Exploring the Impact of CYP2D6 and UGT2B7 Gene-Drug Interactions, and CYP-mediated DDI on Oxycodone and Oxymorphone Pharmacokinetics using Physiologically-Based Pharmacokinetic Modelling and Simulation

Eur J Pharm Sci. 2024 Jan 1:106689. doi: 10.1016/j.ejps.2023.106689. Online ahead of print.ABSTRACTOxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the dose is excreted unchanged into the urine. Oxymorphone, the metabolite primarily formed by CYP2D6, has a 40- to 60-fold higher mu-opioid receptor affinity than the parent compound. While CYP2D6-mediated gene-drug-interactions (GDIs) and drug-drug interactions (DDIs) are well-studied, they only account for a portion of the variability in oxycodone and oxymorphone exposure. The combined impact of CYP2D6-mediated GDIs and DDIs, CYP3A4-mediated DDIs, and UGT2B7 GDIs is not fully understood yet and hard to study in head-to-head clinical trials given the relatively large number of scenarios. Instead, we propose the use of a physiologically-based pharmacokinetic model that integrates available information on oxycodone's metabolism to characterize and predict the impact of DDIs and GDIs on the exposure of oxycodone and its major, pharmacologically-active metabolite oxymorphone. To this end, we first developed and verified a PBPK model for oxycodone and its metabolites using published clinical data. The verified model was then applied to determine the dose-exposure relationship of oxycodone and oxymorphone stratified by CYP2D6 and UGT2B7 phenotypes respectively, and administered perpetrators of CYP-based drug interactions. ...
Source: European Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Authors: Source Type: research