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

All seven drugs were tested at both a pharmacologic dose and at a microdose (one hundredth of the pharmacologic dose, not to exceed 100 μg). For six of the seven drugs, an intravenous (IV) microdose was compared with an IV therapeutic dose from data generated within EUMAPP and with the literature or from EUMAPP data alone. For all seven drugs, an oral microdose was compared with an oral therapeutic dose. For five of the seven drugs, the comparison was made from data generated from EUMAPP and the literature. For two drugs, the comparison was with the literature only.

PharmTech Xceleron has conducted its own microdosing research. Can you share these results and results from the Consortium for Resourcing and Evaluating AMS Microdosing (CREAM) study?

Table I: Pharmacokinetic data of select drugs in microdosing.
Tarrant: A total of 25 drugs (that we know of) have been tested at both a microdose and pharmacologic dose. This total consists of several compounds from the peer-reviewed literature and a number of molecules that are not yet in the public domain as they are either Xceleron research projects or sponsor studies that are confidential. Of the 25 drugs, 21 exhibited linear PK, and 4 drugs exhibited some nonlinearity. Thus, 84% of the drugs examined showed linear PK between a microdose and therapeutic dose.

Table II. Pharmacokinetic (PK) data for select drugs and drug types in microdosing.
Tables I and II are a compilation of the published data and the data that we are aware of that is not currently in the public domain. The data includes fexofenadine (an EUMAPP molecule) as data on this drug was published by a Japanese group, but the listing excludes the other six EUMAPP molecules. The drugs tested in the CREAM trial (4) are also listed.

PharmTech How are microdosing studies conducted? Are there any limitations in the type of the active ingredient that can be tested?

Tarrant: Microdosing studies are normally conducted as a two-way crossover design with an oral microdose, followed by an appropriate wash-out period, then the IV microdose. The number of human volunteers is usually between four and six subjects per molecule. It is most common to test multiple molecules in parallel groups of subjects within one human Phase 0 clinical study. A microdose is categorized as a hundredth of the pharmacologic dose (or predicted pharmacologic dose) and cannot exceed 100 μg. The dose contains only the active ingredient, which has a radiolabelled tag incorporated into the compound structure, most commonly 14 C. To date, microdosing has been conducted predominantly on small molecules. Xceleron's research and development team is currently researching ways to label biologics without altering the activity of the compound. A significant amount of work has been conducted on biologics in preclinical studies; however, there are no published data from microdose testing of biologics in humans as yet.


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