The last thing drug companies need now is an increase in time consuming and expensive clinical trials. But ongoing problems with Cox-2 inhibitors and others mean that regulators are likely to make just such a demand. At the same time, both the regulators and the drug companies want to reduce the number of potential products that fail during clinical development.
One solution to this could be human microdosing. The aim here is to use ultrasensitive methods such as accelerator mass spectrometry (AMS) and microgram quantities of drugs to conduct full human metabolism studies. AMS is one of the most precise bioanalytical approaches currently available up to 100000 times more sensitive than LC-MS/MS and 1000000 times more sensitive than liquid scintillation counting.
A January 2003 guidance position paper on microdosing from the European Agency for the Evaluation of Medical Products (EMEA) encourages the pharmaceutical industry to adopt this novel approach. The guidance stated that in appropriately chosen cases, human microdosing could allow quicker access to safer and more efficacious doses of novel drugs reduce attrition in clinical trials and facilitate more economical drug development. However, it also noted the paucity of data to support the concept.
All that has changed with publication of preliminary results from the long-awaited Consortium for Resourcing and Evaluating AMS Microdosing (CREAM) trial which is aimed at evaluating the concept of human microdosing.
CREAM was designed to determine if human PK data, obtained after a sub-pharmacological microdose of drug, allows acceptable prediction of pharmacokinetics at pharmacological dose levels with the aim of facilitating drug candidate selection for subsequent human development.
The trial was instigated by the UK-based specialist contract research organisation (CRO) and AMS expert Xceleron and Dutch Phase I/IIa clinical CRO Pharma BioResearch. Four international industry sponsors were also involved: F Hoffmann-La Roche of Switzerland, Eli Lilly and Company from the USA, Servier Laboratories of France and German company Schering.
In the trial, five drug compounds were selected with known and different pharmacokinetic characteristics, which are considered representative of the types of issues that arise in preclinical development that may make prediction of human pharmacokinetics problematic. Each of the compounds 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.
CREAM's sponsors have reviewed the trial data and made the following preliminary conclusions: u Microdosing is a valuable tool in drug development. 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. u Given the fact that the compounds were selected because of their difficult pharmacokinetic properties, we consider the outcome of the CREAM trial to be a success - microdosing is a useful tool in drug development.
Professor Malcolm Rowland, chairman of the CREAM trial, concurred with this summary: “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.“
The findings are also good news for other CROs who are keen to develop microdosing techniques. Pharmaceutical Profiles, a niche Phase I/IIa CRO based in Nottingham, England, is one example.
Founded in 1990, the company says it is dedicated to assisting the pharmaceutical industry to make the right product development decisions in early clinical development.
Late last year it reported the completion of its own microdosing study. The company believes that the technique is the start of a new era in drug development in which human absorption, distribution, metabolism and excretion (ADME) data plays an increasing role in candidate selection or deselection.
The study was carried out for Swedish organisation Tripep, a biotech research company that develops and commercialises candidate drugs based on patented and patent-pending technologies. Tripep is active in several areas, including the R&D of alphaHGA, an HIV-inhibiting drug. It is in this field of research that the microdosing study was utilised.
The sophisticated human microdosing study took less than six months from inception to completion and examined the pharmacokinetics (PK) of the HIV inhibiting molecule in healthy subjects, following dosing with sub-pharmacological, microgram quantities of drug candidate.
The microdosing approach has provided Tripep with pivotal early human PK data on the performance of its candidate drug much more quickly and accurately than would have been possible using conventional development strategies.
Encouragingly for the development of alphaHGA, the microdose study has shown 100percent oral bioavailability for the candidate, allowing fast-tracking of the molecule into proof-of-concept studies with an enhanced chance of success and significantly reduced risk.
Tripep's acting ceo and head of research Anders Vahlne is in no doubt of the benefits of a microdosing study at this stage of development of the peptide: “The results were very encouraging for the future development work on alphaHGA and helps us design the clinical study on HIV infected individuals.“
Through its human microdosing service, Pharmaceutical Profiles combines its own early clinical development capabilities and expertise with ultra-sensitive AMS. “Microdosing studies provide a smarter way to develop drugs by providing very early human data,“ explained Ian Wilding, executive chairman of Pharmaceutical Profiles.
“Tripep utilised the microdosing study approach and now they have early human data they can clearly see the benefits of undertaking a microdosing study early in the development of their alphaHGA product. Many other biotechs and major pharmaceutical companies are actively discussing human microdosing studies with Pharmaceutical Profiles. We believe these studies will create a much greater understanding and awareness of the importance of PK and ADME issues in early phase drug development. Up to 40percent of new drugs currently fail during phase I trials and human microdosing offers the promise of selecting the best drug candidates before advancing into full development, thereby increasing the chance of success,“ he added.
Pharmaceutical Profiles described the CREAM trial as an aenormous boost' to human microdosing studies.
Meanwhile, Tripep has just submitted the necessary documents to the authorities in Thailand for the approval of the company's first Phase I/II trial of alphaHGA in HIV-positive patients.
