Gatto G J, Krovi A, Li L, Massud I, Holder A, Gary J, Mills P, Mitchell J, Luecke E, Demkovich Z R, Heneine W, García-Lerma J G, Marzinke M A, Brand R M, Dobard C W, Johnson L M, Van Der Straten A
RTI International, Research Triangle Park, NC, United States.
Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, United States.
Front Pharmacol. 2022 Jul 19;13:923954. doi: 10.3389/fphar.2022.923954. eCollection 2022.
The administration of antiretrovirals (ARVs) for HIV pre-exposure prophylaxis (PrEP) is highly efficacious and may benefit from new long-acting (LA) drug delivery approaches. This paper describes a subcutaneous, reservoir-style implant for the LA delivery of tenofovir alafenamide (TAF) and documents the preclinical assessment of implant safety and pharmacokinetics (PK) in New Zealand White (NZW) rabbits (3 groups of = 5), beagle dogs (2 groups of = 6), and rhesus macaques (2 groups of = 3). Placebo implants were placed in rabbits ( = 10) and dogs ( = 12). Implant parameters, including selection of the TAF form, choice of excipient, and PCL formulation were tuned to achieve targeted concentrations of the active anabolite of TAF, tenofovir diphosphate (TFV-DP), within peripheral blood mononuclear cells (PBMCs) and mucosal tissues relevant to HIV transmission. Sustained concentrations of TFV-DP in PBMCs over 100 fmol/10 cells were achieved in all animal species indicating that the implants effectively delivered TAF for 3-6 months. Unlike placebo implants without TAF, all active implants resulted in local adverse events (AEs) proximal to the implant ranging in severity from mild to moderate and included dermal inflammation and necrosis across all species. Despite these AEs, the implant performed as designed and achieved a constant drug release profile, supporting the continued development of this drug delivery platform.
用于艾滋病病毒暴露前预防（PrEP）的抗逆转录病毒药物（ARV）给药效果显著，采用新型长效（LA）给药方法可能会更有益。本文介绍了一种用于长效递送替诺福韦艾拉酚胺（TAF）的皮下储库式植入物，并记录了在新西兰白兔（3组，每组5只）、比格犬（2组，每组6只）和恒河猴（2组，每组3只）中对植入物安全性和药代动力学（PK）的临床前评估。在白兔（10只）和犬（12只）中植入了安慰剂植入物。对植入物参数进行了调整，包括TAF剂型的选择、辅料的选择和聚己内酯配方，以在外周血单核细胞（PBMC）和与HIV传播相关的粘膜组织中实现TAF的活性代谢物替诺福韦二磷酸（TFV-DP）的目标浓度。在所有动物物种中，PBMC中TFV-DP的浓度持续超过100 fmol/10⁶细胞，这表明植入物能有效递送TAF达3至6个月。与不含TAF的安慰剂植入物不同，所有活性植入物均在植入物近端导致局部不良事件（AE），严重程度从轻度到中度不等，所有物种均出现皮肤炎症和坏死。尽管有这些不良事件，但植入物仍按设计发挥作用并实现了恒定的药物释放曲线，支持该给药平台的持续研发。
