Application of PBPK Modeling and Virtual Clinical Study Approaches to Predict the Outcomes of CYP2D6 Genotype-Guided Dosing of Tamoxifen.
Application of PBPK Modeling and Virtual Clinical Study Approaches to Predict the Outcomes of CYP2D6 Genotype-Guided Dosing of Tamoxifen.
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DOI：
10.1002/psp4.12307
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Sugiyama Y
中科院分区：
文献类型：
--
作者：
Nakamura T;Toshimoto K;Lee W;Imamura CK;Tanigawara Y;Sugiyama Y
2012 年至 2017 年在日本进行了基于 CYP2D6 基因型的他莫昔芬治疗反应 1 (TARGET-1) 研究 (n = 180)，以确定细胞色素 P450 2D6 (CYP2D6) 基因型指导下的他莫昔芬剂量的疗效。为了在完成之前预测其结果，我们构建了他莫昔芬及其代谢物的综合生理药代动力学 (PBPK) 模型，并进行了虚拟 TARGET-1 研究。我们的分析表明，达到终点的预期概率（证明在携带 CYP2D6 变异的患者中，增加他莫昔芬剂量比标准剂量的疗效更佳）平均为 0.469。随着虚拟临床研究 (VCS) 群体规模的增加，预期概率大幅增加（n = 260 时为 0.674）。我们的分析还表明，在 TARGET-1 研究中达到终点的概率受到内多昔芬水平的巨大变异性的负面影响。我们目前的努力证明了 PBPK 建模和 VCS 方法在前瞻性设计有效临床试验中的应用前景。
The Tamoxifen Response by CYP2D6 Genotype‐based Treatment‐1 (TARGET‐1) study (n = 180) was conducted from 2012–2017 in Japan to determine the efficacy of tamoxifen dosing guided by cytochrome P450 2D6 (CYP2D6) genotypes. To predict its outcomes prior to completion, we constructed the comprehensive physiologically based pharmacokinetic (PBPK) models of tamoxifen and its metabolites and performed virtual TARGET‐1 studies. Our analyses indicated that the expected probability to achieve the end point (demonstrating the superior efficacy of the escalated tamoxifen dose over the standard dose in patients carrying CYP2D6 variants) was 0.469 on average. As the population size of this virtual clinical study (VCS) increased, the expected probability was substantially increased (0.674 for n = 260). Our analyses also informed that the probability to achieve the end point in the TARGET‐1 study was negatively impacted by a large variability in endoxifen levels. Our current efforts demonstrate the promising utility of the PBPK modeling and VCS approaches in prospectively designing effective clinical trials.
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影响因子：
3.5
作者：
Yamada, A;Maeda, K;Kiyotani, K;Mushiroda, T;Nakamura, Y;Sugiyama, Y
通讯作者：
Sugiyama, Y
影响因子：
3.7
作者：
Toshimoto K;Tomaru A;Hosokawa M;Sugiyama Y
通讯作者：
Sugiyama Y
影响因子：
--
作者：
Yoshida K;Maeda K;Kusuhara H;Konagaya A
通讯作者：
Konagaya A
影响因子：
2.1
作者：
Chiba, Koji;Kato, Motohiro;Sugiyama, Yuichi
通讯作者：
Sugiyama, Yuichi
DOI：
10.1124/jpet.108.146647
发表时间：
2009-02-01
影响因子：
3.5
作者：
Watanabe, Takao;Kusuhara, Hiroyuki;Sugiyama, Yuichi
通讯作者：
Sugiyama, Yuichi