Altered cytochromes P450 enzymes (CYP) and P-glycoprotein transporter (P-gp) activity may explain variabilities in drug response. In this study, we analyzed four years of phenotypic assessments of CYP/P-gp activities to optimize pharmacotherapy in psychiatry. A low-dose probe cocktail was administered to evaluate CYP1A2, 2B6, 2D6, 2C9, 2C19, 3A4, and P-gp activities using the probe/metabolite concentration ratio in blood or the AUC. A therapeutic adjustment was suggested depending on the phenotyping results. From January 2017 to June 2021, we performed 32 phenotypings, 10 for adverse drug reaction, 6 for non-response, and 16 for both reasons. Depending on the CYP/P-gp evaluated, only 23% to 56% of patients had normal activity. Activity was decreased in up to 57% and increased in up to 60% of cases, depending on the CYP/P-gp evaluated. In 11/32 cases (34%), the therapeutic problem was attributable to the patient’s metabolic profile. In 10/32 cases (31%), phenotyping excluded the metabolic profile as the cause of the therapeutic problem. For all ten individuals for which we had follow-up information, phenotyping allowed us to clearly state or clearly exclude the metabolic profile as a possible cause of therapeutic failure. Among them, seven showed a clinical improvement after dosage adaptation, or drug or pharmacological class switching. Our study confirmed the interest of CYP and P-gp phenotyping for therapeutic optimization in psychiatry.
ONC201 (dordaviprone) is a new drug substance used in a compassionate manner to treat patients with glioblastoma. Given the clinical context and the particularly promising preclinical results, we have been asked by the medical authorities to make a first treatment available throughout France as a hospital preparation to allow access to treatment and to conduct clinical trials. However, to control the quality and safety conditions inherent in this academic manufacturing process, while there is virtually no data available to date to understand the stability of ONC201, we had to determine the stability profile of ONC201, i.e., its sensitivity to different stressors and the types of impurities that could form during its degradation. We found that ONC201 was sensitive to oxidation in the presence of hydrogen peroxide or under light irradiation. Both conditions resulted in the formation of 20 degradation products detected and identified by liquid chromatography–high-resolution mass spectrometry. Their structural elucidation required an in-depth study of the fragmentation pattern of protonated ONC201, described for the first time. The product ions of the degradation products were compared to those of ONC201 protonated ion to assign the most plausible structures for all the detected degradation products. Of these degradation products, those that were rapidly produced, of high intensity and/or identified as potentially having a different toxicity profile to ONC201 by in silico studies, were selected to be monitored during batch release testing and stability studies.
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