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1. Optimizing drug discovery through microdosing
Defining a microdose
The EMEA Position Paper defines the human microdose as the 1/100th of the dose calculated to
yield a pharmacological effect of the compound based on primary pharmacodynamic data obtained
from animal and in vitro models. According to the EMEA guidelines, the total amount of drug
compound(s) being tested and administered in a human microdosing study must not exceed 100
micro grams.
Microdosing in optimizing drug discovery
Advances in areas of combinational chemistry, molecular and cell biology, high throughput
technology and strong economic forces have lead to greater competition and rapid changes in non-
clinical drug development. Patients, physicians and pharmaceutical sponsors alike are looking for
more effective and safer medicines to be developed faster and also have improved cost-
effectiveness (Lesko et al., 2000).
Reigner et al. (1996) have explained that predictive power of preclinical drug metabolism has
advanced due to a considerable betterment in the understanding of the relationships between in
vitro, animal and human pharmacokinetics. They further emphasize that focussed application of
pharmacokinetics and pharmacodynamics has improved the efficacy of the drug development
process in the pharmaceutical industry. Microdosing has proven to be an effective method to
understand the pharmacokinetic and pharmacodynamic behaviour of new drugs in humans.
Microdosing has hastened the pharmaceutical preclinical to clinical translation involved in the drug
development process. Pang, Rodrigues and Peter (2009, p. 363) elucidate that microdosing has not
been developed to determine the safety or efficacy of test compounds when administered to
humans. The main purpose of human microdosing studies is to determine key pharmacokinetic
parameters in reaction to very small doses of a new drug being tested.
Advent of microdosing
Drug discovery is a long drawn process that involves preclinical pharmacological testing and clinical
application in animals and then humans, before drugs can be certified for normal dosage and
prescription. Considering the fact that microdoses help decipher the pharmacokinetics in humans
for varied newly developed pharmaceutical compounds, large amount of resources in the form of
time, energy and money need not be invested into a new drug candidate that is unsuccessful at
this level itself.
As a matter of fact, around 40% of the newly developed drugs are withdrawn after phase 1 clinical
trial because of undesirable pharmacokinetic properties (Lappin and Garner, 2003).
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2. Accordingly, a phase 0 testing has been introduced before the traditionally followed phase 1 clinical
trial in humans. Through this, microdosing can be performed in human volunteers in phase 0
following minimal trials in animals. Based on the performance and pharmacokinetic behaviour
during this stage, failure drugs can be easily identified and eliminated at the earlier stages without
wasting much of time and energy in further drug development and testing, On the other hand,
microdosing also helps identify the more promising drug compounds from a pool that could be
further explored and developed to achieve desired clinical results in humans when they are tested
at later stages of drug development. Sarapa (2003) highlights that two of the most important
positive outcomes of performing phase 0 studies by administering microdoses to humans are the
reduction in time and resources wasted in prolonged further testing and reduced attrition during
drug testing.
Concentration of microdoses
A microdose is usually 100 times less concentrated than the medication that would be administered
once tested and verified. This way the concentration of the newly developed drug entering the
human system would be well less than 1/100 concentration of the drug. This is less liable to
produce any harm to the human volunteers during testing.
>> Read more on:
• Microdose synthesis
• Administration of Human microdose
• Bio analysis post microdosing
• Advantages of Microdosing
• Limitations of Microdosing
• Microdosing in drug development
• Regulations for microdosing
• Conclusion
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3. References
European Agency for the Evaluation of Medicines for Human Use (EMEA). Position Paper on the
Nonclinical Safety Studies to Support Clinical Trials with a Single Microdose. CPMP/SWP2599/02,
28 January 2003.
Food and Drug Administration Guidance for Industry: Single Dose Acute Toxicity Testing for
Pharmaceuticals. Center for Drug Evaluation and Research, August 1996.
Lappin, G., Garner, R. C., Big Physics, Small Doses: The Use of AMS and PET in Human
Microdosing of Development Drugs. Nature Reviews Drug Discovery. 2003. Vol. 7. p. 233.
Lappin, G., Garner, R., C. (2008). The utility of microdosing over the past 5 years. Expert Opin
Drug Metab Toxicol, vol.4, pp. 1499-1506.
Lesko, L. J., Rowland, M., Peck, C. C., Blaschke, T. F. Optimizing the Science of Drug
Development: Opportunities for Better Candidate Selection and Accelerated Evaluation in Humans.
Pharmaceutical Research 2000. Vol. 17. p.1335.
Pang, K. S., Rodrigues, A. D., Peter, R., (2009). Enzymatic-and Transporter-Based Drug-Drug
Interactions: Progress and Future Challenges. pp. 363- 365. New York: Springer Publishing
company.
Reigner, B. G., Williams, P. E. O., Patel, I. H. et al. Integration of PK/PD has Improved Recent
Roche Drug Development. Clinical Pharmacology and Therapeutics. 1996. Vol. 59. p. 191.
Sarapa, N. (2003). Early Human Microdosing to Reduce Attrition in Clinical Drug Development.
APO, September/ October 2003, Vol.4, Issue 5, pp. 42-47.
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