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PharmTech » How is microdosing used in drug development?

»Tarrant: Microdosing, sometimes referred to as a human Phase 0 study, is the administration of subpharmacologic doses of experimental drugs to human volunteers, up to a maximum of 100 μg. For purposes of this discussion, I will only address studies conducted using accelerator mass spectrometry (AMS), but studies have also been conducted using positron emission tomography and, in some cases, liquid chromatography–tandem mass spectrometry (LC–MS/MS). The intent of the microdose study is to get a very early read on the PK of novel molecules to make critical decisions about which molecules to advance. This evaluation can be accomplished in as little as six months with minimal preclinical toxicology and GLP [good laboratory practices] material under an exploratory investigational new drug application (eIND) in the United States or under an abbreviated common technical document (CTD) in Europe (1, 2). A microdose study allows drug developers to rank the order of several drug candidates coming out of discovery and select those that are most appropriate based upon human PK data. In the traditional development cycle, this evaluation can take up to 18 months for one molecule at a cost of $3–5 million. In a Phase 0 study, however, one can test as many as five molecules in one clinical study and gain all of the relevant PK data in six months. Microdosing is about making decisions on early drug-candidates in the context of all the other tools at a company's disposal by using humans as the model instead of animals while at the same time de-risking the likelihood of clinical failure later.

»Tarrant: EUMAPP is funded by the European Commission under the Framework Program 6 (3). It was founded in 2006, and the project is coordinated by Xceleron. The group consists of 10 organizations from five different European countries (France, The Netherlands, Poland, Sweden, and the United Kingdom). Its goal is to boost Europe's expertise in microdosing and to show the role that AMS can play in enabling more effective drug development. The EUMAPP project tested seven different drugs to show the reliability of the microdosing approach for predicting a drug's PK at pharmacological doses. The group's aims are to certify AMS as the most accurate and appropriate technology for reproducible measurements required by microdosing studies and to develop an in silico modeling application to predict PK parameters from data derived from microdosing studies.

PharmTech » Can you highlight EUMAPP's recently released microdosing data?

»Tarrant: The details of the EUMAPP project have not yet been disclosed as scientific discussion is ongoing. The data will be published in a peer-reviewed journal as soon as all the EUMAPP participants are in agreement that all calculations are accurate.

Seven compounds were tested as part of EUMAPP: clarithromycin, fexofenadine, paracetamol (acetaminophen), phenobarbital, propafenone, sumatriptan, and "S-19812," an investigational compound by Servier (Neuilly-sur-Seine, France) that was dropped in Phase I development. These compounds were chosen to rigorously test the predictability of human microdosing by studying drugs that exhibited properties in humans that are difficult to predict in animal or in vitro models and drugs with properties that might be difficult to predict at a therapeutic dose from microdose data.