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Master Thesis

Suivi thérapeutique pharmacologique des anticorps monoclonaux thérapeutiques : de l’analytique à l’évaluation de la variabilité pharmacocinétique du rituximab et du tocilizumab

Abstract : Medical care of chronic disease has been revolutionized by the use of monoclonal therapeutic antibodies (mAbs). Despite these advances, the clinical response of these drugs is eminently variable and could be linked to their important pharmacokinetic variability. That is why therapeutic drug monitoring (TDM) of mAbs was proposed. Immunoassays like Enzyme-Linked Immunosorbent Assay (ELISA), the most currently used methods for mAbs quantification are limited by a lack of specificity. Thus, the pharmacology lab of the University Hospital of Grenoble Alpes has developed a highly-specific method by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify mAbs. Monitoring of a new proteotypic peptide of rituximab (RTX) and the use of stable isotope-labeled RTX as internal standard enable a lowering of the limit of quantification at 1.0 μg.mL-1, allowing TDM of RTX. RTX concentrations measured with this LC-MS/MS method were correlated to those obtained by ELISA, but an important bias existed for the Promonitor® kit. This improved LC-MS/MS method was then used in a bioclinical study that showed very variable RTX and tocilizumab (TCZ) serum concentrations in patients with rheumatoid arthritis, without evidence of any concentration-clinical response link. Finally, this thesis allowed to improve the LC-MS/MS method of mAbs quantification and to confirm the important pharmacokinetic variability of RTX and TCZ. Further studies are necessary to investigate the concentration-effect link of these mAbs and evaluated the interest of their TDM.
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Master Thesis
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https://dumas.ccsd.cnrs.fr/dumas-03245955
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Submitted on : Wednesday, June 2, 2021 - 10:13:29 AM
Last modification on : Friday, June 4, 2021 - 3:21:58 AM
Long-term archiving on: : Friday, September 3, 2021 - 6:37:10 PM

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  • HAL Id : dumas-03245955, version 1

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Aurélie Truffot. Suivi thérapeutique pharmacologique des anticorps monoclonaux thérapeutiques : de l’analytique à l’évaluation de la variabilité pharmacocinétique du rituximab et du tocilizumab. Sciences pharmaceutiques. 2020. ⟨dumas-03245955⟩

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