Physiologically based pharmacokinetic and pharmacodynamic modelling of alprazolam: Implications for anxiety and addiction.

Abstract

Alprazolam is an anxiolytic compound that can lead to psychological and physiological dependence especially with prolonged use. This study utilized physiologically based pharmacokinetic (PK) and pharmacodynamic (PD) modelling to further examine the underlying mechanisms of anxiety treatment and addiction. Data and parameter values for this study were obtained from PubMed and DrugBank literature searches. The physiologically based PK models for alprazolam were developed using PK-Sim software and PD models were implemented with the MonolixSuite 2021R platform. After single administrations, peak unbound interstitial brain concentrations range from 4 to 33 nM for 0.25-2mg-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 nM for a 2-mg alprazolam immediate-release dose and 122 nM 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 nM. The 10-90% rise times for the brain concentration-time profile following a single 1-mg immediate-release administration is 22.8min and 3.8h for a 3-mg extended-release administration. Unbound interstitial brain concentration-time profiles of alprazolam corresponded to changes in β rhythm activity, peak saccade velocity, mood improvement, cognitive speed slowing and digit symbol substitution test scores. PD models for these endpoints suggest that alprazolam immediate-release maximal effects on cognitive slowing, cognitive impairment, sedation and mood improvement occur sequentially following the brain concentration-time profile.