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首页> 外文期刊>Amyloid: the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis >Personalized medicine approach for optimizing the dose of tafamidis to potentially ameliorate wild-type transthyretin amyloidosis (cardiomyopathy)
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Personalized medicine approach for optimizing the dose of tafamidis to potentially ameliorate wild-type transthyretin amyloidosis (cardiomyopathy)

机译：个性化医学方法，可优化塔法米酯的剂量，以潜在地改善野生型转甲状腺素蛋白淀粉样变性病（心肌病）

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摘要

Placebo-controlled clinical trials are useful for identifying the dose of a drug candidate that produces a meaningful clinical response in a patient population. Currently, Pfizer, Inc. is enrolling a 400-person clinical trial to test the efficacy of 20 or 80 mg of tafamidis to ameliorate transthyretin (TTR)-associated cardiomyopathy using clinical endpoints. Herein, we provide guidance for how to optimize the dose of tafamidis for each WT TTR cardiomyopathy patient using its mechanism of action as the key readout, i.e. we identify the dose of tafamidis that maximally kinetically stabilizes TTR in the blood. Tetramer dissociation is rate limiting for TTR aggregation, which appears to drive the pathology of the TTR amyloidoses. Hence, we measure the TTR tetramer dissociation rate (kinetic stability) in the patient's plasma as a function of tafamidis dose to optimize the dose employed to maximize kinetic stability. Historical data tell us that a subset of patients exhibiting higher tafamidis plasma concentrations are maximally kinetically stabilized at the 20-mg tafamidis dose, whereas the patient studied herein required a 60 mg once daily dose to achieve maximum kinetic stabilization. We anticipate that establishing the dose of tafamidis that achieves maximal TTR kinetic stabilization will translate into a maximal clinical effect, but that remains to be demonstrated.
机译：安慰剂对照的临床试验可用于确定在患者人群中产生有意义的临床反应的候选药物的剂量。目前，辉瑞公司（Pfizer，Inc.）正在招募400人的临床试验，目的是通过临床终点测试20或80 mg他法米地改善转甲状腺素蛋白（TTR）相关性心肌病的功效。本文中，我们提供了有关如何以其作用机理作为关键读数，为每位WT TTR心肌病患者优化塔法米的剂量的指南，即，我们确定能最大程度地稳定血液中TTR的塔法米的剂量。四聚体解离是TTR聚集的速率限制，这似乎驱动了TTR淀粉样蛋白的病理。因此，我们测量了患者血浆中TTR四聚体的解离速率（动力学稳定性）与他法米第剂量的函数关系，以优化所用剂量，以最大化动力学稳定性。历史数据告诉我们，在20 mg他法米地剂量下，表现出较高他法米地血药浓度的部分患者最大动力学稳定，而本文研究的患者每天需要60 mg一次剂量才能达到最大的动力学稳定度。我们预计，确定达到最大TTR动力学稳定性的他法米地的剂量将转化为最大的临床效果，但这仍有待证明。

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