Do We Need to Overhaul Human ADME Studies?

The past two years have seen a vigorous discussion in the print and online media and at various scientific meetings on the general topic of what is the proper methodology, objective, timing and sequencing of the time-honored “ADME” study in animals and humans (Penner et al., 2011).  It is not hard to see why this is happening.

The basic human ADME experiment has changed little in decades, yet many clinically relevant questions could be addressed these days if there was sufficient impetus from scientists and expectation from regulators for improvements in the way ADME studies are designed and carried out.  Regulatory guidance’s requiring early identification of major human metabolites before the traditional conduct time of radiolabeled human ADME studies have stimulated analytical chemists to invent advances in analytical technology, especially high-resolution mass spectrometric instrumentation and data-mining algorithms (Zhu et al., 2011).  This new technology can be used creatively in many additional ways, not merely to satisfy MIST requirements. And, of course, the constant pressure to make drug development more rapid and cost-effective rightfully encourages sponsors to question everything.

An example of this debate from the recent literature illustrates the interest in this topic among industry experts.  In early 2012, Obach et al. raised the question whether radiolabeled ADME studies in animals provide value in clinical drug development justifying their expense and resource commitment.  Their main point was that metabolism information derived from preclinical species such as rats was not reliably predictive of human metabolism.  Thus, it was better to leave investigation of animal metabolism until after the human metabolite profile had been established, at which point one could focus on only the human-relevant aspects of animal metabolism, such as establishing coverage of all major human metabolites in preclinical safety studies.  These authors also suggested that the use of “lightly labeled” radioactive drug combined with detection by accelerator mass spectrometry (AMS) as a way to be able to conduct the human ADME study very early in clinical development, as well as to be able to achieve true pharmacokinetic steady state by multiple administration of extremely low doses of 14C (< 50 nCi).

However, in a subsequent response to that article, another group (White et al.) indicated several benefits that, in their opinion, justified continuation of preclinical radiolabeled studies to learn as much as possible about the behavior of drug candidates in a living organism before administration of radiolabeled drug to humans.  Suggested benefits included discovery of unexpected routes of metabolism, elucidating the major clearance mechanisms, and understanding the relevance of certain metabolism-based animal toxicities to humans.  Most recently, Obach et al. defended their original proposal while acknowledging that the issue deserves a wide discussion (2013).

In the inquisitive and innovative spirit of Obach, Nedderman and Smith, I propose some additional questions that ADME scientists ought to discuss.

  1. Does the newest MS methodology offer the opportunity to obtain data from human ADME experiments that is more useful for clinical development than is currently obtained?
  2. Can we extend the gathering of extensive ADME data from a handful of young, healthy male volunteers to large numbers of actual patients and investigate the effects of the variables of age, gender, ethnicity and health on metabolic profile?
  3. Can present QWBA studies in animals be enhanced to provide chemically specific assessment of tissue distribution of parent drug and metabolites in addition to the core objective of radiodosimetry?
  4. Does a human 14C-ADME study as presently conducted by most sponsors provide the information that regulatory agencies ought to have to properly assess the clinical efficacy and safety profile of a new drug candidate?
  5. Can “lightly labeled” radioactive drug with AMS detection provide ADME data of the same quality as traditional 14C-ADME studies?
  6. Can contemporary technology eliminate the need to administer radiolabeled drugs to human beings?

It is easy to think of additional questions along these lines.  The purpose of my short blog here is not to answer all these questions, but to stimulate the scientific community in the academic, industrial and regulatory sectors to share their thoughts and ideas with all of the rest of us.

REFERENCES

Obach RS, Nedderman AN, and Smith DA (2012) Radiolabelled mass-balance excretion and metabolism studies in laboratory animals: are they still necessary? Xenobiotica 42, 46–56.

Obach RS, Nedderman AN, and Smith DA (2013) A response to “radiolabelled mass-balance excretion and metabolism studies in laboratory animals: a commentary on why they are still necessary”. Xenobiotica 43, 226–227.

Penner N, Xu L, and Prakash C. (2012) Radiolabeled absorption, distribution, metabolism and excretion studies in drug development: why, when and how? Chem Res Toxicol 25, 513-531.

White RE, Evans DC, Hop CECA, Moore DJ, Prakash C, Surapaneni S, and Tse FLS (2013) Radiolabeled mass-balance excretion and metabolism studies in laboratory animals: a commentary on why they are still necessary. Xenobiotica 43, 219–225.

Zhu M, Zhang H, and Humphreys WG (2011) Drug Metabolite Profiling and Identification by High-resolution Mass Spectrometry. J Biol Chem 286, 25419-25425.

One thought on “Do We Need to Overhaul Human ADME Studies?

  1. I read with interest Dr Ron White’s comments re human ADME studies and when should these be conducted. Having spent the past 15 years advocating the use of human Phase 0 microdosing studies (Garner, 2010) it is difficult for me to understand why the debate is still ongoing. Human PK data trumps all animal and in vitro data and the earlier the former is obtained the better. Why do we continue with our traditional animal PK studies before obtaining human microdose PK information? I ask the question because microdose PK studies have proven to be between 70-80% predictive of human therapeutic dose PK, a figure which contrasts with the US PHRMA collaborative study of 23% for oral administration using PBPK modelling (Poulin et al, 2011). Indeed my experience of microdosing real development drugs is that predictivity can be close to 100% for the standard PK parameters of AUC, F, V, CL etc.
    I have been thinking about why there has been a general lack of adoption of microdosing and offer the following comments;
    1) there is a perception that microdosing is not predictive of thereapeutic dose PK (untrue)
    2) costs of microdosing studies with AMS analysis are expensive. Also untrue. Costs have dropped to around $100 per sample
    3) AMS and radiolabelled drugs have to be used. Also untrue – there is literature data on using LC/MS. Using labelled drugs however provides quantitative mass balance and metabolite profile information which cannot be obtained using LC/MS
    4) there are only a few small AMS providers. True. Only one pharma company, GSK has taken AMS in-house
    5) Problems have arisen when AMS studies have been conducted. True but as with any new technology and methodology there will always be teething problems
    6) AMS instruments are large and expensive. Untrue. The newest AMS instruments are a fraction of the size of the original instruments
    7) the LC/MS community is reluctant to switch to another technology. They feel more comfortable with waht they know and have used for many years and are reluctant to step outside their comfort zone. Probably true but as scientists we should be always seeking new methods and approaches.
    8) We have solved human PK prediction and that human ADME is not a significant reason for drug failure. Untrue. Efficacy and safety failures are often linked with PK but we don’t know it.
    9) Microdose studies delay drug development as once the study has been conducted and a suitable molecule identified then Phase I preclinical work has to commence. The result is that a delay of up to 6-9 months occurs. Untrue. Phase I preclinical work should be taking place in parallel
    10) Only a handful of pharma companies have adopted microdosing with AMS analysis. True.
    11) Regulators are receptive to microdose data. Untrue. Both the EMA, US FDA and Japanese MHW all have guidance documents in place.
    12) Many drugs show non-linear PK. Untrue. As we develop better and more potent drugs then dose linearity should be expected and targeted.
    If one puts microdosing into the context of overall drug development, for a cost of around $300,000 per molecule, failure down the road for PK reasons can be prevented or dramatically reduced. I believe the debate is really over. I direct the reader to Professor Malcolm Rowland’s recent commentary which gives a very balanced view of the current position (Rowland, 2012).

    Garner R C (2010) Practical experience of using human microdosing with AMS analysis to obtain early human drug metabolism and PK data. Bioanalysis, vol 2, pp 429-440.
    Poulin P et al (2011) PHRMA CPCDC Initiative on Predictive Models of Human
    Pharmacokinetics, Part 5: Prediction of Plasma Concentration–Time Profiles in Human by Using the Physiologically-Based Pharmacokinetic Modeling Approach. J Pharm Sci, vol 100, pp4127-4157
    Rowland M (2012) Microdosing: a critical assessment. J Pharm Sci vol 101, pp4067-4074.

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