临床前研究与开发人体最大推荐起始剂量的适当翻译和确定是新药开发和研究中的一项重要任务。异形缩放是最常用的基于剂量-体表面积归一化的剂量外推方法。对异速剂量转换和安全系数应用的误解可能导致在首次人体临床试验中计算最大推荐安全起始剂量的主要问题。因此,剂量转换总是需要仔细考虑体表面积,药理学,生理和解剖因素,药代动力学参数,代谢功能,受体,和寿命。估计人类首次剂量的概念,物种间的比例变化以及影响剂量递增的因素进行了综述。确定人类首次剂量的各种方法的利弊,包括异速缩放,药代动力学指导方法,最小预期生物效应水平,药代动力学-药效学建模,类似的药物方法,和微量给药进行了解释。详细阐述了通过比例因子估算人体研究最大推荐起始剂量的五个步骤。几个例子,还展示了不同方法的应用,以及应用此类方法时可能考虑的问题。此外,剂量给药的典型考虑因素,通过饮食给药,最大可吸收剂量,采血,并对动物种类的麻醉进行了讨论。总之,对于参与临床前和早期临床药物开发各个阶段的研究人员,这篇综述可以作为预测动物物种中人类等效剂量的简明指南。
Preclinical Research & Development Appropriate translation and determination of the maximum recommended starting dose in human is a vital task in new drug development and research. Allometric scaling is the most frequently used approach for dose extrapolation based on normalization of dose-to-body surface area. Misinterpretation of allometric dose conversion and safety factor application can lead to major problems in calculating maximum recommended safe starting dose in first-in-human clinical trials. Therefore, dose translation always necessitates careful consideration of body surface area, pharmacological, physiological and anatomical factors, pharmacokinetic parameters, metabolic function, receptor, and life span. The concept of estimating the first-in-human dose, interspecies scaling between species and the factors influencing the dose escalation were reviewed. The pros and cons of various approaches to determine first-in-human dose including allometric scaling, pharmacokinetically guided approach, minimal anticipated biological effect level, pharmacokinetic-pharmacodynamic modeling, similar drug approach, and microdosing were explained. The five steps to estimate maximum recommended starting dose for human studies by scaling factor were elaborated. Few examples, illustrating the application of different approaches were also demonstrated along with concerns that may be considered while applying such methods. Furthermore, typical considerations in dose administration, dosing through diet, maximum absorbable dose, blood sampling, and anesthesia in animal species were discussed. In summary, this review may serve as a concise guide for predicting human equivalent dose from animal species for researchers involved in various phases of preclinical and early clinical drug development.