Gilead Sciences, Inc., Foster City, California, USA.
Clin Pharmacol Ther. 2022 Feb;111(2):416-424. doi: 10.1002/cpt.2439. Epub 2021 Oct 27.
Tirabrutinib is an irreversible, small-molecule Bruton's tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU) to treat B-cell malignancies and is in clinical development for inflammatory diseases. As an application of model-informed drug development, a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two phase I studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis. The developed model adequately described and predicted the PK and PD data. Overall, the model-based simulation supported a total daily dose of at least 40 mg, either q.d. or b.i.d., with adequate BTK occupancy (> 90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model-predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.
替拉鲁替尼是一种不可逆的小分子布鲁顿酪氨酸激酶（BTK）抑制剂，已在日本获批（VELEXBRU）用于治疗 B 细胞恶性肿瘤，并正在开发用于炎症性疾病的治疗。作为模型指导药物开发的应用，我们开发了一个半机械性的药代动力学/药效动力学（PK/PD）模型，用于替拉鲁替尼对不可逆 BTK 的抑制作用，以支持在临床开发中的剂量选择，该模型基于两项 I 期研究的临床 PK 和 BTK 占有率数据，这些研究在健康志愿者和类风湿关节炎患者中具有广泛的 PK 暴露。所开发的模型充分描述和预测了 PK 和 PD 数据。总体而言，基于模型的模拟支持至少 40mg 的每日总剂量，无论是每日一次还是每日两次，以获得进一步开发炎症性疾病的足够 BTK 占有率（>90%）。在 PK/PD 建模和模拟之后，还探索了模型预测的 BTK 占有率与初步临床疗效数据之间的关系，并通过线性回归确定了在 RA 治疗中，BTK 占有率超过足够水平的时间与更好的疗效之间存在正相关趋势。
