全新藥物從臨床前向臨床推進(jìn)的過程中，首次臨床試驗(yàn)起始劑量的擬定是一個(gè)關(guān)鍵風(fēng)險(xiǎn)控制節(jié)點(diǎn)。生物制品與小分子藥物存在不同的藥理作用特點(diǎn)和毒性風(fēng)險(xiǎn)，在首次臨床試驗(yàn)起始劑量的擬定上具有與小分子藥物不同的考慮側(cè)重點(diǎn)。重點(diǎn)闡述支持首次臨床試驗(yàn)起始劑量擬定所需要的臨床前研究信息；根據(jù)國(guó)內(nèi)外的指導(dǎo)原則，介紹了基于毒性終點(diǎn)、藥理終點(diǎn)、以及PK/PD模型進(jìn)行起始劑量擬定的方法；通過回顧性分析，發(fā)現(xiàn)盡管毒性反應(yīng)劑量法依然是傳統(tǒng)保守的方法，但是對(duì)于具有免疫激發(fā)作用的生物制品更傾向于采用最低預(yù)期生物效應(yīng)劑量法。研究者應(yīng)基于藥物的特點(diǎn)，采用多種方法擬定首次臨床試驗(yàn)起始劑量，選取最合適安全的劑量，并加強(qiáng)與監(jiān)管機(jī)構(gòu)溝通與交流。

In the development process from the preclinical stage to the subsequent clinical phase, one critical risk controlling step is the determination of the first-in-human (FIH) dose. There is difference in the mechanisms of action and toxic risks between biopharmaceuticals and small molecule drugs, therefore different considerations will be involved in the determination of the FIH dose for biopharmaceuticals. This paper presents the overall review of the preclinical studies supporting the determination of FIH dose and the approaches based on the NOAEL, MABLE, and PK/PD model. The experience-based views that the MABLE-based FIH dose for immune activating products would be reasonably safe, although the NOAEL approach remains conservative and widely used for a majority of biopharmaceuticals are also presented. It is suggested that sponsors should determine the appropriate and safe FIH dose by diverse approaches according to the characteristics of product. Early communication between sponsors and regulators is always beneficial.