PBPK模型在HIV和HIV- tb合并感染患者中推荐奈韦拉平剂量:利用酶自身诱导、药物相互作用和种族差异

IF 3.7 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Xuexin Ye, Feiyan Liu, Zeneng Cheng, Feifan Xie
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引用次数: 0

摘要

奈韦拉平主要由CYP2B6和CYP3A4代谢,在其药代动力学(PK)上表现出酶自身诱导和显著的种族差异。在HIV-TB合并感染患者中,这些复杂性进一步加剧,在这些患者中,奈韦拉平通常与利福平/异烟肼类抗结核(TB)疗法共同使用。利福平(强CYP3A4诱导剂和中度CYP2B6诱导剂)和异烟肼(中度CYP3A4抑制剂)产生复杂的药物相互作用,挑战奈韦拉平的最佳剂量策略,导致临床不确定性和争论。我们为奈韦拉平建立了一个基于生理的药代动力学(PBPK)模型,该模型整合了自身诱导、药物相互作用和种族差异。该模型成功捕获了在利福平/异烟肼联合或不联合给药的情况下,高加索人、非洲人和亚洲人对奈韦拉平的时间依赖性PK。模拟显示,标准奈韦拉平方案(200mg QD导入,200mg BID维持)适用于高加索和非洲HIV患者,但亚洲人需要调整为150mg QD导入和150mg BID维持,以尽量减少毒性。在HIV-TB合并感染患者中,奈韦拉平与利福平/异烟肼合用由于亚治疗水平不适合白种人。对于非洲人,建议增加方案(200mg QD引入,300mg BID维持),而药物相互作用并未改变对亚洲人减少奈韦拉平剂量的建议。我们的研究结果强调了将种族差异和药物相互作用纳入奈韦拉平剂量策略的必要性,以优化HIV和HIV- tb合并感染患者的治疗效果和安全性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PBPK Modeling to Recommend Nevirapine Dosing in HIV and HIV-TB Co-infected Patients: Leveraging Enzyme Auto-Induction, Drug Interactions, and Ethnic Variability.

Nevirapine, primarily metabolized by CYP2B6 and CYP3A4, exhibits enzyme auto-induction and significant ethnic variability in its pharmacokinetics (PK). These complexities are further exacerbated in HIV-TB co-infected patients, where nevirapine is often co-administered with rifampicin/isoniazid-based anti-tuberculosis (TB) therapies. Rifampicin, a strong CYP3A4 inducer and moderate CYP2B6 inducer, and isoniazid, a moderate CYP3A4 inhibitor, create intricate drug interactions that challenge optimal nevirapine dosing strategies, leading to clinical uncertainty and debate. We developed a physiologically based pharmacokinetic (PBPK) model for nevirapine that integrates auto-induction, drug interactions, and ethnic variability. The model successfully captured the time-dependent PK of nevirapine across Caucasian, African, and Asian populations, with and without rifampicin/isoniazid co-administration. Simulations revealed that the standard nevirapine regimen (200 mg QD lead-in, 200 mg BID maintenance) was appropriate for Caucasian and African HIV patients but required adjustment to 150 mg QD lead-in and 150 mg BID maintenance for Asians to minimize toxicity. In HIV-TB co-infected patients, nevirapine co-administration with rifampicin/isoniazid was unsuitable for Caucasians due to sub-therapeutic levels. For Africans, an increased regimen (200 mg QD lead-in, 300 mg BID maintenance) was recommended, while drug interactions did not alter the reduced dosing recommendation of nevirapine for Asians. Our findings underscore the necessity of incorporating ethnic variability and drug interaction profiles into nevirapine dosing strategies to optimize therapeutic efficacy and safety in HIV and HIV-TB co-infected patients.

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来源期刊
AAPS Journal
AAPS Journal 医学-药学
CiteScore
7.80
自引率
4.40%
发文量
109
审稿时长
1 months
期刊介绍: The AAPS Journal, an official journal of the American Association of Pharmaceutical Scientists (AAPS), publishes novel and significant findings in the various areas of pharmaceutical sciences impacting human and veterinary therapeutics, including: · Drug Design and Discovery · Pharmaceutical Biotechnology · Biopharmaceutics, Formulation, and Drug Delivery · Metabolism and Transport · Pharmacokinetics, Pharmacodynamics, and Pharmacometrics · Translational Research · Clinical Evaluations and Therapeutic Outcomes · Regulatory Science We invite submissions under the following article types: · Original Research Articles · Reviews and Mini-reviews · White Papers, Commentaries, and Editorials · Meeting Reports · Brief/Technical Reports and Rapid Communications · Regulatory Notes · Tutorials · Protocols in the Pharmaceutical Sciences In addition, The AAPS Journal publishes themes, organized by guest editors, which are focused on particular areas of current interest to our field.
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