MICRODOSING: A PHASE 0 CLINICAL TRIAL

Introduction
Drug development is a scientific endeavor
and is highly regulated because of
legitimate public health concerns. Drug
development process involves integration
of different expertise, conduct of many
experiments and involvement of lot many
resources, considerable time and
significant cost. It takes about 2 to 12 years
for a new drug for development [1] and the
cost of a new drug development range
from USD$92 million to USD$883.6
million [2]. During the drug development
process, many animals are used for
experiments and during clinical trials,
many human subjects are exposed to the
drug at various dose. Even after spending
lot of resources, time, cost and
experimentation on animals and humans;
the drug may fail to provide desired
clinical efficacy and safety. Only one in
10,000 compounds ever reaches the market
and of those, only one in three ever
recaptures its development costs [1]. There
are many reasons for failure of the drug
candidate during drug development or after
market entry. They are Poor
pharmacokinetic (39%), Lack of efficacy
(30%), Animal toxicity (11%), Adverse
effects in man (10%), Commercial reasons
(5%), Miscellaneous (5%) [3,4] and are
appeared at different stage of drug
development or sometimes after market
entry of the drug. Hence, at each stage of
drug development, the developer needs to
make “go/no-go” decision based on
available information. On one side, it is
good to make “go” decision at each stage
of development based on the available
data, but on other side, it is highly

desirable to identify limiting factor (if any)
as early as possible so as to make earliest
“no-go” decision with the drug candidate
in order to save time, money and efforts.
The drug development phase which tests
the drug’s performance in humans is call
clinical development. The drug’s fate,
eventually the developer’s fate, depends
upon the performance of the drug in target
population (humans) during clinical
development and then in market use.
Hence, it is very important to have data of
drug’s performance in humans as early as
possible in order to make “go/no-go”
decision.

Microdosing

Microdosing is a new technique to study
new drug especially for human
pharmacokinetic before the usual
expensive clinical development phase
starts. A microdose is defined as less than
1/100th of the pharmacological (predicted)
dose of a test drug candidate or a
maximum dose of < 100 μg. Due to
differences in molecular weights as
compared to synthetic drugs, the maximum
dose for protein products is d” 30
nanomoles to be said as microdose [5].
Studies using such a microdose are called
microdose studies. In microdose studies,
sub-pharmacological doses of prospective
drug candidates are administered to human
subjects in order to obtain pharmacokinetic
and if possible some pharmacodynamic
information (e.g. mechanisms of a drug
action). European and USFDA guideline
now permit microdosing studies in human
subjects very early in the drug
development process. The preclinical

toxicology data required for microdosing
studies are minimal and hence these
studies can be used as a drug candidate
selection tool to effectively eliminate drug
candidates that show sub-optimal human
pharmacokinetic before spending time and
effort in the kind of extensive toxicology
that is required prior to conventional Phase
1 and other conventional clinical
pharmacokinetic studies for such drug
candidates. The term “Phase 0” is therefore
used to refer to such microdose studies.

To measure drug concentration in
microdose studies, ultrasensitive analytical
methods like Accelerator Mass
Spectrometry (AMS) and Positron
Emission Tomography (PET) are used.
AMS is the most sensitive analytical
method being used in microdosing study
using radiolabeled substance. AMS differs
from other forms of mass spectrometry in
that it accelerates ions to extraordinarily
high kinetic energies before mass analysis.
The special strength of AMS among the
mass spectrometric methods is its power to
separate a rare isotope from an abundant
neighboring mass. AMS measures
individual atom of the isotope and not
radioactive decay events, this makes AMS
highly sensitive than conventional Liquid
Scintillation Counting and upto 100000
times more sensitive than liquid
chromatography mass spectrometry (LCMS).
In studies using high performance
liquid chromatography-AMS, limits of
detection of 0.0008 dpm/fraction have
been reported. Using AMS, drug developer
can generate human pharmacokinetic data
of drug candidate using microliter or
milligram quantities of sample and minute

levels of 14C tracer, which is virtually
undetectable and of nanocurie level of
radioactivity [6,7]. PET is 3-dimensional
imaging technique using radioactive tracer
to label drug. PET can be used to study
pharmacodynamic information like
receptor selectivity, receptor occupancy
profile etc. 11C or 18F are generally used for
radiolabeling which generate images using
gamma cameras and can be used to study
distribution of labeled drug candidate in
body in real time including penetration in
central nervous system, cross of blood
brain barrier etc [6-8]. Sometimes, liquid
chromatography coupled with tandem
mass spectrometry (LC-MS-MS) is also
used in microdose studies. Below are some
of the advantages and limitation of
microdosing technique (Table 1).

Microdosing technique is significant
technological advancement in the field of
clinical development which generates
some human pharmacokinetic and
pharmacodynamic data to improve and
speed-up drug development process. It
greatly helps in generating early
pharmacokinetic data to make early
“go/no-go” decision in order to save cost,
time and efforts. Lappin and Garner [9]
had reviewed literature comparing
pharmacokinetics at a microdose with a
therapeutic. They concluded that of the 18
drugs reported, 15 demonstrated linear
pharmacokinetics within a factor of 2
between a microdose and a therapeutic
dose. There are currently a total 35
compounds where microdose and
therapeutic dose data have been compared
(oral, intravenous, human and animal)
[10]. Of these 35 compounds (human and

Data of microdose studies are helpful in
establishing likely pharmacological
dose and thereby determining the first
dose for the subsequent phase-1 study.
• Data of microdose studies are helpful in
selection of best animal species for long
term toxicology studies.
• It may be an attractive approach for the
study of new and existing drugs in
vulnerable populations (children,
pregnant women, elderly, hepatically
and renally impaired), who are
routinely excluded from clinical trials
due to safety concerns.

References
[1] Tonkens R. An Overview of the
Drug Development Process. The
Physician Executive, 2005, 31:48-
52.

[2] Morgan S, Grootendorst P, Lexchin
J, Cunningham C, Greyson D. The
cost of drug development: a
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2011, 100(1):4-17.

[3] Kubinyi H. Drug research: myths,
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Discov., 2003, 2(8):665-8.

[4] Wang J, UrbanThe L. The impact of
early ADME profiling on drug
discovery and development strategy.
Drug Discovery World Fall, 2004,
73-86.

[5] ICH Harmonised Tripartite
Guideline. Guidance on Nonclinical

• Experience with microdosing studies
are emerging; and as of today, it has
been used for BDDCS
(Biopharmaceutical Drug Disposition
and Classification System) class 1 drug
only. No information exists for
experience with other BDDCS class
drugs.

Safety Studies for the Conduct of
Human Clinical Trials and
Marketing Authorization for
Pharmaceuticals. Step 4 Version, 11-
June-2009.

[6] Lappin G, Garner RC. Big physics,
small doses: the use of AMS and
PET in human microdosing of
development drugs. Nat. Rev. Drug
Discov., 2003, 2(3):233-40.

[7] Harada Y. A New Movement in Drug
Development Technology –
Microdosing and its challenges.
Quarte. Rev., 2011, 40:9-20.

[8] Bergstrom M, Grahnen A,
Långstrom B. Positron emission
tomography microdosing: a new
concept with application in tracer
and early clinical drug development.
Eur. J. Clin. Pharmacol., 2003,
59(5-6):357-66.

[9] Lappin G, Garner RC. The utility of
microdosing over the past 5 years.
Expert Opin. Drug Metab. Toxicol.,
2008, 4(12):1499-506.

[10] Lappin G, Noveck R, Burt T.
Microdosing and drug development:
past, present and future. Expert
Opin. Drug Metab. Toxicol., 2013,
9(7):817-34.

[11] Committee for Medicinal Products
for Human Use (CHMP), European
Medicines Agency. Position Paper
on Non-clinical Safety Studies to
Support Clinical Trials with a Single
Microdose. 2004.

[12] U.S. Department of Health and
Human Services, Food and Drug
Administration, Center for Drug
Evaluation and Research (CDER).
Guidance for Industry, Investigators
and Reviewers Exploratory IND
Studies. January 2006.