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CREAM trial results positive
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Human microdosing proves its value in drug development |
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Additional Information
Xceleron announces the results of the CREAM trial into the efficacy of human microdosing in drug development. The results of the independent CREAM trial were presented recently at ASCPT 2005, Orlando, Florida and clearly demonstrated that microdosing provides a valuable insight into the human pharmacokinetics (PK) of new drug candidates which can then be used to
- Assist in the compound candidate selection process
- Help establish the likely pharmacological dose and thereby determine the first dose for the subsequent Phase I study
- Select the best animal species for long term toxicological studies from microdose metabolite profiling data
- Calculate the likely cost of goods
According to Professor Colin Garner, CEO of Xceleron, "this is the result for which everyone in drug development has been waiting. In their 'Critical Path' document, the FDA asked why the tools of the last century are being used to develop drugs of the 21st. In fact they stated that: "A new product development tool kit.... is urgently needed to improve predictability and efficiency along the critical path". We now have a 21st century tool that does just that".
Working on the principle that 'the best model for man is man', human microdosing, using Accelerator Mass Spectrometry, enables the introduction of sub-pharmacological doses of new drugs into man much earlier than ever before possible.
However, there has been concern within the pharmaceutical industry that a microdose may not predict the behaviour of clinical doses. It is suggested that non-linearities may be induced when binding, metabolising or eliminating systems become saturated. To address this issue, a collaborative industry sponsored trial (CREAM: Consortium for Resourcing and Evaluating AMS Microdosing) was undertaken using several drugs with known human PK characteristics at pharmacological dose levels. Each compound was administered at a microdose level and at a therapeutic dose level to subjects in an appropriate cross-over design. The trial was set up to be a rigorous test using compounds that were expected to strongly challenge the microdosing concept.
Of the 5 drugs studied microdose PK data reflected pharmacological dose PK for 3 and gave important metabolism data for 1 (1 compound was a no-test). Details of the individual molecules chosen and the reason for their choice are shown in this table.
| CREAM trial drug | Selection Rationale | Microdose Result |
| Midazolam | A selective substrate for CYP3A4. High first pass metabolism. | Predictive: Excellent correlation of key PK parameters |
| Diazepam | Low clearance, basic compound eliminated via CYP2C19. Linear kinetics over a range of doses - possibly not at microdose. | Predictive: Excellent correlation of key PK parameters |
| ZK 253 (drug candidate dropped after Phase I) | Bio-availability difficult to predict from animal models. Low bio-availability in humans. | Predictive: Extremely low bio-availability was found by microdosing |
| Warfarin | Stable in vitro but exhibits extensive although slow human metabolism in vivo. A CYP2C9 substrate | Not predictive: though slow metabolism and long half life identified |
| Erythromycin | Substrate for both CYP3A4 and the intestinal efflux transporter P-glycoprotein | Issue in administration: no test |
Dr Graham Lappin, Head of R&D at Xceleron, observed that "the results will represent a surprise for some in the pharmaceutical community as the concept works in circumstances that were cited as being unlikely for microdosing to succeed. For example the microdosing study carried out with Midazolam gave excellent correlation with the pharmacological dose that was seen as highly significant as this is a well known substrate for CYP3A4. Many sceptics of the microdosing concept suggested that drugs with high first pass metabolism would not be predictive at microdose".
Whilst this study was not exhaustive, it demonstrated approximately 70% correspondence between microdose and pharmacological dose PK. Given the fact that the compounds were selected due to difficult PK properties, Xceleron considers the outcome of the CREAM trial to be a great success.
To see Professor Malcolm Rowland's recent presentation on CREAM trial results follow this link.
http://www.xceleron.co.uk/metadot/index.pl?id=2314&isa=Category&op=show
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