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 nonclinical drug development. Patients, physicians and pharmaceutical sponsors alike are looking for more effective and safer medicines to be developed faster and also have improved costeffectiveness (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 As a matter of fact, around 40% of the newly developed drugs are withdrawn after phase 1 clinical trial because of undesirable pharmacokinetic properties (Lappin and Garner, 2003).

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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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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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