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An application of accelerator mass spectrometry (AMS) in pediatric clinical studies. Paracetamol, midazolam and spironolactone radiosynthesis and certification.

Kamil Eksanow ,  Grzegorz Grynkiewicz ,  Łukasz Jedynak ,  Łukasz S. Kaczmarek ,  Damian Kowalski ,  Grzegorz Lipner ,  Wioleta Maruszak ,  Kinga Trzcinska ,  Anna Witkowska ,  Joanna Zagrodzka 

Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland


Combined application of linear accelerator and high resolution mass spectrometer (AMS) for detection of organic compounds containing suitable label, allows to achieve levels of sensitivity which are not attainable for other analytical methods. For active pharmaceutical substances, which contain molecules labeled with carbon 14, femtomolar concentrations can be determined, which allows to study pharmacokinetic parameters (PK) and metabolic fate of a drug, from single sub-pharmacological dose (e.g. 100 micrograms). This novel way of collecting the PK data, customary obtained during Phase I clinical trials, is described as “microdosing” (or Phase 0 clinical trial).

In case of isotopically labeled compound designated for microdosing study with AMS detection, design of synthetic route requires taking into consideration all known methods of preparation, and commercially available or potentially labeled synthons, securing reasonably late entry of radioactive material into the process. Additionally, metabolic transformations have to be considered, in order to place the label in a position which is not susceptible to biotransformation. Labeled compounds require slightly different certification then parent drug compounds and they may need elaboration of a new method of qualitative analysis, as well as for quantification.

Pharmaceutical Research Institute (PRI) currently participates in second EU project which uses microdosing/AMS technique, this time for benefits of pediatric patients. The origin of this studies is the problem that to this date there is no data about PK or metabolism routes for children in a different age because clinical studies on children were (and still are) generally considered as unethical. Because of very small quantities of labeled drug which are given to patients and using very sensitive AMS technique as an analytical tool it should be finally possible to find a proper way for medical treatment of children.  

In the ERA-NET PrioMedChild program which is planned for three years, the role of PRI is to provide three [14]C-labeled active pharmaceutical ingredients: Paracetamol, Spironolactone and Midazolam. These API have to have exact quality, they should also be certified and permitted as a suitable for using as a medicine for children. On the poster presentation selected synthetic issues connected with mentioned above [14]C-drugs will be shown. We also would like to outline a development of analytical methods, analysis and certification procedures for labeled compounds that are done by PRI. Moreover further aspects about clinical studies and AMS utility in this project will be briefly disclosed.

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Related papers

Presentation: Poster at VIII Multidyscyplinarna Konferencja Nauki o Leku, by Grzegorz Lipner
See On-line Journal of VIII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2012-04-02 08:51
Revised:   2012-04-11 10:20