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.

New Applications of Advanced LC-MS/MS Technologies at XBL

Plainsboro, NJ, August 17, 2012 – XenoBiotic Laboratories (XBL) has enhanced its bioanalytical services with the acquisition of two Waters ACQUITY UPLC® I-Class coupled with Xevo™ TQ-S tandem mass spectrometers. Over recent months, these systems have been validated according to FDA’s 21CFR Part 11 requirements. The increased sensitivity of the Xevo™ instruments has afforded significant reductions in plasma sample aliquot volume while still maintaining the required high sensitive LLOQ, and/or allowed additional reductions in the LLOQ to as low as 0.1 pg/mL. XBL has applied these systems to several of its most sensitive bioanalytical methods currently in use for clinical sample analyses. For example, for the inhaled drugs fluticasone (a corticosteroid that works directly on the nasal passages to relieve seasonal and year-round, allergic and non-allergic nasal symptoms) and salmeterol (a long-acting β2-adrenergic receptor agonist used in the management of asthma and/or chronic obstructive pulmonary disease (COPD)), a reduction in the LLOQ from 3 and 4 pg/mL, respectively, to 0.4 pg/mL from a 0.5 mL plasma sample has been achieved for both compounds. For situations in which a low blood draw volume is the critical factor, we have also developed methods for these compounds that have reduced the sample volumes by 2-5-fold while maintaining pg/mL LLOQ values. In another example, for our bioanalytical assay for formoterol (another inhaled long-acting β2-adrenergic receptor agonist used in the management of asthma and/or COPD), XBL has achieved an LLOQ of 0.1 pg/mL from a 0.5 mL plasma sample.

Another recent implementation within XBL’s bioanalytical department to improve efficiency is the routine application of dual HPLC (Shimadzu Prominence Device) coupled with AB SCIEX API-5000 tandem mass spectrometers to significantly increase sample analysis throughput and bioanalytical operational efficiency. “These multiplexed LC-MS systems have allowed faster turnaround times for large batches of clinical samples that require the sensitivity of the API-5000”, commented Dr. Xinping Fang, VP, Bioanalytical Services, “we have also recently implemented direct to network acquisition of LC-MS/MS data that improves raw data security the data review process”.

The addition of state-of-the-art Waters UPLC®/Xevo™ LC-MS system is another example of how XBL continues to enhance its core services in the bioanalytical, non-clinical ADME, and metabolite profiling areas available to the pharmaceutical, biotechnology, animal health and agrochemical industries. XBL facilities in Plainsboro, NJ (www.xbl.com) and in Nanjing, China (www.xbl-china.com) operate to GLP standards, are licensed for radioisotopes, and are AAALAC accredited for animal research.

For further information, contact:

Dennis P. Heller, Ph.D., VP Pharmaceutical Development, dheller@xbl.com or inquire at www.xbl.com

XenoBiotic Laboratories, Inc., 609 799-2295 or 888 XENO-880 (936-6880)