Phase 0-Microdosing strategy in clinical trials

Drug development is an activity that is long, complex and expensive. In 2004, attrition in the drug development paradigm prompted the US Food and Drug Administration (FDA) to introduce its ‘Critical Path’ document, which highlighted the serious discordance between major scientific advances and limited drug development process. One issue addressed was that of microdosing. The concept of microdosing involves the use of extremely low, nonpharmacologically active doses of a drug to define the pharmacokinetic profile of the medication in human subjects. Microdosing, thus, appears as a new viable concept in the ‘toolbox’ of the drug development activity. It appears that microdosing strategy could complement standard animal-to-human scaling, redefining the existing concept of phase I clinical research. In future, when research methods and technology involved in Phase 0 studies become more sophisticated, human microdosing may be applied to a number of drugs developed subsequently.


Introduction
Human drug development is a dynamic process that keeps pace with the recent advances within the pharmaceutical analytical labs, combined with a precise understanding of the integrated pharmacokinetic-pharmacodynamicpharmacogenomic drug profile.New drugs are a great need for many clinical conditions but, unfortunately, development costs are rising and the number of drugs receiving marketing approval has fallen.Further, drug development is a long, complex and expensive activity.It typically involves a total cost of US$ 500 million to 1 billion per marketed drug and is spread over 10-15 years. [1]In the past decade, attrition was the highest (62%) during Phase II, 45% during phase III and significant (23%) at the time of registration. [2]5] One important attribute of a drug is its pharmacokinetic profile.Suboptimal pharmacokinetics is stated to be a reason for failures during drug development.Too low concentrations of drug at the target organ for lesser time can lead to efficacy failures, while wrong concentrations reaching wrong targets for longer time may lead to toxicity.Thus, a new experimental approach has been developed, known as Phase 0 or microdosing studies, to address issues pertaining to drug metabolism and pharmacokinetics.1] Microdosing and Regulatory Advances

Department of Clinical
The changes observed in the recent regulatory guidelines also stimulate the more frequent use of microdosing in subjects.Although regulatory authorities may not make microdosing a mandatory requirement as the data can be obtained by other methods, the regulatory agencies may provide approval or similar incentives for companies bringing certain drugs like lifesaving medications to the development and commercialization stages more rapidly.
Further, accurate characterization of the kinetics of a drug over time, after administration, is an important regulatory requirement.This can be achieved by administration of radiolabeled drug to the subject and following its fate in plasma and excreta.Since AMS studies require very minute quantities of radiolabeled compounds, it may not be a significant source of material risk by regulatory authorities.Furthermore, recently, European Medicinal Agency and USA Federal Drugs Authority have published articles and supported evaluation. [4,5]

Advantages of Microdosing
First of all, microdosing requires minute quantities of the drug for safety testing.A microdose is so small that when administered to human subjects, it is not intended to produce any pharmacologic action; hence, the risk of adverse events is less.
A smaller toxicology package is required.As per the regulatory requirement, animal studies, at least in one species, are required to establish microdose in humans, but at a much reduced level.Further, if human screening of compounds is done earlier in the drug development process, fewer animal studies are required before Phase I clinical trials.Thus, further animal studies can be avoided with compounds having unsuitable pharmacokinetic profiles.
From preliminary toxicology data of animals, pharmacokinetic data for the initial dose selection can be obtained in a short time of 4-6 months, whereas in Phase I studies it takes 12-18 months.During drug development, when a large number of me-too compounds are screened and found to have similar or differing animal pharmacokinetics, comparative human microdose studies can be done to establish pharmacokinetics.This pharmacokinetic data can further be used [1] to help in selection of the ideal candidate drug, [2] obtain the first in man dose of that selected drug [3] Establish the tentative pharmacological dose and [4] calculate the probable cost of the deliverable.7] A rigorous assessment of the utility of microdosing studies to accurately predict drug disposition in small groups of humans should include a comparative trial pairing the pharmacokinetic results obtained from paired therapeutic dose and microdose data. [6]In a study performed to compare the pharmacokinetics of five drugs -warfarin, ZK253, diazepam, midazolam and erythromycin, administered at a microdose or pharmacological dose, the authors concluded that when used appropriately and intelligently, microdosing offers the potential to aid in early candidate selection. [12]urther, the cost of conducting a microdose study is phenomenally less, as compared to a full Phase I study.A conventional phase I study may cost about US$ 1.5 to 3.0 million, whereas in the microdosing approach, the cost drops to about US$ 0.3 -0.5 million. [13]uman microdosing promises to be a significant analytical tool.In future, as research methods and technology involved in Phase 0 trials become more sophisticated, human microdosing may be applied to a number of drugs that could potentially be administered consequently. [13,14]dditionally, microdosing could be useful in the discovery of endogenous biomarkers, which would assist in the quantitative evaluation of the in vivo effects of drugs.
Last but not the least, in oncology, phase 0 clinical trials are welcome in a big way.These studies are designed with the objective to establish at the very earliest opportunity -before a large numbers of patients have been accrued and exposed to potential drug-associated toxicity -whether an agent is modulating its target in a tumor, and consequently whether further clinical development is warranted. [14]

Limitations of Microdosing
There are many questions which need to be answered regarding the predictive accuracy of microdosing.We still do not have enough studies to clearly exemplify whether the body's reaction to a particular compound is similar, when used as microdose and in its pharmacological dose; otherwise, it could lead to false negatives (compound being rejected) or false positives (compound acceptable based on microdose data but rejected subsequently when used in pharmacological doses). [15]nother question of concern is whether microdosing predicts pharmacokinetic parameters accurately for drugs showing nonlinear kinetics.This aspect has been addressed in CREAM study (Consortium for Resourcing and Evaluating AMS Microdosing), where the disparity in warfarin disposition is described.9] Thus, a microdose may not be able to predict the behaviour of a clinical dose of the drug.However, though the CREAM study was not exhaustive, it demonstrated about 70% approximation between microdose and pharmacological dose pharmacokinetics.
Another limitation of microdosing relates to metabolism and stability of certain compounds.Some compounds dissolve readily at microdose, yielding good absorption characteristics; however, at therapeutic doses, they exhibit limited solubility, and absorption becomes dependent on the rate and extent of dissolution, which cannot be predicted at microdose levels.
Further, AMS (accelerator mass spectrometry) and PET (positron emission tomography) are applied to analyze the concentration of the drugs in low picogram to femotgram range, when microdose is used.These radiotracer assays have the disadvantages of short tracer half-life and limited specificity (as assay may include metabolites also).Both for PET and AMS, the drugs must be labeled at metabolically stable sites. [5,9,15]he limitations of microdosing relate to compound metabolism and solubility of compound.Many processes within the body involve the use of specialized transporters, enzymes and binding sites, which can be saturated such that the pharmacokinetic profile is very different at the higher therapeutic dose than seen with the microdose. [16]Further, the compounds must be soluble to pass across the cell membranes and act within the body.Most compounds dissolve rapidly at microdose levels, yielding rapid and often extensive absorption.However, at higher therapeutic doses, many compounds exhibit limited solubility.This means, absorption becomes more dependent on the rate and extent of dissolution, which cannot be predicted by microdose.Thus, it has been suggested that the dose of 100 micrograms may be too low to achieve the full potential of microdosing. [17]

Conclusion
Human microdosing clearly holds significant promise as an analytical tool.In the coming years, as research methods and technology involved in Phase 0 trials become more sophisticated, human microdosing may be applied to a number of drugs that could potentially be administered consecutively.Microdosing may later become an accepted approach in drug development, when first in man studies may begin with a Phase 0 study.However, the true utility of Phase 0 microdosing studies lies with the ability to predict under what circumstances this approach will provide data within a specified and acceptable range, as compared to the therapeutic dose data.Capitalizing on the continuing rapid advances in drug development technology, there is no question that decreasing the time of drug development, reduces the cost phenomenally.Until further information is available, we opine that microdosing strategy could complement the standard animal-to-human allometric scaling, redefining the present phase I study designs.This strategy may help to reduce animal testing in the identification of novel drug candidates.
Further, microdosing may help both patients and the pharma industry with earlier availability of new test medication and reduced attrition of compounds at later stages of drug development.Microdosing allows not only selection of drug candidates more likely to be developed successfully, but also helps in determination of the first dose for the subsequent Phase I clinical studies.