Discussion of microdosing with Xceleron CEO

Pharma industry chiefs predict microdosing will soon be ubiquitous in clinical trial industry

[Editor's note: In this question-and-answer article, R. Colin Garner, BPharm, PhD, DSc, FRCPath, chief executive officer of Xceleron, Ltd. of York, England, discusses with Clinical Trials Administrator how microdosing, which has been called the Phase 0 clinical trial, works, and why it is useful for reducing cost and time in clinical trial work. For more information about microdosing, you may view Xceleron's Web site at www.xceleron.com.]

CTA: What is the basic premise behind microdosing, and how was the technology developed?

Garner: The basic premise behind microdosing is it enables drug developers to get human data much earlier than they could historically. The reason I say that is because, primarily, man is the best model for man. So this is really a method to obtain specific human metabolism and PK [pharmacokinetics] information on development drug candidates without going to the great expense of manufacturing large quantities of API [active pharmaceutical ingredient] and having to conduct reasonably expensive toxicology studies.

The reason that microdosing exists was really through the introduction of ultrasensitive analytical techniques, such as accelerated mass spectrometry (AMS), which is what our company is focused on. The main role of microdosing is as a way of selecting drug candidates early in order to take them forward or, more importantly, to kill drug candidates early before you spend large amounts of money on development. That's perhaps a rather negative view. But it's the potential of a fast kill earlier that is one of the things people talk about.

CTA: How long has this technology been available that has made microdosing possible?

Garner: The actual AMS instrumentation was developed in both the U.S. and Canada in the mid-70s. So it's been around for a long time. But it's mainly been used by archeologists. It's the main way that archeologists date artifacts through a process called radiocarbon dating. So that's the technique people have been using. And it's really only been used for biomedical research probably since the early 1990s.

We really pioneered the commercial application of AMS in biomedical research.

CTA: How extensively is it being used now? Have some of the major U.S. pharmaceutical companies adopted this in some form or another?

Garner: We have worked for 16 of the world's top 20 pharma companies since we were created in 1997. We've been around for a bit of time. We've worked with all the major pharmaceutical companies really, in the U.S., Europe and Japan.

CTA: Tell us about the technology for a "fast kill."

Garner: If you're developing a novel drug you need to know it has some pharmacological activity, which usually is established using in vitro systems or animal models. Then perhaps the next important property you need to know is its pharmacokinetics and metabolism, because without appropriate human pharmacokinetics, you might have a very nice molecule, but you will never make a drug. So you either administer the molecule orally and none of it gets absorbed, or that's the end of the molecule. So that's the information that microdosing, in particular, provides. The pharma companies we've worked with have used our technology for many different applications, not only microdosing.

We can use this technology for combined phase 1 mass balance; so that's where you want to know the rates and routes of excretion of a drug. We've used it for human metabolic profiling, and we've used it for absolute viability studies. There's quite a broad range of information, but all within the drug metabolism, pharmacokinetic area.

What microdosing does is give you pharmacokinetic information, and on the basis of that information you can determine if your molecule will have suitable properties to make the drug. And that's why if it doesn't you would kill the molecule at that stage, and if it does, then you would probably take it forward.

CTA: If you take a drug forward, in the phase I clinical trial, would the fact that microdosing occurred provide any assurance of less risk to subjects?

Garner: What can you use microdosing data for? Well, you can use it to help set the first dose in the phase I study back up, and you might be able to reduce the number of doses you might give in a phase I study, having got microdose data.

Also, clearly you will have to question the ethics as it were of a phase I study where you have taken a drug in a concentration that may be significant and then you find in a human study that pharmacokinetics are inappropriate. Well, haven't you unnecessarily exposed someone to a drug when you could have found out that information at a much lower dose, i.e., a microdose. So there will be a trend, I believe, of being more cautious when going into humans, particularly after the incident in London. Therefore, microdosing could provide a safer way of getting dosing into humans for the first time.

CTA: I was going to ask you about the London phase I clinical trial of TGN1412, a humanized agonistic anti-CD28 monoclonal antibody, created by TeGenero AG of Wurzburg, Germany. This was the disaster in which six participants were hospitalized after suffering severe reactions to the study substance. Could microdosing have helped to prevent that problem?

Garner: We've obviously been asked that quite a lot. In that particular circumstance I suspect that microdosing could not have been useful. This is simply because the questions being asked in that study were safety and tolerability questions, rather than metabolism questions. For biologicals, metabolisms, certainly historically, has not been regarded as an important parameter, whereas with small molecules it has. So I think that all that the London incident demonstrates really is that we need to be more cautious when we go into humans for the first time, and microdosing does that.

The other thing is when you're thinking about the ethics aspects, when you go into humans in phase I and you end up killing the compound, you've exposed a lot of animals to a drug to get the preclinical information to allow you to go into a phase I study. So, again, using microdosing allows you to use much fewer animals as part of pre-clinical testing. Then if you kill the compound as a result of a microdosing study, then you've exposed many fewer animals.

CTA: That would seem to be very important for studies that require use of chimpanzees and other primates?

Garner: I think there's a lot of discussion going on at the moment about whether one should consider using microdosing in humans rather than in primates.

If you're using primates to predict human metabolism, then I would argue, why not do a microdosing study and get human metabolism rather than try to predict it.

You won't get direct safety and efficacy information out of a microdose study; you primarily get metabolism information.

CTA: Is this simply another tool that allows pharmaceutical companies and others in the clinical trial industry to maximize efficiencies in their work?

Garner: I think it's helpful to a variety of buyers. Clearly for the pharmaceutical industry it ultimately should be of benefit to patients because the aim would be to improve the efficiency of the industry and, therefore, the price of drugs as a result should also be reduced because the development times and, ultimately, the development costs would be reduced. The other thing microdosing does is it allows academic groups and non-governmental organizations (NGOS) to do human studies at a much lower cost than using conventional phase I approaches. For an academic lab to get some limited human data could be quite beneficial when they try to develop a molecule themselves for some orphan disease or if they try to sell the molecule to a big pharma company. So the academic groups have quite a big interest in microdosing.

CTA: Where do you see microdosing going in the next decade?

Garner: There has been a recent report which has been published by Cambridge Healthteck Associates, and they asked a question of vice presidents of research and development in the pharma industry and in CROs. They asked, 'Looking at microdosing today, do you use it?' And only 3 percent of people said they use it currently. Then they asked, 'What about in two years time, in 2008?' Then 41 percent of them said they consider it would be used routinely, and by 2010, another 46 percent said they thought it would be used routinely. So about 90 percent said that by 2010 it would be used routinely.