PDF(Pubmed)
Abstract：
Introduction: Bulevirtide is a first-in-class antiviral drug to treat chronic hepatitis B/D. We investigated the drug-drug interaction potential and pharmacokinetics of high-dose subcutaneous bulevirtide (5 mg twice daily) with organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (CYP) 3A4. Methods: This was a single-center, open-label, fixed-sequence drug-drug interaction trial in 19 healthy volunteers. Before and at bulevirtide steady state, participants ingested a single 40 mg dose of pravastatin. A midazolam microdose was applied to quantify CYP3A4 activity. Results: At bulevirtide steady state, pravastatin area under the concentration-time curve (AUC0-∞) increased 1.32-fold (90% CI 1.08-1.61). The 5 mg bulevirtide twice-daily treatment resulted in a mean AUC0-12 of 1210 h*ng/ml (95% CI 1040-1408) and remained essentially unchanged under the influence of pravastatin. CYP3A4 activity did not change to a clinically relevant extent. As expected, total bile acids increased substantially (35-fold) compared to baseline during bulevirtide treatment. All study medication was well tolerated. Discussion: The study demonstrated that high-dose bulevirtide inhibited OATP1B-mediated hepatic uptake of the marker substrate pravastatin but the extent is considered clinically not relevant. Changes in CYP3A4 activity were also not clinically relevant. In conclusion, this study suggests that OATP1B substrate drugs as well as CYP3A4 substrates may safely be used without dose adjustment in patients treated with bulevirtide. However, in patients using high statin doses and where concomitant factors potentially further increase statin exposure, caution may be required when using bulevirtide.
摘要：
简介：Bulevirtide是治疗慢性乙型肝炎/D的一流抗病毒药物我们研究了大剂量皮下丁韦利肽（5mg，每天两次）与有机阴离子转运多肽1B1（OATP1B1）和细胞色素P450（CYP）3A4的药物-药物相互作用潜力和药代动力学。方法：这是一个单中心，开放标签，19名健康志愿者的固定序列药物-药物相互作用试验。在bulevirtide稳定状态之前和之后，参与者摄入单一剂量的普伐他汀40mg.应用咪达唑仑微剂量来定量CYP3A4活性。结果：在bulevirtide稳态下，普伐他汀浓度-时间曲线下面积(AUC0-∞)增加1.32倍(90%CI1.08-1.61)。每天两次的5mg丁韦肽治疗导致平均AUC0-12为1210h*ng/ml（95％CI1040-1408），在普伐他汀的影响下基本保持不变。CYP3A4活性没有改变到临床相关程度。不出所料,与基线相比,在布勒韦肽治疗期间,总胆汁酸显著增加(35倍).所有研究药物均耐受良好。讨论:研究表明,高剂量的bulevirtide抑制标记物底物普伐他汀的OATP1B介导的肝摄取,但该程度被认为是临床上不相关的。CYP3A4活性的变化也没有临床相关性。总之,这项研究表明,在接受布勒韦肽治疗的患者中,OATP1B底物药物和CYP3A4底物药物可以在不调整剂量的情况下安全使用.然而,在使用高剂量他汀类药物以及伴随因素可能进一步增加他汀类药物暴露的患者中，使用bulevirtide时可能需要小心。
