The Effects of Cobicistat and Voriconazole on the Safety, Pharmacokinetics, and Pharmacodynamics of the TLR7 Agonist Vesatolimod in People with HIV.

IF 5.3 3区 医学 Q1 INFECTIOUS DISEASES
Yanan Zheng, Mary Wire, Robert Were Omange, Christiaan R deVries, Liao Zhang, Buyun Chen, Susie S Y Huang, Kimberly Cruz, Howard Hassman, Olayemi Osiyemi, Juan Carlos Rondon, Daina Lim, Steve West, Anita Wen, Jeffrey J Wallin, Devi SenGupta, Yanhui Cai
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引用次数: 0

Abstract

Introduction: Vesatolimod (VES), a toll-like receptor 7 agonist, is being investigated as part of a strategy for human immunodeficiency virus (HIV) cure. VES is metabolized through the CYP3A pathway and is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). This study evaluated the impact of coadministration of VES with cobicistat (COBI; a P-gp, BCRP, and strong CYP3A inhibitor) or voriconazole (VOR; a strong CYP3A inhibitor with no effect on transporters) on the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of VES in people with HIV (PWH).

Methods: A total of 15 people with virally suppressed HIV on antiretroviral therapy received 2 mg VES (on day 1 in period 1, day 2 in period 2, and day 3 in period 3), 150 mg COBI once daily for 5 days in period 2, and 400 mg VOR on day 1 and 200 mg twice daily on days 2-6 in period 3. Blood samples were collected to measure VES PK, expression of interferon-stimulated genes (ISGs), cytokine/chemokine levels, and immune-cell phenotyping.

Results: Coadministration of VES with VOR did not impact VES PK. In contrast, coadministration of COBI increased VES maximum plasma concentration (Cmax), area under the concentration-time curve extrapolated to infinity (AUCinf), and half-life (t1/2) 7.5-, 4.3-, and 1.2-fold, respectively, but did not increase the mRNA expression levels of ISGs, serum cytokines/chemokines, or expression of activation markers on peripheral natural killer or T cells compared with VES alone. There were no serious adverse events, and no participants discontinued study drugs due to study-drug-related adverse events.

Conclusions: VES was well tolerated when administered alone or in combination with COBI or VOR in PWH. Coadministration of COBI, but not VOR, increased plasma VES concentrations, suggesting that inhibition of transporters (P-gp and/or BCRP) may have a greater impact on VES PK than inhibition of the drug-metabolizing enzyme (CYP3A).

Trial registration: ClinicalTrials.gov NCT05458102.

Cobicistat和Voriconazole对TLR7激动剂Vesatolimod在HIV感染者中的安全性、药代动力学和药效学的影响。
Vesatolimod (VES)是一种toll样受体7激动剂,目前正在研究作为人类免疫缺陷病毒(HIV)治疗策略的一部分。VES通过CYP3A途径代谢,是外排转运体p -糖蛋白(P-gp)和乳腺癌抵抗蛋白(BCRP)的底物。本研究评估了VES与cobicistat (COBI,一种P-gp、BCRP和强CYP3A抑制剂)或voriconazole (VOR,一种强CYP3A抑制剂,对转运蛋白无影响)共同给药对HIV (PWH)患者VES安全性、药代动力学(PK)和药效学(PD)的影响。方法:共有15名接受抗逆转录病毒治疗的病毒抑制HIV患者接受2 mg VES(第1期第1天,第2期第2天,第3期第3天),150 mg COBI,每天1次,连续5天,第3期第2-6天,第1天400 mg VOR,每天200 mg 2次。采集血样检测VES PK、干扰素刺激基因(ISGs)表达、细胞因子/趋化因子水平和免疫细胞表型。结果:VES与VOR共给药不影响VES的PK。相反,COBI共给药使VES的最大血浆浓度(Cmax)、外推至无限的浓度-时间曲线下面积(AUCinf)和半衰期(t1/2)分别增加了7.5倍、4.3倍和1.2倍,但与单独给药相比,没有增加ISGs、血清细胞因子/趋化因子mRNA表达水平,也没有增加外周自然杀伤细胞或T细胞活化标志物的表达。没有严重的不良事件,也没有参与者因为与研究药物相关的不良事件而停用研究药物。结论:在PWH患者单独或与COBI或VOR联合用药时,VES耐受性良好。COBI而不是VOR的联合用药增加了血浆VES浓度,表明转运蛋白(P-gp和/或BCRP)的抑制可能比药物代谢酶(CYP3A)的抑制对VES PK的影响更大。试验注册:ClinicalTrials.gov NCT05458102。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Infectious Diseases and Therapy
Infectious Diseases and Therapy Medicine-Microbiology (medical)
CiteScore
8.60
自引率
1.90%
发文量
136
审稿时长
6 weeks
期刊介绍: Infectious Diseases and Therapy is an international, open access, peer-reviewed, rapid publication journal dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of infectious disease therapies and interventions, including vaccines and devices. Studies relating to diagnostic products and diagnosis, pharmacoeconomics, public health, epidemiology, quality of life, and patient care, management, and education are also encouraged. Areas of focus include, but are not limited to, bacterial and fungal infections, viral infections (including HIV/AIDS and hepatitis), parasitological diseases, tuberculosis and other mycobacterial diseases, vaccinations and other interventions, and drug-resistance, chronic infections, epidemiology and tropical, emergent, pediatric, dermal and sexually-transmitted diseases.
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