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Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia or as adjunctive treatment for major depressive disorder. As obesity (body mass index ≥35 kg/m2) has the potential to affect drug pharmacokinetics and is a common comorbidity of both schizophrenia and major depressive disorder, it is important to understand changes in brexpiprazole disposition in this population. This study uses a whole‐body physiologically based pharmacokinetic model to compare the pharmacokinetics of brexpiprazole in obese and normal‐weight (body mass index 18‐25 kg/m2) individuals known to be cytochrome P450 2D6 extensive metabolizers (EMs) and poor metabolizers (PMs). The physiologically based pharmacokinetic simulations demonstrated significant differences in the time to effective concentrations between obese and normal‐weight individuals within metabolizer groups according to the label‐recommended titration. Simulations using an alternative dosing strategy of 1 week of twice‐daily dosing in obese EMs or 2 weeks of twice‐daily dosing in obese poor metabolizers, followed by a return to once‐daily dosing, yielded more consistent plasma concentrations between normal‐weight and obese patients without exceeding the area under the plasma concentration–time curve observed in the normal‐weight EMs. These alternative dosing strategies reduce the time to effective concentrations in obese patients and may improve clinical response to brexpiprazole. [ABSTRACT FROM AUTHOR]

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia, or as adjunctive treatment for major depressive disorder. As cytochrome P450 (CYP) 2D6 contributes significantly to brexpiprazole metabolism, there is a label‐recommended 50% reduction in dose among patients with the CYP2D6 poor metabolizer phenotype. This study uses a whole‐body physiologically based pharmacokinetic (PBPK) model to compare the pharmacokinetics of brexpiprazole in patients known to be extensive metabolizers (EMs) and poor metabolizers (PMs). A PBPK model was constructed, verified, and validated against brexpiprazole clinical data, and simulations of 500 subjects were performed to establish the median time to effective concentrations in EMs and PMs. The PBPK simulations captured brexpiprazole PK well and demonstrated significant differences in the time to effective concentrations between EMs and PMs according to the label‐recommended titration. Additionally, these simulations suggest that CYP2D6 PMs consistently achieve lower minimum concentrations during the dosing interval than CYP2D6 EMs. Simulations using an alternative dosing strategy of twice‐daily dosing (as opposed to once daily) in PMs during the first week of brexpiprazole dosing yielded more consistent plasma concentrations between EMs and PMs, without exceeding the area under the plasma concentration–time curve observed in the EMs. Taken together, the results of these PBPK simulations suggest that product labeling for brexpiprazole titration in CYP2D6 PMs likely overcompensates for the decreased clearance seen in this population. We propose an alternative dosing strategy that decreases the time to effective concentrations and recommend a reevaluation of steady‐state PK in this population to potentially allow for higher daily doses in CYP2D6 PMs. [ABSTRACT FROM AUTHOR]

Objectives: Acetaminophen (APAP) (paracetamol) is a widely used non-prescription drug for pain relief and antipyretic effects. The clearance of APAP is mainly through phase-2 biotransformation catalysed by UDP-glucuronosyl transferases (UGT). Dasabuvir is an anti-hepatitis C drug reported to inhibit several UGT isoforms. The study evaluated the in-vitro inhibitory capacity of dasabuvir versus APAP glucuronidation. Methods: Procedures included human liver microsomal incubations with APAP and isoform-selective probe substrates. Key findings: Dasabuvir inhibited APAP metabolism by a reversible, mixed-type (competitive and non-competitive) partial inhibition, with an inhibition constant Ki = 3.4 µM. The index constant 'a' was 6.7, indicating the relative contribution of competitive and non-competitive inhibition. The enzyme-inhibitor complex was still able to catalyse the reaction by 12% of the control capacity. Dasabuvir produced strong partial inhibition effect of UGT1A1 and UGT1A9 and relatively complete inhibition of UGT1A6. Conclusions: Consistent with previous reports, dasabuvir inhibits the activity of 3 UGT isoforms associated with APAP metabolism. In-vitro to in-vivo scaling by 2 different approaches showed identical results, predicting an increased AUC of APAP by a factor of 1.3-fold with coadministration of dasabuvir. Until the findings are confirmed in clinical drug interaction studies, APAP dosage should not exceed 3 g per day in dasabuvir-treated patients to avoid potentially hepatotoxic APAP exposures. [ABSTRACT FROM AUTHOR]

Noise reduction was studied on a model helicopter rotor using pulsed dielectric barrier discharge (DBD) plasma actuators mounted at the blades' leading edges. The evaluation was performed in a fully anechoic chamber, where thrust and torque were measured concurrently with the acoustic signature using an array of 15 microphones. Acoustic measurements were made for both baseline and actuated cases at a fixed collective pitch angle under conditions of constant thrust. Actuation produced broadband and tonal noise reductions of up to 8 and 3 dB, respectively, while simultaneously increasing the rotor figure of merit by 25%. Broadband noise reductions were due to control of the otherwise separated boundary layer, resulting in smaller and weaker turbulent eddies in the wake and the tip-vortex and, therefore, smaller turbulent surface pressure fluctuations. Noise reduction directivity associated with the blade passing frequency of up to 3 dB was consistent with rotational noise theory. At most of the observer angles, both the plasma pulsation and ionization frequencies were not visible in the spectra above the motor self-noise signature. Peaks in the second harmonic were observed at specific observer angles and were assumed to be due to the geometric mounting of the actuator and amplification of the pulsations in the laminar separation bubble. [ABSTRACT FROM AUTHOR]

Background and Objective: Vancomycin and ceftazidime are commonly used intravitreal antibiotics for suspected bacterial endophthalmitis. Many retina surgical practices prepare aliquoted individual doses in syringes that are then stored frozen for future use, but this practice has not been well studied. This investigation aims to examine the stability of frozen vancomycin and ceftazidime., Materials and Methods: Samples of drugs were reconstituted monthly and placed in a -20°C freezer. At the end of 3 months and again at 6 months, a newly reconstituted drug constant was created and compared to a newly created reference sample. The frozen samples were compared to a freshly produced drug solution. Using high-performance liquid chromatography (HPLC), the peak heights were compared to evaluate stability., Results: The vancomycin reference sample was 100 ± 1.67%. Values over time were 97.4 ± 0.75%, 98.8 ± 0.44%, 102.1 ± 0.4%, 100.5 ± 0.12%, 101.8 ± 0.12, 101.5 ± 0.11, and 100.6 ± 1.87 for 1, 2, 3(A), 3(B), 4, 5, and 6 months, respectively. The ceftazidime reference sample was 100 ± 1.8%. Values over time were 100.7 ± 1.78%, 100.0 ± 1%, 102.3 ± 1.55%, 117.5 ± 11.6%, 112.8 ± 1.64%, 123 ± 2.8%, and 117 ± 2.5% for 1, 2, 3(A), 3(B), 4, 5, and 6 months, respectively., Conclusion: Both vancomycin and ceftazidime were stable over 6 months under frozen conditions at -20°C. [ Ophthalmic Surg Lasers Imaging Retina 2023;54:281-283.] .