将动物模型中的剂量换算至人类临床试验——重新审视体表面积换算

Translating dosages from animal models to human clinical trials--revisiting body surface area scaling.

作者信息

Blanchard Otis L, Smoliga James M

机构信息

*Wilmore Labs Limited Liability Company, San Antonio, Texas, USA; and Department of Physical Therapy, School of Health Sciences, and Department of Basic Pharmaceutical Sciences, School of Pharmacy, High Point University, High Point, North Carolina, USA.

*Wilmore Labs Limited Liability Company, San Antonio, Texas, USA; and Department of Physical Therapy, School of Health Sciences, and Department of Basic Pharmaceutical Sciences, School of Pharmacy, High Point University, High Point, North Carolina, USA

出版信息

FASEB J. 2015 May;29(5):1629-34. doi: 10.1096/fj.14-269043. Epub 2015 Feb 5.

Abstract

Body surface area (BSA) scaling has been used for prescribing individualized dosages of various drugs and has also been recommended by the U.S. Food and Drug Administration as one method for using data from animal model species to establish safe starting dosages for first-in-human clinical trials. Although BSA conversion equations have been used in certain clinical applications for decades, recent recommendations to use BSA to derive interspecies equivalents for therapeutic dosages of drug and natural products are inappropriate. A thorough review of the literature reveals that BSA conversions are based on antiquated science and have little justification in current translational medicine compared to more advanced allometric and physiologically based pharmacokinetic modeling. Misunderstood and misinterpreted use of BSA conversions may have disastrous consequences, including underdosing leading to abandonment of potentially efficacious investigational drugs, and unexpected deadly adverse events. We aim to demonstrate that recent recommendations for BSA are not appropriate for animal-to-human dosage conversions and use pharmacokinetic data from resveratrol studies to demonstrate how confusion between the "human equivalent dose" and "pharmacologically active dose" can lead to inappropriate dose recommendations. To optimize drug development, future recommendations for interspecies scaling must be scientifically justified using physiologic, pharmacokinetic, and toxicology data rather than simple BSA conversion.

摘要

体表面积(BSA)换算已被用于各种药物的个体化剂量处方,美国食品药品监督管理局也推荐将其作为一种利用动物模型物种数据来确定首次人体临床试验安全起始剂量的方法。尽管BSA换算公式已在某些临床应用中使用了数十年,但最近关于使用BSA来推导药物和天然产物治疗剂量的种间等效剂量的建议并不恰当。对文献的全面回顾表明,与更先进的异速生长和基于生理的药代动力学建模相比,BSA换算基于过时的科学,在当前的转化医学中几乎没有依据。对BSA换算的误解和错误解读可能会产生灾难性后果,包括剂量不足导致放弃潜在有效的研究药物,以及意外的致命不良事件。我们旨在证明最近关于BSA的建议不适用于动物到人类的剂量换算,并利用白藜芦醇研究的药代动力学数据来证明“人类等效剂量”和“药理活性剂量”之间的混淆如何导致不恰当的剂量建议。为了优化药物开发,未来关于种间缩放的建议必须使用生理学、药代动力学和毒理学数据进行科学论证,而不是简单的BSA换算。

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