Lundqvist H, Antoni G, Långström B
Biomedical Radiation Sciences, Uppsala University, 751 85 Uppsala, Sweden.
Eur J Clin Pharmacol. 2007 Jul;63(7):641-5. doi: 10.1007/s00228-007-0304-6. Epub 2007 Apr 25.
To obtain the pharmacokinetic properties of drug candidates at an early stage of the development process, a microdosing (phase 0) concept to radiolabel drug candidates and administer them at subtoxic mass to a few volunteers has been suggested. Radiopharmaceuticals are special in the sense that the chemical carrier might be genotoxic, whereas it is well established that ionizing radiation coupled to the molecule is genotoxic, and that the mechanism that causes cancer is similar to certain genotoxic chemicals.
An analysis shows that, e.g., positron emission tomography (PET) pharmaceuticals carry a mass less than what is regarded as an acceptable level of a genotoxic impurity. It has also been shown that the estimated genotoxicity hazard of the radioactivity is 10-100 times higher than that of the administered chemicals.
As radiation doses at this level are accepted in clinical trials, the conclusion is that the regulatory demands on radiopharmaceuticals produced at high specific radioactivity should be reconsidered in order to facilitate the use of the microdosing concept for drug development.
为了在药物研发过程的早期阶段获得候选药物的药代动力学特性，有人提出了微量给药（0期）的概念，即对候选药物进行放射性标记，并以亚毒性剂量给予少数志愿者。放射性药物的特殊之处在于，化学载体可能具有遗传毒性，而与分子结合的电离辐射具有遗传毒性这一点已得到充分证实，并且致癌机制与某些遗传毒性化学物质相似。
一项分析表明，例如正电子发射断层扫描（PET）药物的质量低于被视为遗传毒性杂质可接受水平的质量。研究还表明，放射性估计的遗传毒性危害比所给药的化学物质高10至100倍。
鉴于临床试验中接受这种水平的辐射剂量，结论是应重新考虑对高比活度生产的放射性药物的监管要求，以便于将微量给药概念用于药物研发。
