(T-020) Zolpidemsim: A Web-Application for Simulating Pharmacokinetics of Zolpidem

Hyungsub Kim, M.D. Ph.D. – Professor, Department of Paramedicine, College of Health Sciences, Eulji University, Seongnam, Gyeonggi-do, 13135 Republic of Korea; Sungpil Han, M.D. Ph.D. – Professor, Department of Pharmacology, College of Medicine, the Catholic University of Korea

Objectives: Zolpidem, a nonbenzodiazepine known for its sedative and hypnotic effects, is widely prescribed to treat short-term insomnia [1]. However, there is a growing concern regarding the increase in cases of zolpidem overdose, which can lead to life-threatening complications including respiratory depression and coma [1,2]. Emergency physicians face considerable challenges in effectively monitoring drug concentrations while managing overdose patients. However, our comprehension of the toxicokinetics of zolpidem overdose remains limited. In this study, we have developed ‘Zolpidemsim’, a web-based application (https://pipettox.shinyapps.io/Zolpidem/) designed to predict plasma zolpidem concentration and pharmacokinetic parameters in overdose patients.

Methods: Zolpidemsim is based on population pharmacokinetic(PK) analysis using NONMEM 7.5 with digitized data obtained from twenty-three healthy subjects after a single oral administration of zolpidem. The final model is a one-compartment model with first-order absorption and elimination. PK parameters are estimated by the first-order conditional estimation with interaction method. The population estimates for the final model are absorption rate constant (Ka, 5.41h-1), clearance (CL, 16.9L/h), volume of distribution (Vd, 61.7L), and lag time(ALAG, 0.394h). Interindividual variability (IIV) are included on Ka, CL, and Vd. The open-source R software (version 4.3.2) and R packages, ‘nonmem2rx, ‘rxode’, and ‘shiny’ allow the conversion of the NONMEM output file to RxODE syntax and reactive PK simulation.

Results: The simulator is divided into three panels: ‘Dosage Regimen’, ‘Simulations Results’, ‘About’. The ‘Dosage Regimen’ panel allows the users to input specific dosage regimens and displays a brief simulation result, including simulation plots, current zolpidem concentration, and a summary of the simulation results. The ‘Simulation Results’ panel provides more detailed results, such as PK parameters including minimum, maximum, and median values, and individual plots. The ‘About’ panel contains the authors, user guide, and references.



Conclusions: Zolpidemsim provides prompt simulations in user-defined dosing regimens with outputs including simulation plots and PK parameters. This user-friendly predictive tool will be a valuable asset for healthcare professionals, empowering them to make well-informed decisions and gain critical prognostic insights, ultimately enhancing the management of overdose patients.

Citations: [1] Robert J. Morlock et. al., Patient characteristics and patterns of drug use for sleep complaints in the United States: analysis of National Ambulatory Medical Survey data, 1997-2002. Clin Ther. 2006 Jul;28(7):1044-53. doi: 10.1016/j.clinthera.2006.07.008.
[2] Robert Garnier et. al., Acute zolpidem poisoning analysis of 344 cases. J Toxicol Clin Toxicol. 1994;32(4):391-404. doi: 10.3109/15563659409011040.