Friday, April 25, 2008

Human Microdosing Studies/ Phase Zero

A Phase Zer0 study involves evaluating pharmacokinetics of a drug after administration of sub-therapeutic or sub pharmacology doses to a small group of healthy volunteers. According to
EMEA position paper, microdose is defined as dose less than 1/100th of the dose calculated to yield a pharmacological effect or a maximum of <= to 100 mcg dose. Using such small doses pharmacokinetic parameters can be estimated using highly sensitive techniques like acceleratoor mass spectrometry (AMS) or positron emission tomography (PET).
Determining pharmacokinetics, pharmacodynamics (binding to target) and metabolism of a drug at such an early stage in humans will help in eliminating compounds that have suboptimal properties and can aid in go or no decision of a compound. This is believed to considerably reduce the cost and time of drug development. US FDA followed with Exploratory IND guidance document in 2006 for conducting such early phase clinical trials. Microdosing or phase 0 studies do not provide any information on safety and efficacy (because of subtherapeutic dose used).
Xceleron has been the forefront in microdosing studies and their site provides some valuable information for anyone interested. National cancer institute had organised a conference on Phase 0 in oncology drug development and am still going through the slides posted here. As such, there have been very few publications on the use of this strategy in drug development. A pubmed search revealed few publications listed below, though none of them are real drug development case studies.

So here is my question for you. Were you (or your company) involved in any mircodosing studies? What is your opinion on the long term use of Phase o studies? Can modeling & simulation play any role in extrapolating data from these studies?


Microdosing Study Publications
1. Clinical Cancer Research 13, 4164-4169, July 15, 2007
2. Clin Pharmacol Ther. 2006 Sep;80(3):203-15
3. Clin Pharmacol Ther. 2006 Sep;80(3):216-27
4. J Clin Pharmacol. 2005 Oct;45(10):1198-205

9 comments:

Stephen Dueker said...

Stephen Dueker from Vitalea Science.

We are a spinout of UCD, Lawrence Livermore Lab, and ETH/Switzerland. We have been doing "microdose" studies since 1996 and built our own AMS technology with ETH.

As a CRO, many companies are doing microdosing as a means of "understanding the physiochemistry" of their compounds. The predictive PK topic is not the primary objective of microdosing, as PK can be solved later in formulation development. Microdosing is early ADME and understanding of the human metabolism. Receptor binding, tissue biosies, cell loading, routes of elimination, protein binding, biotransformation, etc...can all be ascertained in a microdosing study. Modeling is highly important only when good data is fed into the model. To model microdosing requires a good understanding of physiolology as endogeneous transporters and reservoirs will affect the biokinetics in ways not observed with saturation doses.

www.vitaleascience.com

Best,
Stephen

AM Lexi said...

Hi Stephen,

Thanks much for your comments. To my understanding based on pubmed search, there have been very few reports on the use of microdosing studies in drug development. I was wondering if you could share some of your experience. The presentation on your site
http://www.vitaleascience.com/pdf/jv.pdf
is very useful in understanding the use of AMS in human Physio Khemistry

Thank you!

Stephen Dueker, PhD said...

I see you found our interpretation of PK, PhysioKemistry. This indeed is what the specificity of a tracer and the sensitivity of AMS uncover.
Binding
Transporters interactions
Resevoirs (deep pools in PK language)
Full complement of metabolites
Molecular softspots

There is a growing body of evidence that microdosing is predictive of macrodose PK, but again, that is not our (Vitalea's) principal focus nor would it be if I were a drug developer. Rank ordering multiple candidates is an interesting idea to supplant animal testing and I am surprised it is not used more, but generally developers are pretty attached to "their" candidate - thus we see scientists simply want to learn more so that they can have more efficient later Phase trials with fewer surprises. Analyses that we have been asked to do in microdosing proper are
Prodrug metabolism
Cellular penetration (cell Loading)
Confirm absence or presence of unwanted metabolites
Potential for protein binding
Balance (does the drug come out).

I think this last point important, as one will never see deep reservoirs with macrodose ADME clearly. We have seen drug material leak out for weeks in some cases for a 6 hr half-life drug. None of it is parent drug. When these drugs become daily doses, these reservoirs accumulate and essentially lead to self-drugging by the drug and its metabolites. The impact this could have on idiosyncratic adverse events and safety in general, is real, and should be known in advance. Macrodoses swamp the system and tell little of the PhysioKemistry that is alway active, but not perceptible.

It is everyones desire to find a panacea to the complexity of drug development. Perhaps that is unrealistic. I see a new age where companies spend more time on their molecules, understanding and viewing metabolism and PhysioKemistry not as a nuisance, but as a tool to understand the drug fully (or class of compounds) avoid the potential for later stage surprises, and streamline IND phase testing once it commences.

The marginal relevance of animal testing is clear despite the objections of the preclin crowd (no disrespect here) - how can subtherapeutical human data not be valuble in myriad ways. That is the question to be asked? Not is microdosing predictive of macrodose PK.

Pharacokinetic prediction is great, but metabolism impacts safety in unexpected ways. Microdosing or Phase 1 ADME using microtracers is a very good option to make better decisions.

I do not see PK as the most important issue. Safety and Efficacy are the issue, and PhysioKemistry provides a view into processes that impact the later.

This is a complex business. I am not sure if "more shots on goal" by emphasizing speed over understanding is the way to go.

Steve

AM Lexi said...

Hi Steve, Thank you very much for taking time to explain the importance of AMS/microdosing studies. In addition to CREAM trial, your paper on Zidovudine (J Pharm Sci. 2008 Jul;97(7):2833-43) further emphasizes the use of AMS in studying microdose PK. I guess this would be true for all compounds showing a linear dose proportionality.

Will you be uploading your ASMS slides on your site?

Thanks

Mike said...

good post!

Stephen Dueker said...

Microdoses for meeting MIST guidance

Just coming back from ASMS, it is clear that MIST guidance has put a good deal of "concern" into the pharma business about how to address this important safety issue of steady state metabolite exposure. While my head is still trying to sort through the myriad configurations of hybridized MS instrumentation, the common theme running through all the very excellent MS talks was that radioanalysis is the most straightforward and absolute means of addressing MIST. Non-traditional radioanalysis, using AMS, expedites the entire endeavor.

It would appear that the field has come full circle - nothing is so powerful as a near 0 background analysis (14C) for unequivocal metabolite discovery, After discovery, one would then need to enlist the many sophisticated and quite impressive MS techniques for metaID when odd metabolites are revealed.


Regards,
Steve Dueker

Mike Butler said...

My name is Mike Butler. I am the CEO of Xceleron. The use of AMS has come a long way from microdosing only. MIST is gaining attention and is being tackled using AMS by a handful of pharma companies that we work with. We are seeing intense interest in the investigation of fundamental parameters using an IV-PK approach. In the latter case, the sophistication of analytical approach is more critical than traditional microdosing and MIST and is critical to avoid erroneous results.

Thanks for this blog, you should write more.

AM Lexi said...

Hi Mike, Thanks for your comments. I have another post in mind and will sure write one.

Best
Ganesh

Dr. Extreem said...

Thank you all for informative discussion.