Gunawardana Manjula, Remedios-Chan Mariana, Sanchez Debbie, Webster Simon, Galvan Patricia, Fanter Rob, Castonguay Amalia E, Webster Paul, Moss John A, Kuo Joseph, Gallay Philippe A, Vincent Kathleen L, Motamedi Massoud, Weinberger Dana, Marzinke Mark A, Hendrix Craig W, Baum Marc M
Department of Chemistry, Oak Crest Institute of Science, Monrovia, CA, United States.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States.
Front Pharmacol. 2020 Nov 25;11:569373. doi: 10.3389/fphar.2020.569373. eCollection 2020.
New HIV-1 infection rates far outpace the targets set by global health organizations, despite important progress in curbing the progression of the epidemic. Long-acting (LA) formulations delivering antiretroviral (ARV) agents for HIV-1 pre-exposure prophylaxis (PrEP) hold significant promise, potentially facilitating adherence due to reduced dosing frequency compared to oral regimens. We have developed a subdermal implant delivering the potent ARV drug tenofovir alafenamide that could provide protection from HIV-1 infection for 6 months, or longer. Implants from the same lot were investigated in mice and sheep for local safety and pharmacokinetics (PKs). Ours is the first report using these animal models to evaluate subdermal implants for HIV-1 PrEP. The devices appeared safe, and the plasma PKs as well as the drug and metabolite concentrations in dermal tissue adjacent to the implants were studied and contrasted in two models spanning the extremes of the body weight spectrum. Drug and drug metabolite concentrations in dermal tissue are key in assessing local exposure and any toxicity related to the active agent. Based on our analysis, both animal models were shown to hold significant promise in LA product development.
尽管在遏制艾滋病疫情蔓延方面取得了重大进展，但新的HIV-1感染率仍远远超过全球卫生组织设定的目标。用于HIV-1暴露前预防（PrEP）的长效（LA）抗逆转录病毒（ARV）制剂具有巨大潜力，与口服方案相比，给药频率降低可能有助于提高依从性。我们开发了一种皮下植入剂，可递送强效ARV药物替诺福韦艾拉酚胺，能提供6个月或更长时间的HIV-1感染防护。对同一批次的植入剂在小鼠和绵羊身上进行了局部安全性和药代动力学（PK）研究。我们是第一份使用这些动物模型评估用于HIV-1 PrEP的皮下植入剂的报告。这些装置看起来是安全的，并且在涵盖体重范围两端的两种模型中研究并对比了血浆PK以及植入剂附近皮肤组织中的药物和代谢物浓度。皮肤组织中的药物和药物代谢物浓度对于评估局部暴露以及与活性剂相关的任何毒性至关重要。基于我们的分析，两种动物模型在长效产品开发中均显示出巨大潜力。
