Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
Pharmaceutical Research & Development, Formulation & Process Sciences, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
AAPS J. 2020 May 26;22(4):78. doi: 10.1208/s12248-020-00463-y.
Entrectinib is a potent and selective tyrosine kinase inhibitor (TKI) of TRKA/B/C, ROS1, and ALK with both systemic and CNS activities, which has recently received FDA approval for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. This paper describes the application of a physiologically based biophamaceutics modeling (PBBM) during clinical development to understand the impact of food and gastric pH changes on absorption of this lipophilic, basic, molecule with reasonable permeability but strongly pH-dependent solubility. GastroPlus™ was used to develop a physiologically based pharmacokinetics (PBPK) model integrating in vitro and in silico data and dissolution studies and in silico modelling in DDDPlus™ were used to understand the role of self-buffering and acidulant on formulation performance. Models were verified by comparison of simulated pharmacokinetics for acidulant and non-acidulant containing formulations to clinical data from a food effect study and relative bioavailability studies with and without the gastric acid-reducing agent lansoprazole. A negligible food effect and minor pH-dependent drug-drug interaction for the market formulation were predicted based on biorelevant in vitro measurements, dissolution studies, and in silico modelling and were confirmed in clinical studies. These outcomes were explained as due to the acidulant counteracting entrectinib self-buffering and greatly reducing the effect of gastric pH changes. Finally, sensitivity analyses with the verified model were applied to support drug product quality. PBBM has great potential to streamline late-stage drug development and may have impact on regulatory questions.
恩曲替尼是一种新型、强效、口服、中枢神经系统活性的酪氨酸激酶抑制剂（TKI），对 TRKA/B/C、ROS1 和 ALK 具有高选择性，近期已获得 FDA 批准，用于治疗 ROS1 融合阳性非小细胞肺癌和 NTRK 融合阳性实体瘤。本文介绍了在临床开发过程中应用生理基于生物药剂学建模（PBBM）来理解食物和胃内 pH 值变化对该亲脂性、碱性、具有合理渗透性但高度依赖 pH 值溶解度的分子吸收的影响。使用 GastroPlus™ 来开发整合了体外和计算数据以及溶解研究的生理基于药代动力学（PBPK）模型，并使用 DDDPlus™ 中的计算模型来理解自缓冲和酸化剂对制剂性能的作用。通过比较含酸化剂和不含酸化剂的制剂的模拟药代动力学与来自食物影响研究和有/无胃酸减少剂兰索拉唑的相对生物利用度研究的临床数据，对模型进行了验证。根据生物相关的体外测量、溶解研究和计算模型预测，市场制剂的食物影响可忽略不计，药物相互作用轻微且依赖 pH 值，这在临床研究中得到了证实。这些结果可归因于酸化剂抵消了恩曲替尼的自缓冲作用，极大地降低了胃内 pH 值变化的影响。最后，应用经过验证的模型进行了敏感性分析，以支持药物产品质量。PBBM 具有简化后期药物开发的巨大潜力，并可能对监管问题产生影响。
