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• W4377029054 abstract "<b>Abstract ID 53571</b> <b>Poster Board 376</b> <b>Background:</b> The metabolism of standard antipsychotics (e.g., aripiprazole, lurasidone, risperidone, quetiapine, cariprazine, brexpiprazole, and clozapine) involves CYP3A4. Most treatments realize significant plasma drug concentration changes when co-administered with CYP3A4 inhibitors or inducers. Such interactions are of clinical concern as schizophrenia patients take concomitant medications interacting with CYP3A4, leading to dose adjustment to ensure treatment efficacy, safety, and tolerability. Brilaroxazine, a serotonin/dopamine modulator, is a novel compound in phase 3 development for schizophrenia. It possesses differentiated pharmacological and safety profiles over other treatments in this class. Preclinical i<i>n vitro</i> work identified CYP3A as the primary enzyme involved in the metabolism of brilaroxazine. This clinical study evaluated itraconazole’s (a strong CYP3A inhibitor) and phenytoin’s (a strong CYP3A inducer) effects on brilaroxazine’s pharmacokinetic (PK) profile. <b>Methods:</b> This study involved a single-center, open-label, fixed-sequence, two-part, drug-drug interaction design in healthy adult male and female subjects. Part A evaluated the effects of itraconazole (200 mg QD) dosed to a steady state on the single-dose PK of brilaroxazine and metabolite RP5081 in 13 subjects. Part B assessed the effect of phenytoin (100 mg TID) dosed to a steady state on the single-dose PK of brilaroxazine and metabolite RP5081 in 16 subjects. Determination of brilaroxazine and metabolite RP5081 C_max, AUC_0-tand AUC_0-∞ used noncompartmental methods and statistical inference involving log-transformation and a linear mixed-effects model with treatment as a fixed effect and subject as a random effect. The analysis involved calculating the geometric least squares mean for each treatment, the ratio of the geometric least squares means, and their 90% confidence intervals (CIs). <b>Results:</b> Single brilaroxazine dose co-administered with itraconazole resulted in a slight increase of 8, 15 and 13% in C_max, AUC_0-t, and AUC_0-∞, respectively (90% CI within 80-125%). No difference in the brilaroxazine mean elimination half-life existed between when brilaroxazine administered alone and concomitantly with itraconazole. Alternatively, a single brilaroxazine dose with co-administered phenytoin decreased brilaroxazine C_max, AUC_0-t, and AUC_0-∞ by 33, 57, and 54%, respectively. <b>Conclusions:</b> Itraconazole (a strong CYP3A inhibitor) exerted no effect on brilaroxazine’s PK. Accordingly, brilaroxazine may be co-administered with itraconazole and other strong CYP3A inhibitors. In contrast, phenytoin (a strong CYP3A inducer) decreased brilaroxazine exposure by approximately 50%. Thus, brilaroxazine dose modification may be needed when co-administering with strong CYP3A inducers. This profile presents a useful addition to the clinical management of schizophrenia to minimize the clinical risks associated with drug-drug interactions seen with other antipsychotics, particularly with CYP3A inhibitors." @default.
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• W4377029054 date "2023-05-18" @default.
• W4377029054 modified "2023-09-29" @default.
• W4377029054 title "CYP3A inhibition and induction exert limited effects on brilaroxazine pharmacokinetics" @default.
• W4377029054 doi "https://doi.org/10.1124/jpet.122.535710" @default.
• W4377029054 hasPublicationYear "2023" @default.
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