title: Accelerator mass spectrometry offers new opportunities for microdosing of peptide and protein pharmaceuticals.
abstract: Accelerator Mass Spectrometry (AMS) is an ultra-sensitive analytical method which has been instrumental in developing microdosing as a strategic tool in early drug development. Considerable data is available for AMS microdosing using typical pharmaceutical drugs with a molecular weight of a few hundred Daltons. The so-called biopharmaceuticals such as proteins offer interesting possibilities as drug candidates; however, experimental data for protein microdosing and AMS is scarce. The analysis of proteins in conjunction with early drug development and microdosing is overviewed and three case studies are presented on the topic. In the first case study AMS experimental data is presented, for the measured concentration of orally administered recombinant insulin in the blood stream of laboratory rabbits. Case study 2 concerns minimum sample size requirements. AMS samples normally require about 1 mg of carbon (10 microL of blood) which makes AMS analysis unsuitable in some applications due to the limited availability of samples such as human biopsies or DNA from specific cells. Experimental results are presented where the sample size requirements have been reduced by about two orders of magnitude. The third case study concerns low concentration studies. It is generally accepted that protein pharmaceuticals may be potentially more hazardous than smaller molecules because of immunological reactions. Therefore, future first-in-man microdosing studies might require even lower exposure concentrations than is feasible today, in order to increase the safety margin. This issue is discussed based on the current available analytical capabilities.
authors.affiliation: Ion Physics, Ion Physics Division, Department of Physics and Astronomy, Box 516, Uppsala University, SE-751 20 Uppsala, Sweden. Mehran.salehpour@angstrom.uu.se
authors.forename: Mehran
authors.initials: M
authors.lastname: Salehpour
authors.forename: Jonas
authors.initials: J
authors.lastname: Ekblom
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sabetsky
authors.forename: Karl
authors.initials: K
authors.lastname: Håkansson
authors.forename: Göran
authors.initials: G
authors.lastname: Possnert
mesh_terms: D000818:Animals; D001702:Biopharmaceutics; D002531:Cerebellum / Q000737:chemistry; D017321:Clinical Trials, Phase I as Topic; D055808:Drug Discovery / Q000379:methods*; D054796:Drug Dosage Calculations; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D013058:Mass Spectrometry / Q000379:methods*; D008970:Molecular Weight; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011506:Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011817:Rabbits; D018401:Sample Size
chemical_list: D007328:Insulin; D010455:Peptides; D011506:Proteins