Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based Pharmacokinetic Simulation

Abstract

Several commonly used opioid analgesics, such as fentanyl, sufentanil, alfentanil, and hydrocodone, are by report primarily metabolized by the CYP3A4 enzyme. The concurrent use of ritonavir, a potent CYP3A4 inhibitor, can lead to significant drug interactions. Using physiologically based pharmacokinetic (PBPK) modeling and simulation, this study examines the effects of different dosing regimens of ritonavir on the pharmacokinetics of these opioids. The findings reveal that co-administration of ritonavir significantly increases the exposure of fentanyl analogs, with over a 10-fold increase in the exposure of alfentanil and sufentanil when given with ritonavir. Conversely, the effect of ritonavir on fentanyl exposure is modest, likely due to additional metabolism pathways. Additionally, the study demonstrates that the steady-state exposure of hydrocodone and its active metabolite hydromorphone can be increased by up to 87% and 95%, respectively, with concurrent use of ritonavir. The extended-release formulation of hydrocodone is particularly affected. These insights from PBPK modeling provide valuable guidance for optimizing opioid dosing and minimizing the risk of toxicity when used in combination with ritonavir-containing prescriptions.