Human microdosing proves its value in drug R&D

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Related tags: Pharmacology

Xceleron has announced the long-awaited results of the CREAM trial
into human microdosing in drug development, which demonstrates that
microdosing provides a valuable insight into the human
pharmacokinetics (PK) of new drug candidates.

The concept of microdosing in human subjects has long been an experimental technique that has promised much but has not quite lived up to its potential. However, the results of this study may finally confirm its potential as a new product development tool that improves predictability and efficiency along the development process.

The advantages of human microdosing are clear. By using only a very tiny amount of active substance, one can establish the likely pharmacological dose and thereby determine the first dose for the subsequent Phase I study. In addition, microdosing can elect the best animal species for long-term toxicological studies from microdose metabolite profiling data.

CREAM (Consortium for Resourcing and Evaluating AMS Microdosing), is a collaborative industry sponsored trial 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 crossover design. The trial was set up to be a rigorous test using compounds that were expected to strongly challenge the microdosing concept.

The trial involved 5 drugs of which the microdose PK data was studied. The data reflected the pharmacological dose PK for 3 and gave important metabolism data for 1 of the drugs. 1 compound was considered a no-test.

Versed (midazolam), a sedative drug that is a selective substrate for CYP3A4. The drug displays high first pass metabolism. The results of the experiment showed a high first pass metabolism correlation of key PK parameters.

Dr Graham Lappin, head of R&D at Xceleron​ said: "The results represented 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 CYP2C9 (a polymorphic gene). Many sceptics of the microdosing concept suggested that drugs with high first pass metabolism would not be predictive at microdose."

The other drugs involved in the study included Diazepam, which was selected because of its low clearance. It is a basic compound eliminated via CYP2C19. Linear kinetics was observed over a range of doses. The microdose result showed excellent correlation of key PK parameters.

ZK 253 (drug candidate dropped after Phase I) proved difficult to predict in terms of bio-availability. Low bio-availability was exhibited in humans. Extremely low bio-availability was found by microdosing.

Warfarin was found to be stable in vitro but exhibited extensive although slow human metabolism in vivo. A CYP2C9 substrate, the microdosing though slow metabolism and long half-life identified.

The last drug, Erythromycin, is a substrate for both CYP3A4 and the intestinal efflux transporter P-glycoprotein. It was deemed a no-test.

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 along the critical path'. We now have a 21st century tool that does just that."

"Currently, preclinical studies can take up to 18 months at a cost of $3-5m (€2.3-3.8m). Microdosing techniques could reduce the time to four to six months and the costs to $0.35m (€0.26m) per new molecule."

Not everyone within the pharmaceutical industry shares the view that microdosing is the way of the future. The microdosing method has come under scrutiny with particular concerns that microdosing may not be able to predict the behaviour of clinical doses. It is suggested that non-linearities may be induced when binding, metabolising or eliminating systems become saturated.

In addition, the disadvantages of AMS are that the equipment is expensive and large. It takes up space equivalent to two tennis courts. The hope is that smaller and cheaper instrumentation is likely to be developed in the future.

Ultra-sensitive AMS (accelerator mass spectometry) has made it possible to undertake clinical studies in man using extremely low drug doses to obtain early PK and ADME data. These microgramme doses are up to 100 times below the level calculated to yield a pharmacological effect.

AMS is a sensitive analytical technique with the ability to detect drugs down to attogramme or zeptogramme molar ranges. Screening ADME studies is one of the key biomedical applications increasingly incorporating the use of this technique.

Related topics: Preclinical Research, Ingredients

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