Abstract：
Ritlecitinib, an orally available Janus kinase 3 and tyrosine kinase inhibitor being developed for the treatment of alopecia areata (AA), is highly soluble across the physiological pH range at the therapeutic dose. As such, it is expected to dissolve rapidly in any in vitro dissolution conditions. However, in vitro dissolution data showed slower dissolution for 100-mg capsules, used for the clinical bioequivalence (BE) study, compared with proposed commercial 50-mg capsules. Hence, a biowaiver for the lower 50-mg strength using comparable multimedia dissolution based on the f2 similarity factor was not possible. The in vivo relevance of this observed in vitro dissolution profile was evaluated with a physiologically based pharmacokinetic (PBPK) model. This report describes the development, verification, and application of the ritlecitinib PBPK model to translate observed in vitro dissolution data to an in vivo PK profile for ritlecitinib capsule formulations. Virtual BE (VBE) trials were conducted using the Simcyp VBE module, including the model-predicted within-subject variability or intra-subject coefficient of variation (ICV). The results showed the predicted ICV was predicted to be smaller than observed clinical ICV, resulting in a more optimistic BE risk assessment. Additional VBE assessment was conducted by incorporating clinically observed ICV. The VBE trial results including clinically observed ICV demonstrated that proposed commercial 50-mg capsules vs clinical 100-mg capsules were bioequivalent, with > 90% probability of success. This study demonstrates a PBPK model-based biowaiver for a clinical BE study while introducing a novel method to integrate clinically observed ICV into VBE trials with PBPK models. Trial registration: NCT02309827, NCT02684760, NCT04004663, NCT04390776, NCT05040295, NCT05128058.
摘要：
Ritlecitinib,正在开发用于治疗斑秃（AA）的口服Janus激酶3和酪氨酸激酶抑制剂，在治疗剂量下在生理pH范围内高度可溶。因此，预期其在任何体外溶出条件下迅速溶解。然而,体外溶出度数据显示，100毫克胶囊的溶出度较慢，用于临床生物等效性（BE）研究，与拟议的商业50毫克胶囊相比。因此，不可能使用基于f2相似性因子的可比较的多媒体溶出度来获得较低的50mg强度的生物保护剂。用基于生理学的药代动力学(PBPK)模型评估这种观察到的体外溶出曲线的体内相关性。这份报告描述了发展，验证,以及应用RitlecitinibPBPK模型将观察到的体外溶出数据转化为Ritlecitinib胶囊制剂的体内PK曲线。虚拟BE(VBE)试验使用SimcyppVBE模块进行，包括模型预测的受试者内变异性或受试者内变异系数(ICV)。结果显示预测的ICV比观察到的临床ICV小，导致更乐观的BE风险评估。通过结合临床观察到的ICV进行额外的VBE评估。VBE试验结果包括临床观察到的ICV表明，拟议的商业50-mg胶囊与临床100-mg胶囊是生物等效的，>90%的成功概率。这项研究证明了用于临床BE研究的基于PBPK模型的生物保护者，同时引入了一种新颖的方法来将临床观察到的ICV整合到具有PBPK模型的VBE试验中。试验注册：NCT02309827、NCT02684760、NCT04004663、NCT04390776、NCT05040295、NCT05128058。
