Abstract:
Small interference RNA (siRNA) is a class of short double-stranded RNA molecules that cause mRNA degradation through an RNA interference mechanism and is a promising therapeutic modality. RBD1016 is a siRNA drug in clinical development for the treatment of chronic Hepatitis B Virus (HBV) infection, which contains a conjugated with N-acetylglucosamine moiety that can facilitate its hepatic delivery. We aimed to construct a semi-mechanistic model of RBD1016 in pre-clinical animals, to elucidate the pharmacokinetic/pharmacodynamic (PK/PD) profiles in mice and PK profiles in monkeys, which can lay the foundation for potential future translation of RBD1016 PK and PD from the pre-clinical stage to the clinic stage. The proposed semi-mechanistic PK/PD model fitted PK and PD data in HBV transgenic mice well and described plasma and liver concentrations in the monkeys well. The simulation results showed that our model has a reasonable predictive ability for Hepatitis B surface antigen (HBsAg) levels after multiple dosing in mice. Further PK and PD data for RBD1016, including clinical data, will assist in refining the model presented here. Our current effort focused on model building for RBD1016, we anticipate that the model could apply to other GalNAc-siRNA drugs.
摘要:
小干扰RNA(siRNA)是一类通过RNA干扰机制引起mRNA降解的短双链RNA分子,是一种有前途的治疗方式。RBD1016是一种临床开发用于治疗慢性乙型肝炎病毒(HBV)感染的siRNA药物,它含有与N-乙酰葡糖胺缀合的部分,可以促进其肝脏递送。我们的目的是在临床前动物中构建RBD1016的半机械模型,为了阐明小鼠的药代动力学/药效学(PK/PD)谱和猴子的PK谱,这为RBD1016PK和PD从临床前阶段到临床阶段的潜在转化奠定了基础。提出的半机械PK/PD模型很好地拟合了HBV转基因小鼠中的PK和PD数据,并很好地描述了猴子中的血浆和肝脏浓度。模拟结果表明,我们的模型对小鼠多次给药后的乙型肝炎表面抗原(HBsAg)水平具有合理的预测能力。RBD1016的进一步PK和PD数据,包括临床数据,将有助于完善这里介绍的模型。我们目前的工作集中在RBD1016的模型构建上,我们预计该模型可以应用于其他GalNAc-siRNA药物。