Microdosing in Phase O: A Q&A with J. Scott Tarrant, Xceleron - Pharmaceutical Technology

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Microdosing in Phase O: A Q&A with J. Scott Tarrant, Xceleron
J. Scott Tarrant, executive vice-president of Xceleron, explains the role of microdosing in drug development. He describes how microdose data can be used to predict pharmacological dose absorption, distribution, metabolism, and excretion/pharmacokinetic outcomes using accelerator mass spectrometry.


Pharmaceutical Technology


PharmTech How is AMS used in microdosing and what properties of the instrument allow for testing at increased sensitivity? How does the technique differ from traditional mass spectroscopy (MS)? Aside from AMS, are other analytical testing methods used in to evaluate the microdose?

Tarrant: AMS was developed in the mid-1970s as means of analyzing archaeological artifacts through radiocarbon (14 C) dating. Xceleron pioneered AMS in biomedical analysis with the launching of the company in 1997. AMS is the most sensitive analytical technique ever developed: AMS is 1 million times more sensitive than liquid-scintillation counting (LSC) and up to 100,000 times more sensitive than conventional MS. Rather than measuring radioactive-decay events as LSC does, AMS separates elemental isotopes on the basis of mass, charge, and potential-energy differences. By analyzing 14 C at attomole (10-18) to zeptomole (10-21) levels, AMS allows human radioactive dosing to be reduced to a level where regulatory approval for the use of ionizing radiation is no longer required. Therefore, a traditional radioactive human clinical study can be converted to a nonradioactive study from a regulatory perspective by reducing the radioactive exposure up to 1000-fold. This reduction permits safer human absorption, distribution, metabolism, and excretion to be investigated in a wider range of subjects. In theory, infants, women of child-bearing age, and patients could be included in the microdosing studie s.

AMS differs from MS in that AMS measures individual atoms and gives no structural information. MS quantifies different chemical structures. The individual atoms measured by AMS can be directly quantitated to the drug concentration in the sample by knowing the exact amount of radioactivity administered.

For microdosing, AMS is coupled with high-performance liquid chromatography (HPLC) as a separation technique. Total 14 C is measured first, which accounts for both the parent compound and metabolites. Using an HPLC-AMS method, the parent concentration is also measured. The difference between the two values measures the extent of metabolism and can provide valuable information as to whether the compound is significantly metabolized as it is absorbed, either in the gastrointestinal tract or by first pass through the liver.

There are certain circumstances where LC–MS/MS can be used in a microdose setting, depending on the drug's PK characteristics. More potent drugs may limit the application of LC–MS/MS because of sensitivity issues. Additionally, if an initial read on the extent of metabolism is important, LC–MS/MS will not be able to provide that information. The bottom line is that AMS is an important tool that can be applied to compliment other existing technologies including LSC, HPLC, and LC –MS/MS.

PharmTech What predictive models are used?

Tarrant: Microdosing data would always be used in conjunction with all other information collected on the molecule in question, whether it be in vitro, in silico, or animal models. From the standpoint of evaluating the data, it is no different from the process used in a typical Phase 1 study. The application of data will, of course, very much depend upon the specifics surrounding the development of the drug. For example, a microdose study on an anti-infective targeted at the lung was designed to evaluate whether the drug could be administered orally or parenterally through an inhalation route. Comparison between the intravenous and oral microdose data showed that the drug was very poorly bioavailable because of limited absorption and first-pass metabolism. Therefore, an inhalation route was necessary.


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