietic output in a large cohort of patients. Finally, we developed a model of de novo hematopoietic niche in the adrenal gland. Altogether, our work provides new strategies to improve our understanding of the hematopoietic niche.

EPFL2022

Chargement

Microdevice-integrated immunoassays for Point-of-Care Therapeutic Drug Monitoring

Elena-Diana Bojescu

EPFL2018

EPFL2022