Olivier Mathieu

La carbamazépine est une molécule antiépileptique très largement utilisée au point de devenir un marqueur environnemental de l'activité humaine. Elle donne lieu à des réactions d'hypersensibilité particulières, rares mais potentiellement létales, associant manifestations cutanées, hyperéosinophilie et atteintes multi-organiques (DRESS syndrome). Les hypothèses physiopathologiques font principalement appel aux métabolites de la carbamazépine mais la voie métabolique minoritaire des dérivés acridiniques est peu explorée. Les résultats obtenus à partir de stimulations ex vivo en laboratoire indiquent d'une part que l'acridine stimule la sécrétion d'interleukine-5 (facteur de croissance principal des éosinophiles), et d'autre part que la formation d'acridine et d'acridone est possible dans le sang à partir de métabolites primaires (époxyde et iminostilbène). Les données cliniques montrent une diminution des taux sanguins du 9-hydroxyméthyl-10-carbamoylacridan et du rapport acridine/acridone au cours de l'état de DRESS. Le co-traitement par l'acide valproïque majore le taux basal d'IL-5 et oriente en partie le profil métabolique vers celui du DRESS. L'étude de l'action des procédés oxydatifs environnementaux indique que les lits bactériens et le lagunage augmentent le rejet d'acridine. Nos travaux en pharmacologie humaine positionnent l'acridine et l'acridone comme des métabolites sanguins, a minima marqueurs et a maxima acteurs de la physiopathologie du DRESS. L'établissement d'un profil métabolique apparaît justifié lors d'une co-thérapie avec l'acide valproïque chez des patients à terrain atopique. L'acridine semble également être un marqueur environnemental d'intérêt.

Isavuconazole is a triazole antifungal agent recently recommended as first-line therapy for invasive pulmonary aspergillosis. With the COVID-19 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been described with a prevalence ranging from 5 to 30%. We developed and validated a population pharmacokinetic (PKpop) model of isavuconazole plasma concentrations in intensive care unit patients with CAPA. Nonlinear mixed-effect modeling Monolix software were used for PK analysis of 65 plasma trough concentrations from 18 patients. PK parameters were best estimated with a one-compartment model. The mean of ISA plasma concentrations was 1.87 [1.29–2.25] mg/L despite prolonged loading dose (72 h for one-third) and a mean maintenance dose of 300 mg per day. Pharmacokinetics (PK) modeling showed that renal replacement therapy (RRT) was significantly associated with under exposure, explaining a part of clearance variability. The Monte Carlo simulations suggested that the recommended dosing regimen did not achieve the trough target of 2 mg/L in a timely manner (72 h). This is the first isavuconazole PKpop model developed for CAPA critical care patients underlying the need of therapeutic drug monitoring, especially for patients under RRT.

There is growing evidence of the presence of pharmaceuticals in natural waters and their accumulation in aquatic organisms. While their mode of action on non-target organisms is still not clearly understood, their effects warrant assessment. The present study assessed the metabolome of the Mediterranean mussel (Mytilus galloprovincialis) exposed to a 10 µg/L nominal concentration of the antidepressant venlafaxine (VLF) at 3 time-points (1, 3, and 7 days). Over the exposure period, we observed up- or down-modulations of 113 metabolites, belonging to several metabolisms, e.g., amino acids (phenylalanine, tyrosine, tryptophan, etc.), purine and pyrimidine metabolisms (adenosine, cyclic AMP, thymidine, etc.), and several other metabolites involved in diverse functions. Serotonin showed the same time-course modulation pattern in both male and female mussels, which was consistent with its mode of action in humans, i.e., after a slight decrease on the first day of exposure, its levels increased at day 7 in exposed mussels. We found that the modulation pattern of impacted metabolites was not constant over time and it was gender-specific, as male and female mussels responded differently to VLF exposure.

Nephrogenic diabetes insipidus due to the inability of the kidneys to concentrate urine is frequently observed during lithium therapy. Lithium concentrates into principal cells in collecting ducts in the kidney and downregulates aquaporin 2 expression, which reduces renal reabsorption of water. This disease is characterized by polyuria - polydipsia leading to intracellular dehydration and hypernatremia. Water deprivation test is performed to confirm insipidus diabetes. The desmopressin permits to distinguish nephrogenic from cranial insipidus diabetes. We report the case of a 64 years old women who presented with global dehydration and severe hypernatremia. Four years ago, she was hospitalized for nephrogenic diabetes insipidus related to a self-induced lithium intoxication. Persistent nephrogenic insipidus diabetes after cessation of lithium therapy are described in literature, and this hypothesis may be consistent with this case report.

Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2–3 g/day and should be slightly increased to reach the therapeutic index of 14–20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h⁻¹ (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.