Scholarlink

Introduction <p>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).</p> Methods <p>A total of 15 people with virally suppressed HIV on antiretroviral therapy received 2&#xa0;mg VES (on day 1 in period 1, day 2 in period 2, and day 3 in period 3), 150&#xa0;mg COBI once daily for 5&#xa0;days in period 2, and 400&#xa0;mg VOR on day 1 and 200&#xa0;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.</p> Results <p>Coadministration of VES with VOR did not impact VES PK. In contrast, coadministration of COBI increased VES maximum plasma concentration (<i>C</i><sub>max</sub>), area under the concentration–time curve extrapolated to infinity (AUC<sub>inf</sub>), and half-life (<i>t</i><sub>1/2</sub>) 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.</p> Conclusions <p>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).</p> Trial Registration <p>ClinicalTrials.gov NCT05458102.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月15日

查看全文
  • 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

摘要

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.