Microdosing studies

Lebre, D. T., Aiello, M., Impey, G., and Bonelli, F. (2007). Microdosing study in rat plasma using high sensitive LC-ESI/MS/MS technique. In Proceedings of the 55th ASMS Conference on Mass Spectrometry and Allied Topics. ASMS, Indianapolis, IN. 

In terms of facilitating radiolabeled safety studies, AMS has generated considerable interest in the field of human microdosing studies, which are designed to generate human pharmacokinetic data earlier in the dmg discovery/development process... 

In a nutshell, microdosing studies involve the administration of a single subtherapeutic dose of a radiolabeled NCE to limited number healthy adult volunteers for no more than 7 days to (1) assess whether the mechanism of action observed in preclinical models translates to humans, (2) select the most promising lead candidate from multiple NCEs, (3) assess human PK and/or metabolism, and (4) to explore an NCE s distribution [211], If necessary, assuming linear PK, the PK and distribution data from microdosing can be used to estimate the PK at therapeutically relevant doses. A recent evaluation of five compounds showed that microdose studies are most reliable for predicting the therapeutic dose level PK of small molecule NCEs that possesse linear PK, short half-lives, and moderate metabolism [213-215],... 

Since the doses are very small, conventional LC-MS techniques are sometimes not sensitive enough to assay samples from microdosing studies. Often accelerator mass spectrometry (AMS) and positron emission tomography (PET) are required for obtaining PK and distribution information, respectively. As described in Section 5.4, although AMS is capable of quantifying 14C-labeled compounds with attomole (10 18M) sensitivity, the technique is not useful for distinguishing between an NCE... 

Wilding, I.R. and Bell, J.A., Improved early clinical development through human microdosing studies, Drug Discov. Today, 10(13), 890, 2005. 

Bauer, M. et al., A positron emission tomography microdosing study with a potential antimyloid drug in healthy volunteers and patients with Alzheimer s disease, Clin. Pharmacol. Ther., 80(3), 216, 2006. 

Administration, US Food and Drug. Guidance for Industry, Investigators, and Reviewers. Exploratory IND Studies including Human Microdose Studies, 2006. http // www.fda.gov/CDER/guidance/7086fnl.htm. 

Metabolism. PET can only measure radioactivity and in order to be able to evaluate those PET data, information about the chemical form of the measured radioactivity is important. Determination of the fraction of intact tracer in plasma and in the target organ in animal experiments can give the required information. The occurrence of labeled metabolites should be assessed at different time points in the human microdosing study. 

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