Appropriate use of triazolam in elderly patients considering a quantitative benefit-risk assessment based on real-world data with a modeling and simulation approach

Abstract

Background Triazolam is a typical drug commonly used in the elderly; however, there have been concerns about its adverse events resulting from age-related changes in physiological function anddrug interactions with concomitant drugs. Thus, updated information contributing to the appropriate use based on the latest pharmacokinetic and post-marketing surveillance methods, is needed. In this study, we evaluated the appropriate use of triazolam in the elderly by integrating real-world data with a modeling and simulation approach. Methods The occurrence risk of adverse events in the elderly was evaluated using the spontaneous adverse event reporting regulatory databases from Japan and the United States. Information on drug concentrations and reactions was extracted from previous publications to estimated the threshold for plasma triazolam concentrations that cause adverse events.. The pharmacokinetic/pharmacodynamic (PK/PD) model was then constructed, and the dose and administration were evaluated in various situations anticipated in medical practice. Results Among all prescriptions, 25.4% were prescribed to individuals aged 80 years or above, and 51.8% were for those aged 70 years or above. A majority of cases involved CYP3A-metabolized drug combinations, accounting for 85.6%. Elderly individuals were at a higher risk of developing delirium and fall-fracture. Based on the constructed PK/PD model, the risk of adverse events increased when the plasma concentration of triazolam exceeded the calculated threshold of 0.44 µg/mL at approximately 6 hours after administration. Administering 0.125 mg of triazolam, which is half the approved dose for the elderly in Japan, was deemed appropriate. Moreover, there was a substantial risk of adverse events even at a dosage of 0.0625 mg in combination with a moderate or strong inhibitor of cytochrome P450 3A. Conclusion Analysis by integrating large-scale databases and existing research publications on PK/PD can practically contribute to the optimization of triazolam drug therapy for the elderly in the daily clinical setting.