Janssen Research and Development, Beerse, Belgium (L.S., H.T., N.G., A.V., A.-G.D., J.-J.P.-R.) and Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium (L.S., A.V.).
Janssen Research and Development, Beerse, Belgium (L.S., H.T., N.G., A.V., A.-G.D., J.-J.P.-R.) and Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium (L.S., A.V.)
J Pharmacol Exp Ther. 2022 Oct;383(1):70-79. doi: 10.1124/jpet.122.001229. Epub 2022 Aug 30.
JNJ-73763989 is an N-acetylgalactosamine conjugated short interfering RNA combination product consisting of two triggers in clinical development for chronic hepatitis B virus (HBV) infection treatment that induces a selective degradation of all HBV mRNA transcripts. Our aim is to characterize the plasma and liver pharmacokinetics (PK) of JNJ-73763989 after intravenous and subcutaneous administration in recombinant adeno-associated (rAAV) HBV infected mice. Forty-two male rAAV-HBV infected C57Bl/6 mice received JNJ-73763989 doses of 10 mg/kg i.v. or 1, 3 and 10 mg/kg s.c. Plasma and liver concentrations were analyzed simultaneously using nonlinear mixed-effects modeling with the NONMEM 7.4. A population PK model consisting of a two-compartment disposition model with transporter-mediated drug disposition, including internalization to the liver compartment, linear elimination from plasma and liver, and first-order absorption following subcutaneous administration, was suitable to describe both plasma and liver PK. After subcutaneous dosing, absolute bioavailability was complete and flip-flop kinetics were observed. JNJ-73763989 distributes from plasma to liver via transporter-mediated liver internalization in less than 24 hours, with sustained (>42 days) liver exposure. The saturation of transporter-mediated liver internalization was hypothesized to be due to asialoglycoprotein receptor saturation. Increasing the dose decreased the relative liver uptake efficiency in mice for intravenously and, to a lesser extent, subcutaneously administered JNJ-73763989. Lower dose levels administered subcutaneously in mice can maximize the proportion of the dose reaching the liver. SIGNIFICANCE STATEMENT: Pharmacokinetic modeling of JNJ-73763989 liver and plasma concentration-time data in mice indicated that the proportion of JNJ-73763989 reaching the liver may be increased by administering lower subcutaneous doses compared to higher intravenous doses. Model-based simulations can be applied to optimize the dose and regimen combination.
JNJ-73763989 是一种 N-乙酰半乳糖胺缀合的短干扰 RNA 组合产品，由两种在研用于慢性乙型肝炎病毒 (HBV) 感染治疗的触发剂组成，可诱导所有 HBV mRNA 转录本的选择性降解。我们的目的是描述 JNJ-73763989 在重组腺相关病毒 (rAAV) HBV 感染小鼠中静脉内和皮下给药后的血浆和肝脏药代动力学 (PK)。42 只雄性 rAAV-HBV 感染的 C57Bl/6 小鼠接受了 10 mg/kg 静脉内或 1、3 和 10 mg/kg 皮下 JNJ-73763989 剂量。使用 NONMEM 7.4 进行非线性混合效应建模，同时分析血浆和肝脏浓度。一个包含转运体介导的药物处置的两室分布模型的群体 PK 模型，包括向肝内内化、从血浆和肝内线性消除以及皮下给药后的一级吸收，适合描述血浆和肝 PK。皮下给药后，绝对生物利用度完全，出现翻转动力学。JNJ-73763989 通过转运体介导的肝内内化从血浆分布到肝脏，不到 24 小时，肝暴露持续（>42 天）。转运体介导的肝内化饱和被假设是由于去唾液酸糖蛋白受体饱和。增加剂量会降低静脉内和皮下给药时 JNJ-73763989 在小鼠中的相对肝摄取效率。在小鼠中皮下给予较低剂量可以使到达肝脏的剂量比例最大化。意义声明：对 JNJ-73763989 肝和血浆浓度-时间数据的药代动力学建模表明，与较高静脉剂量相比，通过皮下给予较低剂量，到达肝脏的 JNJ-73763989 比例可能增加。基于模型的模拟可用于优化剂量和方案组合。
