Covance has successfully completed a 'cold' - i.e., non-radiolabelled - microdosing study at its Clinical Research Unit in Honolulu. It believes this is also the first microdosing study to be conducted by a CRO through the exploratory Investigational New Drug (expIND) pathway mapped out by the US Food and Drug Administration (FDA) in a January 2006 guidance document. The first-in-human study, undertaken with an unnamed compound for an unidentified "major pharmaceutical company", provided pivotal pharmacokinetic (PK) data just 10 weeks after an expIND was submitted to the FDA, enabling the sponsor to make a "critical go-forward decision" to pursue further development of the compound, Covance noted. While spokesperson Winnie Bade could not supply any further details of the study or the technology used in lieu of AMS, she said it involved a different form of mass spectrometry that was still highly sensitive. Eliminating the need to use a carbon-14 (14C) label as a tracer in the study made it easier to formulate the compound and avoided the (albeit minimal) risk of the radioisotope to the healthy volunteer, Bade pointed out. Radiolabelling is not generally regarded as a safety problem in microdosing studies, given that the dose of radioactivity required is at most only around double that normally found in the human body. As UK AMS pioneer Xceleron pointed out in its comments on the FDA's draft guidance on exploratory INDs, there is a history in some European countries of dosing 200 nCi of radioactivity in the absence of animal dosimetry data. "Since the human body contains approximately 200 nCi of naturally-occurring radioactivity (14C and 40K), then a further short-term 200 nCi dose represents a negligible risk," the company stated. Far more persuasive are the efficiency advantages of a 'cold' microdosing study. As Covance noted, running its trial without having to radiolabel the compound "greatly" reduced the time and cost of preparing the appropriate dosage. The acute sensitivity of AMS, capable of performing a full human metabolism study following administration of as little as 0.1 milligrams of drug substance, has been widely hailed as the great leap forward for microdosing, although there are practical drawbacks beyond the need to formulate radiolabelled compounds. For example, the equipment is expensive and very large. Covance itself has not hesitated to jump on the AMS bandwagon. In 2006 it expanded its microdosing capabilities by signing a non-exclusive agreement with Xceleron giving Covance access to the UK company's AMS technology. Moreover, the first 14C microdosing study in the US was conducted using AMS by Radiant Research, whose eight early-phase clinical development sites (including the Honolulu clinic) were subsequently acquired by Covance in April 2006. One of the lead researchers in the initial microdosing study with azidothymidine - conducted by Radiant and Vitalea Science - was Dr Jon Ruckle, then medical director of early-phase clinical research at Radiant, now medical director for Covance in Honolulu. Covance views the success of its latest study as "a strong indication that microdosing has practical application in identifying promising compounds for full-scale trials." The company's "depth of knowledge" in this area "was helpful in developing the study protocol and identifying the ideal testing panel in a very short time," it added. The value of microdosing or Phase 0 studies is predicated on the current failure of as many as one in three compounds in Phase I clinical trials, despite extensive preclinical screening. This is often due to sub-optimal pharmacokinetics, leading to potential safety or efficacy issues in humans. In this light, microdosing is regarded as a powerful tool for weeding about potentially problematic compounds earlier in the development cycle, particularly as many of the processes that control a drug's pharmacokinetic profile are believed to be independent of dose level. There is scepticism, though, about just how predictive microdosing can be of a compound's pharmacokinetics at therapeutic doses. Bade acknowledged that client uptake of microdosing technology had been "a bit slow." Pharmaceutical companies were waiting to see what the applications were, she said, although there were already signs that acceptance was growing, while interest in the technique was growing "very fast." Covance is now conducting microdosing studies at its facilities in Honolulu and Madison, Wisconsin, although the service is still only a small part of the CRO's overall business, Bade noted.