Tuesday, June 9, 2009

Phase 0 Microdosing/Microtracing in Phase 1 Studies

Stephen Dueker, PhD, President/CEO of Vitalea Science recently commented on my previous post on Microdosing Studies. I thought of posting his comments and his email content pertaining to Microdosing/Microtracer studies in Phase 1 as a fresh post. Steve has also generously provided his recent presentation at ASMS meeting to be posted on this blog.


All the methods and procedures for bioAMS were developed at Lawrence Livermore National Lab (LLNL) and the latest technology, the BioMICADAS developed by ETH/Zwitzerland and Vitalea Science (who has the original developer of bioAMS). It is important that people know the history of bioAMS and that it was the results of 15 years of intense research at Livermore in genotoxicity, nutrition, chemical interactions, pharmacology, and enviornmental studies. Other companies simply transferred some of the methods from LLNL.

What needs to be understood is that AMS is much more than Phase 0. 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 biopsies, cell loading, routes of elimination, protein binding, biotransformation, etc...can all be ascertained in a microdosing study. This indeed is what the specificity of a tracer and the sensitivity of AMS uncover.

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 is 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 everyone’s 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 sub-therapeutical human data not be valuable in myriad ways. That is the question to be asked? Not is microdosing predictive of macrodose PK. Pharmacokinetic 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.The hot topic is now MIST guidance, not so much Phase 0. AMS finds all metabolites without method development or internal standards.

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.

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.


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Feel free to discuss and share your experience with Microdosing/AMS/Microtracer studies.


Colin Garner said...

I read Steve Dueker's comments on Phase O/microdosing with interest as well as some bemusement. My name is Professor Colin Garner, the founder CEO of Xceleron until I retired at the end of 2008. Xceleron was the company that pioneered the commercial use of AMS in drug development. It may be worth briefly running through the history of biomedical AMS so that the facts are out in the open. LLNL did indeed pioneer the use of AMS in biological studies as Steve Duecker correctly points out. When I first came across AMS at an AACR meeting in 1992, I proposed to the LLNL AMS group at that meeting that my academic cancer research unit at the University of York had the capability of conducting clinical studies whereas all the work the research up to that point had been performed in animals. From the initial discussions, a fruitful research collaboration resulted in which a number of seminal papers were published on the metabolism of 14C-carcinogens. My York group conducted the clinical work and the LLNL AMS group carried out the AMS analysis.

From this collaboration, it became clear to me that AMS had a much wider role to play than simply studying carcinogen metabolism. I set about therefore with my colleagues to raise substantial funds to create the world's first commercial AMS centre focussing on drug development. Steve states that 'other companies simply transferred some of the methods from LLNL'. I wish it had been that simple. The fact is that through my efforts together with those of my collagues supported by Glaxo, Novartis, Johnson and Johnson, Pfizer, the University of York and the UK government department MAFF, sufficient funds were raised to create the world's first fully commercial AMS centre. Before the formation of Xceleron, there was no market for AMS in durg development. It is gratifying to know as I look back on the past 12 years since Xceleron was founded, that other AMS companies have been formed. Clearly there is a market which would not have existed without Xceleron's creation. All scientific endeavour is based on the previous research of others. It does science a great disservice to knock the effort of others. I am pleased that companies such as Vitalea and Accium have been created. Their creation endorses my original concept that indeed AMS has a role to play in drug development.

I would like to turn to the uses of AMS in pharmaceutical research. Xceleron established, through its interaction with drug developers, that the most obvious appplication of the technology was in ADME studies. ADME researchers had been using 14C labelled drugs for nearly 60 years as a tool to identify metabolic pathways as well determining a drug's rate and route of excretion. It was not therefore a quantum leap for ADME researchers to understand the attractions of light radiolabel studies which the ultrasensitivity of AMS permits. The concept of conducting light radiolabel studies in humans was an attractive one as it overcame issues relating to radiation exposure. The principles of ALARP (administering radiation doses As Low As Reasonably Practical)are those that need to be followed when conducting clinical research studies. AMS permits the ALARP principles to be followed and hence should be used routinely for clinical radiolabel drug studies.

Colin Garner said...

In 1999, I first proposed the use of AMS in microdosing studies. Before that time, the PET community had proposed the use of microdosing but owing to the instability of 11C, only limited ADME information can be obtained from PET studies. In contrast 14C can be analysed by AMS at the zeptomole level. Together with Dr Richard Jones, who at that time was working with Johnson and Johnson, we jointly conducted the world's first microdose study of a development drug with AMS analysis. I also coined the term 'human Phase O study' to describe a study which takes place before Phase I. The Phase 0 approach was endorsed by European regulatory agency, the EMEA in 2003, who set out the preclinical requirements for Phase 0 microdose studies. Subsequently the FDA and the Japanese MHW introduced their own microdosing guidance documents. These are currently being harmonised through ICH.

Phase 0 microdose studies are valuable as they give an early indication of human ADME without going through the expense of conducting a full Phase I study. The information obtained in a Phase 0 study is valuable, particularly if several drug candidates are available and where conflicting in vitro or preclinical metabolism data have been found. Xceleron has a number of examples of molecules that were put through a microdosing programme where the human ADME/PK was different to that found in preclinical studies. As a result a different candidate molecule was selected to take through to a full Phase I study. The issue of whether or not there is dose proportionality between microdose and therapeutic dose PK is one that has generated more heat than light. Xceleron has conducted two seminal trials, CREAM and EUMAPP to address this issue. An approximately 70% correspondence between microdose and pharmacological dose PK has been found in these trials. Interestingly for 10 real development drugs which have been microdosed followed by a full Phase I testing programme, all 10 showed dose proportional PK.

Human Phase 0 microdose studies should become part of the drug developers tool box. There is no scientific justification not to do so.

Xceleron has also pioneered the use of AMS in human mass balance and metabolite profile studies as well as intravenous PK studies especially to determine absolute bioavailability. The results from a number of these studies have been published in the peer reviewed scientific literature. Unfortunately for reasons of confidentiality, the results of most of the studies conducted by Xceleron cannot be divulged. Suffice it to say that Xceleron has developed novel approaches which enable sound data to be generated with the ultrasensitive AMS instrumentation including a proprietary recovery curve procedure for IV PK studies. Without using this procedure variable PK data are generated.

I feel proud that the pioneering efforts of Xceleron have resulted in the creation of a new market for AMS. AMS is a disruptive technology which can provide significant value to the drug developer. As a result Xceleron, Vitalea, Accium and any future AMS companies will grow and prosper in this new market. Power to them all’


Professor Colin Garner
Founder/Director Xceleron
Principal, Garner Consulting

Ganesh Mugundu said...

Hi Dr. Garner, Thanks for your comments and the elaborate exlpanation on the evolution of AMS/microdosing. I think the technology that was introduced in 1992 has come a long way and is slowly gaining a place in drug development.

What do you think has been the major drawback and hindrance that has stopped people implementing Phase 0 studies?

Have large molecules been studied been studied?


Penny Zhu said...

Hi. Thank you for these information. My taking on this issue is that AMS at its current state, although a sensitive technology, is still high-cost, low-throughput and not readily accessible to the people who may want to use it everyday. I am not sure when it will become as convenient and affordable to use as regular flow scintilation analysis. If that day comes, of course AMS will be the next hot technique.

Ganesh Mugundu said...

Penny, Thanks for stopping by and commenting. I agree with your thoughts on the cost and accessibility of AMS. As the usage of AMS increases, probably the cost will eventually go down.

Stephen Dueker said...

This is to Penny. You spoke of high costs, and actually AMS is relatively low cost if it prevents late stage failures due to metabolism issues not being uncovered until late in the development program. In terms of throughput, our AMS runs 24/7 without calibration plots as quantiation is absolute, there is minimal to no method development, and metabolite abundances are also absolute without ion suppression or matrix effects concerns. A measurement may not be priced the same as LC/MS, nor can it, but it is in the same ballpark when looks at the bigger picture rather than per sample measurement prices. You are correct in saying that AMS is not priced as a commodity as LC/MS is now. It has not matured to that level yet.

A measurement takes 3 minutes. It is actually a high throughput instrument! An equivalent measurment on an LSC could take hours if not days (this is radioanalysis). The sample preparation procedures are robust and reproducible to well below the FDA bioanalytical guidelines.

If you to know your metabolism in complete detail in phase 1 with trace quantities of radiolabel, AMS is a good choice.

A paper will be out soon by an FDA, author AISAR ATRAKCHI, in Chem. Res. Toxicol. that touches upon AMS as a technique for meeting new MIST guidance under steady state conditions.

The field is evolving and the value proposition must be viewed in the context of many factors that have cost risks far greater than an AMS based study.

Stephen Dueker said...

Colin Garner did an excellent job in opening the regulatory field. No arguments there. This was no small chore as change in pharma is extraordinarily difficult to bring about, especially with techniques principally used by physicists for carbon dating. There were many key players in the early days, too many to mention.

It is also true that bio-AMS is a licensed technology for pharmaceutical science out of the University of California and Lawrence Livermore via the DOE. All AMS providers purchase these licenses. This is substantiation for why I say that bioAMS is primarily a LLNL development. It was patented because it was novel and difficult. Many aspects have now been streamlined and the technology has evolved.