PDF(Pubmed)
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.
摘要：
几种常用的阿片类镇痛药，比如芬太尼,舒芬太尼,阿芬太尼,和氢可酮,据报道，主要由CYP3A4酶代谢。同时使用利托那韦，一种有效的CYP3A4抑制剂，可能导致显著的药物相互作用。使用基于生理学的药代动力学（PBPK）建模和模拟，本研究探讨了利托那韦不同给药方案对这些阿片类药物药代动力学的影响.研究结果表明，利托那韦的共同给药显着增加了芬太尼类似物的暴露，与利托那韦一起使用时，阿芬太尼和舒芬太尼的暴露量增加了10倍以上。相反，利托那韦对芬太尼暴露的影响是适度的，可能是由于额外的代谢途径。此外,该研究表明，氢可酮及其活性代谢物氢吗啡酮的稳态暴露可以增加高达87％和95％，分别,同时使用利托那韦。氢可酮的延长释放制剂尤其受到影响。这些来自PBPK建模的见解为优化阿片类药物剂量和最大限度地降低与含有利托那韦的处方联合使用时的毒性风险提供了有价值的指导。
