Comparative performance of pharmacogenetics-based warfarin dosing algorithms in Chinese population: use of a pharmacokinetic/pharmacodynamic model to explore dosing regimen through clinical trial simulation.

IF 1.7 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pharmacogenetics and genomics Pub Date : 2024-09-12 DOI:10.1097/FPC.0000000000000545
Keli Shi, Jiexin Deng
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Abstract

Objective: Warfarin has a narrow therapeutic window and large variability in dosing that are affected by clinical and genetic factors. To help guide the dosing of warfarin, the Clinical Pharmacogenetics Implementation Consortium has recommended the use of pharmacogenetic algorithms, such as the ones developed by the International Warfarin Pharmacogenetics Consortium (IWPC) and by Gage et al. when genotype information is available.

Methods: In this study, simulations were performed in Chinese cohorts to explore how dosing differences between Western (by IWPC and Gage et al.) and Chinese algorithms (by Miao et al.) would mean in terms of anticoagulation effect in clinical trials. We first tried to replicate a published clinical trial comparing genotype-guided dosing to routine clinical dosing in Chinese patients. We then made simulations where Chinese cohorts received daily doses recommended by Gage, IWPC, and Miao algorithms.

Results: We found that in simulation conditions where dosing specifications were strictly followed, genotype-guided dosing by IWPC and Lenzini formulae was more likely to overshoot the upper limit of the therapeutic window by day 15, and thus may have a lower % time in therapeutic range (%TTR) than that of clinical dosing group. Also, in comparing Gage, IWPC, and Miao algorithms, we found that the Miao dosing cohort has the highest %TTR and the lowest risk of over-anticoagulation by day 28.

Conclusion: In summary, our results confirmed that algorithms developed based on data from local patients may be more suitable for achieving therapeutic international normalized ratio window in Chinese population.

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基于药物遗传学的华法林剂量算法在中国人群中的性能比较:使用药代动力学/药效学模型通过临床试验模拟探索剂量方案。
目的:华法林的治疗窗口较窄,用药剂量受临床和遗传因素的影响变化较大。为了帮助指导华法林的用药,临床药理遗传学实施联合会建议使用药物遗传学算法,如国际华法林药物遗传学联合会(IWPC)和 Gage 等人开发的算法,如果有基因型信息的话:本研究在中国队列中进行了模拟,以探讨西方算法(IWPC 和 Gage 等人)与中国算法(Miao 等人)之间的剂量差异在临床试验中对抗凝血效果的影响。我们首先尝试复制一项已发表的临床试验,将基因型指导用药与中国患者的常规临床用药进行比较。然后,我们进行了模拟,让中国队列接受 Gage、IWPC 和 Miao 算法推荐的每日剂量:结果:我们发现,在严格遵守剂量规范的模拟条件下,采用 IWPC 和 Lenzini 公式的基因型指导剂量更有可能在第 15 天时超过治疗窗的上限,因此治疗范围内时间百分比(%TTR)可能低于临床剂量组。此外,在比较盖奇、IWPC 和苗氏算法时,我们发现苗氏给药组群的抗凝时间百分比(%TTR)最高,到第 28 天时抗凝时间过长的风险最低:总之,我们的研究结果证实,基于本地患者数据开发的算法可能更适合在中国人群中实现国际正常化比率治疗窗。
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来源期刊
Pharmacogenetics and genomics
Pharmacogenetics and genomics 医学-生物工程与应用微生物
CiteScore
3.20
自引率
3.80%
发文量
47
审稿时长
3 months
期刊介绍: ​​​​Pharmacogenetics and Genomics is devoted to the rapid publication of research papers, brief review articles and short communications on genetic determinants in response to drugs and other chemicals in humans and animals. The Journal brings together papers from the entire spectrum of biomedical research and science, including biochemistry, bioinformatics, clinical pharmacology, clinical pharmacy, epidemiology, genetics, genomics, molecular biology, pharmacology, pharmaceutical sciences, and toxicology. Under a single cover, the Journal provides a forum for all aspects of the genetics and genomics of host response to exogenous chemicals: from the gene to the clinic.
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