Curley Paul, Hobson James J, Liptrott Neill J, Makarov Edward, Al-Khouja Amer, Tatham Lee, David Christopher A W, Box Helen, Neary Megan, Sharp Joanne, Pertinez Henry, Meyers David, Flexner Charles, Freel Meyers Caren L, Poluektova Larisa, Rannard Steve, Owen Andrew
Centre of Excellence in Long-Acting Therapeutics (CELT), University of Liverpool, Liverpool L7 8TX, UK.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Centre, Omaha, NE 68198, USA.
Pharmaceutics. 2023 Jun 27;15(7):1835. doi: 10.3390/pharmaceutics15071835.
Long-acting injectable (LAI) formulations promise to deliver patient benefits by overcoming issues associated with non-adherence. A preclinical assessment of semi-solid prodrug nanoparticle (SSPN) LAI formulations of emtricitabine (FTC) is reported here. Pharmacokinetics over 28 days were assessed in Wistar rats, New Zealand white rabbits, and Balb/C mice following intramuscular injection. Two lead formulations were assessed for the prevention of an HIV infection in NSG-cmah humanised mice to ensure antiviral activities were as anticipated according to the pharmacokinetics. Cmax was reached by 12, 48, and 24 h in rats, rabbits, and mice, respectively. Plasma concentrations were below the limit of detection (2 ng/mL) by 21 days in rats and rabbits, and 28 days in mice. Mice treated with SSPN formulations demonstrated undetectable viral loads (700 copies/mL detection limit), and HIV RNA remained undetectable 28 days post-infection in plasma, spleen, lung, and liver. The in vivo data presented here demonstrate that the combined prodrug/SSPN approach can provide a dramatically extended pharmacokinetic half-life across multiple preclinical species. Species differences in renal clearance of FTC mean that longer exposures are likely to be achievable in humans than in preclinical models.
长效注射（LAI）制剂有望通过克服与不依从性相关的问题为患者带来益处。本文报道了恩曲他滨（FTC）的半固体前药纳米颗粒（SSPN）LAI制剂的临床前评估。在Wistar大鼠、新西兰白兔和Balb/C小鼠肌肉注射后，评估了28天的药代动力学。评估了两种先导制剂对NSG-cmah人源化小鼠预防HIV感染的效果，以确保抗病毒活性与药代动力学预期一致。大鼠、兔子和小鼠分别在12、48和24小时达到Cmax。大鼠和兔子在21天时血浆浓度低于检测限（2 ng/mL），小鼠在28天时低于检测限。用SSPN制剂治疗的小鼠病毒载量检测不到（检测限为700拷贝/mL），感染后28天血浆、脾脏、肺和肝脏中的HIV RNA仍检测不到。本文给出的体内数据表明，前药/SSPN联合方法可在多个临床前物种中显著延长药代动力学半衰期。FTC肾清除率的物种差异意味着人类可能比临床前模型有更长的暴露时间。
