Talking R&D: Microdosing studies
pharmafile | January 18, 2010 | Feature | Research and Development | Microdosing, Talking R&D, Xceleron
A microdose study is performed at an early stage of development in order to obtain preliminary pharmacokinetic or distribution data on a drug candidate in human volunteers.
As its name implies, the dose administered in a microdose study is very small, the amount being defined by both the EMEA and FDA as 100th of the predicted pharmacologic dose or 100 Ìg whichever is the smaller [1-3]. These low doses are considered inherently safer than pharmacologically active doses and therefore the regulatory authorities will approve human microdose studies based upon a much reduced preclinical safety evaluation.
This enables the drug candidate to be administered to human volunteers earlier and with less expenditure compared to a phase-1 clinical study as only around 10-20 g of drug substance is required and full GMP quality is not necessary [4]. Microdosing therefore circumvents many of the obstacles to the administration of drugs at proposed therapeutic dose levels to humans at an early stage of drug development. Microdosing studies however, should have no pharmacologic effect on the subjects and are used solely to gain information on the metabolism and pharmacokinetics of a candidate drug in humans, albeit at very low concentrations. The technique tends to be applied when there is doubt over the ability of more traditional methods, such as PB-PK modelling or allometric scaling to predict what the pharmacokinetics might be once the molecule is administered to humans.
There has been some debate about how well the pharmacokinetics observed at such low doses will extrapolate to those expected at the higher clinically-relevant doses. There is however, a growing body of evidence that now shows that the technique is better than 80% predictive [5].
Assisting development decisions
Knowledge of the pharmacokinetics of a drug candidate in humans can be pivotal to the decision on whether take the compound forward into full development. For example, low bioavailability may be seen in humans that was not detected in animals models [6]. A rapidly cleared drug may require more frequent dosing than one with a lower clearance. Knowledge of the likely systemic concentrations of drug over time can be critical particularly when developing a drug with a low therapeutic index or with anti-infectives to ensure levels are in excess of the Minimum Inhibitory Concentration over sufficient time periods. Early knowledge of a drug’s absorption profile and systemic concentrations are important to understanding the likely clinically-relevant dosages and dosing regimen. Preliminary pharmacokinetics from human microdose studies may add confidence to the choice of doses in the Single Ascending Dose studies, which otherwise can be difficult to judge. In addition, an understanding of the likely dose range and regimen, can enable an estimate of the cost of manufacturing to be made, which may reduce the rate of attrition on economic grounds.
The role of biopsies
A common inclusion in microdose study design is the collection of biopsy samples. Although there are clearly ethical limitations on what biopsies can be taken, by using state of the art, highly sensitive analytical technologies such as Accelerator Mass Spectrometry, biopsy collection can be facilitated by reducing the size of the sample to 1-2 mg. In this way, lung [7] cerebrospinal fluid, skin and other samples have been analysed thereby ensuring the active drug reaches the site of action, not just in the animal models but also in humans.
Where the pharmacokinetics of a drug is a key parameter in the success of its future development, microdosing has proven to be a powerful tool for the selection of the most appropriate candidate by using human data at the earliest possible stage.
References
1. EMEA, Position Paper on Non-clinical Safety Studies to Support Clinical Trials with a Single Microdose. Position paper CPMP/SWP/2599, 23 June 2004. 2004.
2. FDA US Department of Health and Human Services Guidance for Industry Investigators and Reviewers. Exploratory IND Studies. January 2006. 2006.
3. ICH Topic M3 Note for Guidance on non-clinical safety pharmacology studies for human pharmaceuticals CPMP/ICH/286/95(December 2009).
4. Lewis, D.F., Early human studies of investigational agents: dose or microdose. Br J Clin Pharmacol, 2009. 67(3): p. 277-279.
5. Lappin, G. and Garner, C., The utility of microdosing over the past 5 years. Expert Opin Drug Metab Toxicol, 2008. 4(12): p. 1499-1506.
6. Lappin, G., Kuhnz, W., Jochemsen, R., Kneer, J., Chaudhary, A., Oosterhuis, B., Drijfhout, W.J., Rowland, M., and Garner, R.C., Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs. Clin Pharmacol Ther, 2006. 80(3): p. 203-215.
7. Lappin, G., Warrington, S., Honeybourne, D., Sanghera, D., Dowen, S., Lister, N., Islam, K., and Lociuro, S., Concentrations of AR-709 in plasma and key compartments of the lungs after microdosing, in Poster presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy. 2007: Chicago, USA.
Contact: Dr Graham Lappin, PhD CBiol FIBiol FRSC
Senior Director of Science and Technology, Xceleron, 20340 Seneca Meadows Parkway, Germantown, MD 20876, USA
graham.lappin@xceleron.com
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