Accelerator Mass Spectrometry
Xceleron uses Accelerator Mass Spectrometry (AMS) to detect sub-pharmacological doses of 14C-labeled drug compounds. Such microdosing or Phase 0 studies, which originated in Europe, are the basis for the FDA’s new exploratory-IND, or e-IND.
The FDA defines e-IND studies based on three main criteria: limited intent (administration of either sub-pharmacologic doses or doses expected to produce a pharmacologic but not a toxic effect); a limited number of subjects and a limited dose range for a limited period of time; and less risk to human subjects than traditional Phase I studies. E-INDs require much less preclinical support to gain approval—only an expanded acute toxicity study in one (versus two for a traditional IND) mammalian species, and no genotoxicity tests.
Regulatory agencies on both sides of the Atlantic are taking a lead in endorsing Phase 0 studies, says Dr. Garner. The EMEA released a position paper on microdosing in 2003, and the FDA provided guidance on e-INDs, which includes microdosing, in 2006.
Microdosing in combination with AMS can be used to assess human metabolism with the administration of as little as 0.5 µg of a drug substance, although a typical microdose is 100 µg. Radiolabeling of carbon or hydrogen does not change a molecule’s structure, and 14C- or 3H-labeled compounds behave the same as their nonradioactive counterparts.
AMS enables microdosing studies by providing a low limit of quantitation (20–50 x 10-18 M), highly sensitive radioactivity detection (50–200 nCi 14C per dose), and a dynamic range of six orders of magnitude, according to Michael Chansler, vp of business development at Accium BioSciences (www.acciumbio.com), a CRO specializing in accelerator mass spectrometry bioanalytical services.
Chansler identifies two primary applications and advantages of microdosing. For large pharma, Phase 0 studies help companies select the best lead compound to take into clinical trials from among multiple candidates that have performed similarly in animal studies or cannot be prioritized based solely on animal and in vitro data. Phase 0 results expand the compound profile and the company’s knowledge base by adding some human data. For smaller pharmaceutical or biotechnology companies that have a promising compound coming out of preclinical development but lack the funds to initiate a full Phase I trial, the main advantage of microdosing studies is to demonstrate that the compound can pass through the human gut, be absorbed into the circulation, and reach the target tissue. This knowledge can make the compound more attractive to investors and potential partners interested in licensing the compound.
“It can take some of the PK risk off the table,” says Chansler. Accium completed installation and validation of its AMS instrument in 2006, and has established partnerships with Covance, Quintiles, and Analytical Bio-Chemistry Laboratories (ABC Labs; www.abclabs.com).
The growing acceptance and implementation of Phase 0 studies is important because there is no substitute for studying the behavior of a compound in humans, agrees Noel Premkumar, Ph.D., director of regulatory strategy, preclinical/clinical at Analytical Bio-Chemistry Laboratories. If a company were trying to choose a lead compound from among a handful of viable candidates, and if all the compounds were derived from the same scaffold, shared the same target, and demonstrated an acceptable safety profile in animal studies, then the FDA would allow the company to evaluate as many as three or four compounds in a single Phase 0 microdosing trial, explains Dr. Premkumar. With the right program and study design, this can translate into time and cost savings.
In February, ABC Labs announced a collaboration with Accium BioSciences to provide 14C-labeled molecules for use in the company’s AMS-based analytical services. ABC and Accium plan to co-market a package that will provide synthesis of 14C-labeled drug substance, dose preparation for 14C-labeled drug, and AMS services.
ABC Labs has developed expertise in radiolabeling of drug compounds and is leveraging that expertise to design radiosynthesis strategies that yield labeled compounds with the highest chemical and metabolic stability at the lowest cost. The radiolabeled compounds are produced under GMP conditions and in the form required for administration to humans, whether delivered orally, intravenously, subcutaneously, or via inhalation.
Dr. Premkumar predicts that pre-IND bridging strategies and Phase 0 studies will change the drug development process, although few companies have adopted this approach yet. Instead of the current model, in which companies typically use 14C-labeled drug compound to assess ADME in late-stage preclinical testing, microdosing studies will work their way up the pipeline into lead optimization, and Phase 0 trials will act to bridge lead optimization with preclinical development.
“As sponsors continue to focus on optimizing return on their R&D dollars, more of them will use Phase 0-related toxicity studies at the lead-optimization stage,” predicts Dr. Premkumar, “rather than waiting for the preclinical or later stages of development.”
Dr. Garner says the main technology hurdles for AMS are to improve the throughput and lower the cost of the instruments. The primary obstacle to broader application of the technology is “overcoming skepticism,” notes Dr. Garner. Currently “there is probably not a sufficient body of evidence to state categorically that microdose PK will be predictive of pharmacologic dose PK.” But as the database supporting the technology continues to grow, Dr. Garner predicts that the correlation between microdose and pharmacologic dose PK, currently about 70% to 80%, will increase.