Quantitative Simulation on Concentration-Time Profiles of Oxycodone Co-administration with Diazepam

In recent years, drug abuse has posed a great threat to public health. Among abused drugs, prescription opioids have caused a significant problem. Oxycodone is a pervasive semi-synthetic prescription opioid, indicated for treatment of moderate to severe pain. Marked as a Schedule II controlled substance, it possesses a high potential for abuse. Along with Hydrocodone and Methadone, Oxycodone has become one of the three most commonly overdose-involved prescription opioids. Previous studies indicate that the combination of oxycodone and benzodiazepines can render higher overdose liability and stronger effects. Other researchers have examined their pharmacological interactions by experiments and explained this problem’s severity from statistical angle. As both drugs undergo phase I metabolism through CYP 3A4 enzyme, we believe that their concurrent use produces drug-drug interactions (DDIs), leading to increased plasma concentration and prolonged CNS effects. The goal of my research is to quantitatively simulate the concentration-time profiles of oxycodone co-administered with diazepam (a type of benzodiazepines). First, we performed statistical analysis of 40,996 records in FDA Adverse Event Reporting System (FAERS) for oxycodone. The result shows that most death outcomes involve concomitant use of oxycodone with other drugs, and that about half of these co-administrations include benzodiazepines, which manifests the significance of this problem. Based on the pharmacokinetic data of oxycodone administered in different doses, we built a one-compartment model with first-order dosing and linear elimination. Using the model, we obtained the parameters of single oxycodone pharmacokinetic simulations. With the foundation of the model and parameters, we simulated the oxycodone concentration-time profile in the case of concomitant use with diazepam and drew the conclusion. While co-administered with Diazepam, the metabolism of Oxycodone is delayed and renders more threatening overdose symptoms. By conducting the quantitative simulations on pharmacokinetic profiles of oxycodone and its high-risk DDIs, we explored the potential threshold of this overdose and provided rational drug use instructions.