Li Chunze, Wang Bei, Lu Dan, Jin Jin Y, Gao Yuying, Matsunaga Kiyoshi, Igawa Yuriko, Nijem Ihsan, Lu Michael, Strasak Alexander, Chernyukhin Nataliya, Girish Sandhya
Genentech, Inc., South San Francisco, CA, USA.
Quantitative Solutions, Menlo Park, CA, USA.
Cancer Chemother Pharmacol. 2016 Sep;78(3):547-58. doi: 10.1007/s00280-016-3099-2. Epub 2016 Jul 16.
Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities.
Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy.
NCA pharmacokinetic parameters (T-DM1, total trastuzumab, DM1) were comparable across ethnic groups; mean cycle 1 T-DM1 AUCinf was 475, 442, and 518 day µg/mL for white (n = 461), Asian (n = 68), and others (n = 57), respectively. PopPK analysis showed that ethnicity (white, Asian, and others) was not a significant covariate for T-DM1 pharmacokinetics (n = 671). Additionally, visual predictive check plots indicated that observed pharmacokinetic profiles in Japanese patients (n = 42) were within the prediction interval generated from the final PopPK model. Exposure-response analyses showed that ethnicity was not a significant covariate impacting efficacy or hepatotoxicity risk, but there was a trend of greater thrombocytopenia risk among Asians versus non-Asians, which could not be explained by similar exposure between the ethnic groups. Most Asians with thrombocytopenia were able to continue T-DM1 using dose-adjustment rules recommended for the global population.
These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.
曲妥珠单抗-美坦新（T-DM1）适用于既往接受过治疗的HER2阳性转移性乳腺癌。利用八项临床研究的数据对T-DM1进行种族敏感性评估，以确保临床推荐剂量在各民族中均适用。
采用了四种方法：（1）非房室分析（NCA），比较不同种族群体中T-DM1及相关分析物的药代动力学参数；（2）群体药代动力学（popPK）分析，评估种族对药代动力学的影响；（3）比较日本患者与全球人群中T-DM1的药代动力学；（4）暴露-反应分析，评估种族对安全性和疗效的影响。
不同种族群体的NCA药代动力学参数（T-DM1、总曲妥珠单抗、DM1）具有可比性；白人（n = 461）、亚洲人（n = 68）和其他种族（n = 57）第1周期T-DM1的平均AUCinf分别为475、442和518天·µg/mL。PopPK分析表明，种族（白人、亚洲人和其他种族）不是T-DM1药代动力学的显著协变量（n = 671）。此外，直观预测检查图表明，日本患者（n = 42）的观察到的药代动力学曲线在最终PopPK模型生成的预测区间内。暴露-反应分析表明，种族不是影响疗效或肝毒性风险的显著协变量，但亚洲人发生血小板减少症的风险高于非亚洲人，且种族间相似的暴露水平无法解释这一现象。大多数血小板减少的亚洲患者能够按照全球人群推荐的剂量调整规则继续使用T-DM1。
这些结果表明，不同种族群体中T-DM1的药代动力学具有可比性，当前给药方案在各民族中均适用。
