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Blood, cellular, and tissular calcineurin inhibitors pharmacokinetic-pharmacodynamic relationship in heart transplant recipients: the INTRACAR study

Gwendal Coste 1, 2, 3, * Celine Chabanne 3 Camille Tron 1, 2, 3 Bernard Lelong 3 Marie-Clémence Verdier 1, 2, 3 Mikaël Roussel 4, 3 François Le Gall 3 Bruno Turlin 3 Mireille Desille-Dugast 3 Erwan Flécher 2, 3, 5, 6 Bruno Laviolle 1, 2, 3, 6 Florian Lemaitre 1, 2, 3, 6 
* Corresponding author
6 FHU SUPORT - Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation
IRTOMIT - Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques, RESINFIT - Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques, Cellules Dendritiques, Immunomodulation et Greffes, CHU Poitiers - Centre hospitalier universitaire de Poitiers , CHU Limoges, IPPRITT - Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation
Abstract : BACKGROUND: After heart transplantation, calcineurin inhibitors (CNI) (cyclosporin A and tacrolimus) are key immunosuppressive drugs to prevent graft rejection. Whole-blood concentration (Cblood)-guided therapeutic drug monitoring (TDM) is systematically performed to improve graft outcomes. However, some patients will still experience graft rejection and/or adverse events despite CNI Cblood within the therapeutic range. Other pharmacokinetic parameters, such as the intra-graft, or intracellular concentration at the CNI site of action could refine their TDM. Nonetheless, these remain to be explored. The objective of the INTRACAR study was to describe the relationship between whole blood, intra-graft, and intracellular CNI concentrations as well as their efficacy in heart transplant recipients (HTR). METHODS: In a cohort of HTR, protocol endomyocardial biopsies (EMB) were collected to assess rejection by anatomopathological analysis. Part of the EMB was used to measure the intra-graft concentrations of CNI (CEMB). Cblood, and the concentration inside peripheral blood mononuclear cells (CPBMC), a cellular fraction enriched with lymphocytes, were also monitored. Concentrations in the three matrices were compared between patients with and without biopsy-proven acute rejection (BPAR). RESULTS: Thirty-four HTR were included, representing nearly 100 pharmacokinetic (PK) samples for each CNI. Cblood, CEMB and CPBMC correlated for both CNI. BPAR was observed in 74 biopsies (39.6 %) from 26 patients (76.5 %), all except one of low-grade. None of the PK parameters (Cblood, CEMB, CPBMC, CEMB/blood and CPBMC/blood) was associated with BPAR. CONCLUSION: In this cohort of well-immunosuppressed patients, no association was observed for any of the PK parameters including Cblood, with the occurrence of BPAR. However, a trend was noticed for the CEMB and CEMB/blood of cyclosporin A. Further studies in higher-risk patients may help optimize the use of CEMB and CPBMC for CNI TDM in HTR.
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Submitted on : Wednesday, September 21, 2022 - 10:06:56 AM
Last modification on : Thursday, October 13, 2022 - 3:22:50 PM


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Gwendal Coste, Celine Chabanne, Camille Tron, Bernard Lelong, Marie-Clémence Verdier, et al.. Blood, cellular, and tissular calcineurin inhibitors pharmacokinetic-pharmacodynamic relationship in heart transplant recipients: the INTRACAR study. Therapeutic Drug Monitoring, 2022, ⟨10.1097/FTD.0000000000001025⟩. ⟨hal-03776020⟩



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