TNO, Zeist, The Netherlands, UK.
Centre for Human Drug Research, Leiden, The Netherlands, UK.
Clin Pharmacol Ther. 2015 Aug;98(2):196-204. doi: 10.1002/cpt.131. Epub 2015 May 19.
Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first-in-human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 μg) [(14) C]-hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs.
新型生物实体（NBE）的临床前开发，如人体蛋白治疗药物，需要大量的时间和成本。人体药代动力学预测不佳进一步降低了净效率。在这项研究中，我们首次表明，通过在一小部分健康受试者中使用微量剂量结合超灵敏加速器质谱法（AMS），可以在药物开发过程的早期成功获得 NBE 的人体药代动力学数据。在进行最低限度的临床前测试后，我们对一种人重组治疗性蛋白（RESCuing Alkaline Phosphatase，人重组胎盘碱性磷酸酶 [hRESCAP]）进行了首次人体 0 期/1 期试验，以评估其安全性和动力学。药代动力学分析显示，从小剂量（53μg）[(14)C]-hRESCAP 到健康志愿者的治疗剂量（高达 5.3mg），药物呈剂量线性。这项研究证明了在非常小的队列中进行微量剂量方法的价值，可加速 NBE 的临床开发。
