LAUSR

AIMS Alprazolam is an anxiolytic compound that can lead to psychological and physiological dependence especially with prolonged use. This study utilized physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PD) modeling to further examine the underlying mechanisms of anxiety treatment and addiction. METHODS Data and parameter values for this study were obtained from PubMed and DrugBank literature searches. The PBPK models for alprazolam were developed using PK-Sim software and PD models were implemented with the MonolixSuite 2021R platform. RESULTS After single administrations, peak unbound interstitial brain concentrations range from 4 - 33 nM for 0.25 - 2 mg doses of the immediate-release form and 3 - 54 nM for 0.5 - 10 mg doses of the extended-release form. With repetitive administrations, peak concentration is 59 nanomolar for a 2 mg alprazolam IR dose and 122 nanomolar for a 10 mg extended-release dose. Potentiation of EC10 GABA-gated currents from recombinant GABAA Rs composed of α1β2γ2, α2β3γ2, and α5β3γ2 subunit combinations is 92, 150, and 75%, respectively, for an alprazolam concentration of 59 nanomolar. The 10-90% rise times for the brain concentration-time profile following a single 1 mg immediate-release administration is 22.8 minutes and 3.8 hours for a 3 mg extended-release administration. CONCLUSIONS Unbound interstitial brain concentration-time profiles of alprazolam corresponded to changes in β activity, peak saccade velocity, mood improvement, cognitive speed slowing, and DSST scores. Pharmacodynamic models for these endpoints suggest that alprazolam IR maximal effects on cognitive slowing, cognitive impairment, sedation, and mood improvement occur sequentially following the brain concentration-time profile.