Genotoxic hazard of radiopharmaceuticals in humans: chemical and radiation aspects coupled to microdosing.
BACKGROUND
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.


CONCLUSIONS
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.
Lundqvist
H
H
Biomedical Radiation Sciences, Uppsala University, 751 85 Uppsala, Sweden. Hans.Lundqvist@bms.uu.se
Antoni
G
G
Långström
B
B
D002986:Clinical Trials as Topic / Q000331:legislation & jurisprudence; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D009152:Mutagenicity Tests; D009369:Neoplasms / Q000209:etiology; D049268:Positron-Emission Tomography; D017410:Practice Guidelines as Topic; D011832:Radiation Injuries / Q000209:etiology / Q000517:prevention & control; D011839:Radiation, Ionizing; D011868:Radioisotopes / Q000008:administration & dosage / Q000633:toxicity*; D019275:Radiopharmaceuticals / Q000633:toxicity*; D018570:Risk Assessment
D011868:Radioisotopes; D019275:Radiopharmaceuticals