32 Background: Since 2018, the World Health Organization has recommended integrase strand transfer inhibitors (INSTIs) as first-line and second-line antiretroviral therapies for all people living with human immunodeficiency virus (HIV). ACC017 is a novel INSTI with potent anti-HIV activity, an in vitro resistance profile different from those of other INSTIs and favourable preclinical safety and pharmacokinetic properties, which is being developed for the treatment of HIV-1 infection. Methods: This randomized, double-blind, placebo-controlled, single-dose escalation study was conducted from 24 January 2024 to 20 May 2024, at a single centre in China. Thirty-six healthy participants, aged 18 to 55 years, were randomly assigned in a 4:1 ratio to receive a single dose of ACC017 (5, 20, 40, 80 or 120 mg) or placebo. Safety, tolerability and pharmacokinetics were evaluated through blood sampling, vital sign monitoring, electrocardiograms (ECGs), laboratory testing and pharmacokinetic analysis performed at regular intervals. This trial is registered with ClinicalTrials.gov, number NCT06278389. Results: Among the participants receiving ACC017 (5 to 120 mg), six subjects (22%, 6/27) reported seven adverse events (AEs), while three subjects (33%, 3/9) in the placebo group experienced four AEs. There was no statistically significant difference in the incidence of AEs between the two groups. All observed AEs were mild (Grade 1) and resolved spontaneously without intervention. Pharmacokinetic analysis showed that the average maximum plasma concentration (Cmax) of ACC017 was 193.7, 926.0, 900.8, 1671.7 and 2055.5 ng/mL across dose levels. The corresponding average areas under the plasma concentration-time curve from time zero to infinity (AUC0-∞) values were 3191.7, 15252.4, 16918.9, 29286.7 and 31759.4 h*ng/mL. Both Cmax and AUC0-∞ exhibited less than dose-proportional increases were observed. The median time to peak concentration (Tmax) ranged between 2 and 4 h with mean terminal half-life of 10.5 to 13.1 h. Discussion: ACC017 demonstrated good tolerability and dose-dependent, nonlinear pharmacokinetics. The inhibitory quotient (IQ), defined as the ratio of the clinical trough concentration (C24h) to the protein-binding adjusted 90% effective concentration (pa-EC90), was 3.2 to 29.8 for ACC017 at doses of 5 to 80 mg. These findings suggest that a once-daily oral dosing regimen of ACC017 at low doses may achieve therapeutic concentrations, supporting its potential as a promising antiretroviral therapy for HIV-1 infection.

2025-03-01·BIOMEDICINE & PHARMACOTHERAPY

Interactive effects of morphine and the HIV integrase inhibitor, cabotegravir, in male and female mice

Article

作者: Tose, Lilian Valadares ; Rodriguez, Myosotys ; Stone, Nicole ; Fernandez-Lima, Francisco ; Owens, Florida ; Carbajal, Candy ; Swickley, Jordan ; Jordan, Matthew ; Nefzi, Adel ; Buch, Shilpa ; El-Hage, Nazira

Cabotegravir is a novel therapeutic option for HIV prevention. Similar to the opioid morphine, cabotegravir, undergoes glucuronidation through the enzymes uridine diphosphate glucuronosyltransferase (UGT) in the liver. We hypothesize that their combination could lead to drug-drug interactions, and this notion was explored in both male and female mice. Our findings indicate a better analgesic response to morphine in females compared to male animals, which was to be mediated by μ-opioid receptors and proteins associated with synaptic plasticity. Co-administration with cabotegravir appears to intensify morphine concentrations in the brain and the analgesic response in male animals only. Moreover, cabotegravir-induced fluctuations in the expression of the UGT enzymes correlated with alterations in drug metabolism and excretion and in the production of inflammatory cytokines primarily driven by morphine in the brains and cabotegravir in the liver. The increased levels of inflammatory cytokines in males aligned with noticeable morphological changes in the liver. In summary, co-exposure with cabotegravir changed the biodistribution in the brain, affected liver metabolism, and altered kidney excretion, leading to changes in gene expression and inflammatory effects that could disrupt morphine analgesia responses.

2025-03-01·BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Synthesis of dolutegravir derivatives modified by 1,2,3-triazole structure and their anti-inflammatory activity in LPS-induced BV2 cells

Article

作者: Wang, Jianji ; Wang, Lan ; Zhang, Xuanwei ; Hou, Xixi ; Wang, Xi ; Mao, Longfei

Given the promising anti-inflammatory activity of the HIV integrase inhibitor dolutegravir and the widespread use of the 1,2,3-triazole structure in anti-inflammatory drug development, this study aimed to enhance dolutegravir's efficacy by introducing a 1,2,3-triazole group. As a result, four series of dolutegravir derivatives were synthesized. Screening these derivatives for anti-inflammatory activity in microglial cells revealed that compound 6k demonstrated the most potent anti-inflammatory effect without significant cytotoxicity. Specifically, 6k significantly reduced the transcription levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Additionally, 6k decreased the LPS-induced overproduction of inflammatory mediators such as nitric oxide (NO), IL-6, and TNF-α. Further investigation into the upstream inflammatory enzymes iNOS and COX-2 showed that 6k markedly reduced their transcription and protein levels. To elucidate the mechanism underlying the anti-inflammatory effects of dolutegravir derivatives, it was found that compound 6k modulates microglial inflammation by inhibiting the phosphorylation and nuclear translocation of signal transducer and activator of transcription 1/3 (STAT1/3). Moreover, acute toxicity testing in mice indicated that compound 6k exhibited low toxicity, suggesting its potential as a lead compound for the treatment of neuroinflammation.

项与 HIV integrase抑制剂(药友制药) 相关的新闻（医药）

2023-08-22

·BioSpace

Exavir Therapeutics Receives $3M Award from NIH / NIAID to Advance Ultra-Long-Acting Integrase Inhibitor XVIR-110

SAN FRANCISCO--(BUSINESS WIRE)-- Exavir Therapeutics, a company dedicated to transforming the lives of patients with chronic viral infections and CNS disorders with ultra-long-acting therapeutics, today announced that the company has received a $3M award from the National Institute of Allergy & Infectious Diseases (NIAID), a division of the National Institute of Health (NIH), to support the development of XVIR-110. XVIR-110 is an ultra-long-acting HIV integrase inhibitor with a preclinical pro suggests best-in-class potential for HIV pre-exposure prophylaxis (PrEP), and for HIV treatment as the cornerstone of a next-generation multi-drug regimen. “We are thankful for the NIH’s support of American companies and innovative biotechnology, particularly in an area like HIV / AIDS that affects so many millions of people worldwide,” said Alborz Yazdi, co-founder and CEO of Exavir. “This award speaks to XVIR-110’s transformative potential, but also the importance of American agencies and public-private partnerships in improving population health outcomes. We look forward to filing our IND in short order to mark our transition to a clinical-stage company, and to fighting for our mission of transforming the lives of patients with chronic disease using ultra-long-acting medicines.” “XVIR-110 has demonstrated ultra-long-acting pharmacokinetics in preclinical models, appropriate for dosing as infrequently as once-every-six-months or longer,” said Mark Cockett, Chief Scientific Advisor to Exavir. “This agent shows attenuated injection site reactions compared to commercially available Q2M cabotegravir in head-to-head animal studies, and also avoids drug-drug-interactions due to CYP3A and other mechanisms that may be present with investigational capsid inhibitors or ‘third-generation’ INSTIs and could limit the potential for use in a broad patient population.” “This award is a testament to the strength of the data package in hand for our ultra-long-acting HIV integrase inhibitor,” said Brian Kearney, Chief Scientific Officer at Exavir. “The support of the NIH will catalyze our mission to rapidly advance XVIR-110 into development as the first Q6M+ INSTI, and the only ultra-long-acting agent with the potential clinical pro widespread adoption by a broad group of patients with unmet medical need.” About Exavir Therapeutics, Inc. Exavir Therapeutics is a San Francisco, CA-based biotechnology company dedicated to developing transformative ultra-long-acting therapeutics for patients with chronic viral infections and central nervous system disorders. HIV is one of the world's most serious public health challenges: it is estimated that there are more than 37 million people living with HIV worldwide, nearly 1.2 million people living with HIV in the United States alone. Approximately $30 billion is spent annually on HIV antiretroviral drugs worldwide.

临床研究

100 项与 HIV integrase抑制剂(药友制药) 相关的药物交易

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