Physiologically based pharmacokinetic modelling of oxycodone drug–drug interactions

Abstract

Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug-drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3-4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4-4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be coadministered with oxycodone.

The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

“…Codeine may become less safe following the induction of CYP2D6 activity, because of the formation of morphine as an active metabolite (Crews et al, 2021; Haertter, 2013). Conversely, inhibition of CYP3A metabolism may cause a delay in the clearance of oxycodone, exacerbating its opioidergic side effects (Rytkönen et al, 2020; Umukoro et al, 2021). In the case of mitragynine, the results presented here suggest that induction of the CYP3A metabolic pathway may increase the chance of toxicity being achieved with kratom, due to enhanced formation of 7‐OH mitragynine.…”

“…Codeine may become less safe following the induction of CYP2D6 activity, because of the formation of morphine as an active metabolite (Crews et al, 2021;Haertter, 2013). Conversely, inhibition of CYP3A metabolism may cause a delay in the clearance of oxycodone, exacerbating its opioidergic side effects (Rytkönen et al, 2020;Umukoro et al, 2021).…”

An Overview of Physiologically-Based Pharmacokinetic Models for Forensic Science

“…Other oral, IV, or subcutaneous opioid PBPK models exist for morphine [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], alfentanil [ 49 , 50 , 51 , 52 ], remifentanil [ 53 , 54 , 55 ], sufentanil [ 56 ], tramadol [ 56 , 57 , 58 , 59 , 60 , 61 ], fentanyl [ 62 , 63 , 64 , 65 , 66 , 67 ], oxycodone [ 40 , 64 , 68 , 69 ], buprenorphine [ 64 , 70 , 71 , 72 , 73 , 74 , 75 ], codeine [ 76 , 77 ], methadone [ 78 , 79 , 80 , 81 , 82 , 83 , 84 ], and carfentanil to predict drug-drug interactions and drug disposition in the plasma and various ...…”

Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy

“…Ketoconazole and delavirdine are strongly competitive and time-dependent inhibitors (TDIs) against the CYP3A4 enzyme, and rifampicin is a strong CYP3A4 inducer. It is well known that ketoconazole and rifampicin are often recommended to assess potential DDIs for other drugs mainly metabolized by the CYP3A4 enzyme ( Rytkönen et al, 2020 ; Xu et al, 2021 ). To our knowledge, owing to irreversible loss of P450 enzyme functions, TDIs are regarded to have a longer persistent time on the drug metabolic enzyme and consequently to cause clinically more significant DDIs in contrast to competitive inhibitors ( Kosaka et al, 2017 ; Eng et al, 2020 ; Tanna et al, 2021 ).…”