Study of the relationships between blood concentrations, bile concentrations, intracellular concentrations and immunosuppressive effect of tacrolimus in liver transplantation

Le tacrolimus est la pierre angulaire du traitement préventif du rejet de greffe en transplantation hépatique. Les posologies de tacrolimus doivent être adaptées aux patients en fonction des concentrations résiduelles sanguines mesurées tout au long du traitement. Cependant, ce suivi thérapeutique pharmacologique présente des limites puisque la réponse au tacrolimus n’est pas optimale chez tous les patients. Dans ce contexte, ce travail avait pour objectifs d’évaluer l’intérêt de nouveaux biomarqueurs de suivi pharmacologique du tacrolimus chez les patients transplantés hépatiques. Un premier axe de recherche a permis de montrer que la variabilité intra-individuelle des concentrations sanguines était un facteur de risque de perte de greffon et de survenue de toxicités. Dans la seconde partie du travail, une méthode de dosage du tacrolimus dans la bile a été développée, un métabolite glucuronide direct du tacrolimus a été mis en évidence dans la bile des patients, et la concentration biliaire a été identifiée comme un potentiel biomarqueur prédictif de la neurotoxicité de l’immunosuppresseur. La dernière partie du travail s’est consacrée à l’étude in vitro et in vivo des relations entre l’exposition sanguine, l’exposition intra-cellules mononuclées sanguines et l’effet pharmacodynamique du tacrolimus sur sa cible la calcineurine. L’ensemble de ces travaux de pharmacologie translationnelle ont permis d’améliorer la compréhension de la relation exposition-effet du tacrolimus et d’identifier de nouveaux biomarqueurs qui pourraient permettre de faire un pas en avant dans l’optimisation et la personnalisation du traitement immunosuppresseur des transplantés hépatiques.Tacrolimus is the cornerstone of preventive treatment of allograft rejection in liver transplantation. Tacrolimus dosages must be tailored according to trough whole-blood concentrations measured all along the therapy. However, this therapeutic drug monitoring approach has some limitations since tacrolimus response is not optimal for all patients. In this context, this work aimed at evaluating the interest of alternative pharmacological biomarkers of tacrolimus monitoring in liver transplant recipients. The first part of the research led to emphasize that intra-patient variability of tacrolimus trough whole-blood concentrations was a risk factor for graft loss and drug side effects. In the second part of the work, an analytical method of quantification of tacrolimus in bile was developed, evidences of the presence of tacrolimus direct-glucuronide metabolite in bile were provided and tacrolimus bile concentration was found to be a potential predictive biomarker of the drug neurotoxicity onset. The last part of the work was focused on in-vitro and in-vivo studies of the relationships between tacrolimus blood and intracellular exposures and its pharmacodynamic effect on its target calcineurin. Taken together, this translational pharmacology research program led to improve our understanding of tacrolimus exposure-effect relationship and to identify new biomarkers that could allow making a step forward in optimizing and personalizing the immunosuppressive treatment in liver transplant recipients

Perspective on the Use of Limited Sampling Strategies to Assess Drug Exposure in the Era of Microsampling

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JAKi Salvage Therapy Followed by Curative Cord Blood Transplantation in a XIAP-Deficient Infant with Relapsing HLH

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Pharmacokinetics of baricitinib in critically ill COVID-19 patients

International audienceBackground: The use of the selective Janus Kinase 1/2 inhibitor baricitinib has shown a survival benefit in mechanically ventilated COVID-19 patients but this is not without adverse drug reactions. Although critically ill patients are at risk of altered drug exposure, data on baricitinib pharmacokinetics (PK) are scarce. This study describes real-life baricitinib plasma exposure in critically ill COVID-19 patients.Methods: This retrospective observational study was conducted in critically ill patients with COVID-19 treated with baricitinib 4 mg/day. Plasma concentrations were measured at predose (C0), 1 h (C1) and 3 h (C3) after the drug intake. PK and area under the curve (AUC) were estimated using non-compartmental pharmacokinetic analysis.Results: Seven patients contributed to 22 baricitinib plasma concentration measurements after a median [range] of 3 days [2-3] of treatment. Median baricitinib plasma concentrations were 2.2 ng/mL [1.4-8.0], 24.0 ng/mL [4.9-37.3] and 14.1 ng/mL [8.3-15.1] for trough (C0), C1 and C3 concentrations respectively. The median AUC 0-24 h was 188.8 ng.h/mL [141.3-236.3]. No difference was observed in C0 and C1 when comparing patients according to body mass index 30. The patient with the lowest glomerular filtration rate (74 mL/min) had the highest baricitinib trough concentration. Overall, 2 patients had liver function test perturbation and both of them had atypical PK with delayed time to reach maximum concentration.Conclusion: High inter-patient variability and relatively low baricitinib trough concentrations and AUC were observed in critically ill COVID-19 patients receiving the usual dosage of 4 mg/day. This preliminary study encourages further exploration of the concentration-effect relationship of baricitinib in this clinical context

Intrapatient variability in solid organ transplantation: Should we make the first move earlier?

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First Experience of Optimization of Tacrolimus Therapeutic Drug Monitoring in a Patient Cotreated With Nirmatrelvir/Ritonavir: How Microsampling Approach Changes Everything

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Pharmacogenetics of Membrane Transporters of Tacrolimus in Solid Organ Transplantation

International audienceMembrane transporters play an essential role in the pharmacokinetics of drugs as they mediate exchanges between biological compartments. Tacrolimus is characterized by wide interpatient variability in terms of its pharmacokinetics that may in part be due to genetic factors. The pharmacogenetics of drug transporters is therefore a promising area to explore in the clinical pharmacology of tacrolimus. The aim of this review is to provide an overview of currently available data regarding the pharmacogenetics of membrane transporters that may be involved in the interindividual variability of the response to tacrolimus. Several genetic variants in genes coding for influx or efflux membrane transporters (e.g. ABCB1, ABCC2, ABCC8, SLC30A8, SLCO1B1/3, SLC28A1, SLC22A11, and SLC28A3) have been associated with tacrolimus pharmacokinetics variability or the occurrence of toxicity; however, there is still a degree of controversy as to the impact of these variants in vivo and further investigations are needed to confirm these results in larger cohorts and to validate the relevance of such genetic biomarkers for personalization of immunosuppressive therapy in solid organ transplantations. The relationship between transporter polymorphisms and the intracellular concentration of tacrolimus should also be further investigated. Finally, the main challenge could be elucidation of the interplay of biological mechanisms underlying genetic variations that alter the drug concentration or its clinical effect

Controlling the polymerization of coniferyl alcohol with cyclodextrins

International audienceThe mono-electronic oxidation of coniferyl alcohol leads to phenoxy radicals and ultimately to the synthesis of dimericlignans. Coniferyl alcohol and lignans are all potential guests for cyclodextrins (CDs) to form noncovalent host-guestinclusion complexes. Here, the influence of CDs with different cavity volumes (i.e. α, β or γCD) on the laccase-drivenoxidation of coniferyl alcohol is studied. We are clearly showing that βCD interacts with the lignan products and selectivelyprevent their further oxidation by the enzyme. Moreover, amongst the three lignans generated the system made of alaccase and βCD allows a selective enrichment of pinoresinol, a behaviour somehow mimicking that of plant dirigentproteins

Pharmacokinetic parameters of infliximab influence the rate of relapse after de-escalation in adults with inflammatory bowel diseases

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