Halozyme Therapeutics, San Diego, California, USA.
Clin Transl Sci. 2024 Apr;17(4):e13788. doi: 10.1111/cts.13788.
Predicting the subcutaneous (SC) pharmacokinetics (PK) of antibodies in humans is challenging, with clinical data currently being the only reliable data source for modeling SC absorption and bioavailability. Recombinant human hyaluronidase PH20 (rHuPH20) is an enzyme that facilitates SC delivery of high-dose, high-volume therapeutics. Numerous monoclonal antibodies have been co-administered SC with rHuPH20 in a clinical setting, establishing an extensive PK database. The goal of this work is to demonstrate how aggregated clinical data can be leveraged in a universal modeling framework for characterizing SC antibody PK, resulting in parameterization that can be used in predictive simulations of new antibodies. Data for 10 individual antibodies co-administered SC with rHuPH20 were obtained from publicly available sources. PK modeling of each antibody was conducted using the same model structure, but uniquely parameterized. The model structure consisted of a two-compartment model to capture linear kinetics, plus a target-binding mechanism to accommodate nonlinear kinetics driven by antibody-target complex formation and elimination. The clinical PK profiles for all antibodies were accurately described using the universal modeling framework. The SC PK parameters of absorption and bioavailability were consistent across the range of antibody and target properties evaluated. SC administration with rHuPH20 yielded a 30% increase in absorption rate on average and similar or better bioavailability. These parameter values can serve as initial conditions for model-based PK predictions for new antibodies co-administered SC with rHuPH20 to enable evaluation of optimal SC dose and schedule regimens prior to and during clinical development.
预测人体的皮下(SC)药代动力学(PK)具有挑战性,目前临床数据是建模 SC 吸收和生物利用度的唯一可靠数据来源。重组人透明质酸酶 PH20(rHuPH20)是一种促进高剂量、大容量治疗药物 SC 递送的酶。许多单克隆抗体已在临床环境中与 rHuPH20 联合 SC 给药,建立了广泛的 PK 数据库。这项工作的目的是展示如何在通用建模框架中利用聚集的临床数据来描述 SC 抗体 PK,从而得出可用于新抗体预测模拟的参数化。从公开来源获得了 10 种单独的抗体与 rHuPH20 联合 SC 给药的临床 PK 数据。使用相同的模型结构但独特参数化对每种抗体进行 PK 建模。该模型结构由一个两室模型组成,以捕获线性动力学,加上一个靶标结合机制,以适应由抗体-靶标复合物形成和消除驱动的非线性动力学。所有抗体的临床 PK 曲线都使用通用建模框架准确描述。吸收和生物利用度的 SC PK 参数在评估的抗体和靶标特性范围内是一致的。与 rHuPH20 联合 SC 给药平均使吸收速率提高 30%,且生物利用度相似或更好。这些参数值可用作与 rHuPH20 联合 SC 给药的新抗体基于模型的 PK 预测的初始条件,以在临床开发之前和期间评估最佳 SC 剂量和方案方案。
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