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To the best of our knowledge, no prior fatal cases have been reported and documented with both ticagrelor and AR-C124910XX concentrations. Our findings highlight the need for a specific antidote to manage such complications resulting from ticagrelor overdose.

Purpose Since the early 2010s, deaths due to the use of new synthetic opioids (NSO) including fentanyl and its analogs have been increasing dramatically. As fentanyl analogs bear strong structural similarities, they can share common metabolites. In some clinical or forensic cases, it can be important to demonstrate the presence of both the metabolite and the parent product to confirm that the compound is responsible for the intoxication. Norcarfentanil is a common metabolite of carfentanil (NSO) and remifentanil (widely used in medical care). This article reported the investigation of norcarfentanil origin in three cases. Methods Comprehensive screenings were performed using gas chromatography coupled to mass spectrometry and liquid chromatography coupled to a diode array detection, whereas targeted screening of NSO were performed using liquid chromatography coupled to tandem mass spectrometry. Results Norcarfentanil was detected at concentrations ranging from 0.05 to 15.8 ng/mL in plasma and from 8.8 to 1820 ng/ mL in urine, but carfentanil was detected in two out of the three cases. The presence of norcarfentanil has been supposed to be due to the treatment with remifentanil during the medical care of the patient. Conclusions In the first two cases, norcarfentanil was present as the metabolite of carfentanil, whereas in the last case, norcarfentanil was the metabolite of remifentanil. Without the identification of remifentanil, confusion could occur, and norcarfentanil could be attributed to carfentanil misuse.

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Therapeutic drug monitoring (TDM) of antifungal triazole was recommended, except for isavuconazole (ISA) whose target trough concentrations (Cmin) need to be specified. Concerning posaconazole (POS), tablet formulation results in higher exposure but no upper Cmin threshold has been yet proposed. We aimed to investigate the pharmacokinetic–pharmacodynamic relationship of POS and ISA, using a bioassay approach as surrogate marker of antifungal activity, in order to refine the therapeutic Cmin of both antifungals. A bioassay using a cellulose disk diffusion method was performed to determine the growth inhibition zone (GIZ) of POS and ISA on Aspergillus fumigatus and Candida parapsilosis (ISA only). GIZs of plasma from patients undergoing TDM for POS (n = 136) or ISA (n = 40) were determined. GIZs of plasma patients and antifungal Cmin were highly correlated for ISA (A. fumigatus: ρ = 0.942, P < 0.0001; C. parapsilosis: ρ = 0.949, P < 0.0001) and POS (ρ = 0.922, P < 0.0001), and these relationships were represented with a Michaelis–Menten model. Based on this modeling, the recommended thresholds of 0.7, 1, and 1.25 mg/L for the POS Cmin corresponded to 50.1, 55.2, and 59.1% of the maximal GIZ, respectively. We propose an upper threshold of 4.8 mg/L for the POS Cmin and a lower threshold of 2.0 mg/L for the Cmin of ISA, as they respectively corresponded to concentrations leading to 90% and 50% of the maximal GIZ on A. fumigatus. The determination of antifungal activity using this bioassay allowed refining target Cmin of POS and ISA, especially the upper threshold of POS (4.8 mg/L) and the lower threshold of ISA (2.0 mg/L).

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