Human microdose trial data encouraging
from a trial evaluating the concept of human microdosing is set to
offer great potential in drug development. The pharmaceutical
industry is placing importance in finding ways of getting new, safe
drugs to the market within a quicker time period.
Microdosing relies on the ultrasensitivity of Accelerator Mass Spectrometry (AMS). Using AMS it is possible to conduct a full human metabolism study after administration of as little as 0.1 milligram of drug substance, measuring drug concentrations in biological fluids up to 1000 times less than the levels one observed in Phase I clinical study.
Results from the Consortium for Resourcing and Evaluating AMS Microdosing (CREAM) trial were encouraging as the trial determined if human pharmacokinetic data, obtained after a sub-pharmacological microdose of drug, allowed acceptable prediction of pharmacokinetics at pharmacological dose levels with the aim of facilitating drug candidate selection for subsequent human development.
The essential aim of microdosing studies is to obtain pK and/or PD information for new drug candidates rather than efficacy of safety data. This contrasts with conventional phase I studies in which the aim is to demonstrate tolerability and safety in a small number of subjects starting with a relatively low drug exposure.
In addition to pK data, metabolite profiles can also be obtained from samples derived from microdose studies. Such profiles can be used for example to compare human metabolism with that of the species used for the preclinical toxicology studies.
The trial was instigated by CRO and Accelerator Mass Spectrometer (AMS) specialists Xceleron and Dutch Phase I/IIa clinical CRO Pharma BioResearch. Industry sponsors included F Hoffmann-La Roche (Switzerland), Eli Lilly and Company (USA), Servier Laboratories (France) and Schering AG (Germany)
The trial involved five drug compounds, each with different pharmacokinetic characteristics, considered representative of the types of issues that arise in preclinical development. Each of the compounds 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 results revealed that three of the five selected drugs resulted in predictive human pharmacokinetic data, which would have allowed the right decision to be made for further drug development. Two of the drugs deviated from linear pharmacokinetic behaviour but nevertheless the microdose results gave useful insights into the properties of the drugs.
Professor Malcolm Rowland, chairman of the CREAM trial, commented that: "The results are sufficiently encouraging to suggest that, applied intelligently, microdosing coupled with AMS offers a promising additional tool to facilitate decisions at an early stage in candidate selection. More data on a wider range of compounds will help to further clarify the uses and limitations of this approach".
A European guidance (EMEA/CPMP, January 2003) position paper written by the European Medicines Agency, regulated the nonclinical safety package to support human microdosing studies. In appropriately chosen cases, human microdosing could allow for patients' quicker access to safer and more efficacious doses of novel drugs reduce attrition in clinical trials and facilitate more economical drug development. While it encouraged the pharmaceutical industry to adopt this novel approach there is a scarceness of data to support the concept.
