Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-06-28 , DOI: 10.1007/s40262-022-01148-9 Ying Fei Li 1 , Francois Pierre Combes 1 , Matthias Hoch 2 , Sebastien Lorenzo 3 , Sherwin K B Sy 1 , Yu-Yun Ho 1
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Background
Asciminib, a first-in-class, highly potent and specific ABL/BCR-ABL1 inhibitor, has shown superior efficacy compared to bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, treated with two or more tyrosine kinase inhibitors. This study aimed to describe pharmacokinetic (PK) properties of asciminib and to identify clinically relevant covariates impacting its exposure.
Methods
A population PK (PopPK) model was developed using a two-compartment model with delayed first-order absorption and elimination. The analysis included PK data from two clinical studies (Phases 1 and 3) involving 353 patients, with total daily dose of asciminib in the range of 20–400 mg.
Results
The nominal total daily dose was incorporated as a structural covariate on clearance (CL), and body weight (BW) was included as a structural covariate via allometric scaling on CL and central volume. Renal function and formulation were included as statistically significant covariates on CL and absorption (ka), respectively. The simulation results revealed a modest but clinically non-significant effect of baseline BW and renal function on ka. Correlations between covariates, such as baseline demographics and disease characteristics, heavy smoking status, hepatic function, and T315I mutation status, were not statistically significant with respect to CL, and they were not incorporated in the final model. Additionally, the final model-based simulations demonstrated comparable exposure and CL for asciminib 40 mg twice daily and 80 mg once daily (an alternative regimen not studied in the Phase 3 trial), as well as similar PK properties in patients with and without the T315I mutation.
Conclusions
The final PopPK model adequately characterized the PK properties of asciminib and assessed the impact of key covariates on its exposure. The model corroborates the use of the approved asciminib dose of 80 mg total daily dose as 40 mg twice daily, and supports the use of 80 mg once daily as an alternative dose regimen to facilitate patient’s compliance.
Trial Registration Number [Date of Registration]
First-in-human (CABL001X2101, Phase 1), ClinicalTrials.gov identifier: NCT02081378 [28 February 2014]; ASCEMBL (CABL001A2301, Phase 3), ClinicalTrials.gov identifier: NCT03106779 [10 April 2017].
中文翻译：
Asciminib 在接受酪氨酸激酶抑制剂治疗的费城染色体阳性慢性粒细胞白血病慢性期和急性期患者中的群体药代动力学
背景
Asciminib 是一种一流的、高效的特异性 ABL/BCR-ABL1 抑制剂，与博舒替尼相比，它在慢性期费城染色体阳性慢性粒细胞白血病患者中显示出优于两种或多种酪氨酸激酶抑制剂治疗的疗效。本研究旨在描述 asciminib 的药代动力学 (PK) 特性，并确定影响其暴露的临床相关协变量。
方法
使用具有延迟一级吸收和消除的二室模型开发了群体 PK (PopPK) 模型。该分析包括来自两项临床研究（第 1 期和第 3 期）的 PK 数据，涉及 353 名患者，asciminib 的每日总剂量在 20-400 mg 范围内。
结果
标称每日总剂量作为清除率 (CL) 的结构协变量纳入，体重 (BW) 通过 CL 和中心容积的异速生长比例作为结构协变量纳入。肾功能和制剂分别作为 CL 和吸收 ( k a ) 的统计学显着协变量包括在内。模拟结果揭示了基线 BW 和肾功能对k a的适度但临床上不显着的影响. 协变量之间的相关性，例如基线人口统计学和疾病特征、重度吸烟状况、肝功能和 T315I 突变状态，在 CL 方面没有统计学意义，因此它们未纳入最终模型。此外，最终基于模型的模拟表明，asciminib 40 mg 每天两次和 80 mg 每天一次（3 期试验中未研究的替代方案）的暴露量和 CL 相当，以及在使用和不使用 T315I 的患者中具有相似的 PK 特性突变。
结论
最终的 PopPK 模型充分表征了 asciminib 的 PK 特性，并评估了关键协变量对其暴露的影响。该模型证实使用批准的 asciminib 剂量 80 mg 每日总剂量为 40 mg 每天两次，并支持使用 80 mg 每天一次作为替代剂量方案以促进患者的依从性。
试用注册号[注册日期]
首次用于人体（CABL001X2101，第 1 阶段），ClinicalTrials.gov 标识符：NCT02081378 [2014 年 2 月 28 日]；ASCEMBL（CABL001A2301，第 3 期），ClinicalTrials.gov 标识符：NCT03106779 [2017 年 4 月 10 日]。
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