Microdosing - Phase 0 Studies

Rakesh Kr. Rishi

Abstract: New drug development is a long, complex and expensive activity. Surveys over the past 10 years have shown that whereas R & D expenditure is increasing almost exponentially, the number of new drugs being introduced in market is either static or declining. Evaluating the safety and efficacy of a successful human medicine involves many animal studies, which can sometimes be subjected to considerable suffering and distress. Safety, efficacy and toxicology failures are responsible for failures in drug development. Another important reason for drug failures in the development phases is suboptimal pharmacokinetics. Efficacy failure could either result due to low concentration of drug at the target site in the body or drug reaching the target in an inappropriate amount of time. Safety failures may be due to the wrong concentration reaching the wrong target for too long a time period. Toxicity failures in animal studies may be due to metabolic processes or pathways that do not occur in humans. It is very important to understand the pharmacokinetic profile of a new chemical entity (NCE) in its early stage of development to determine whether NCE can be transformed into a drug or not. Animal studies and in vitro methods are conventionally used for studying drug metabolism pathways prior to human studies. Also, it is necessary to extrapolate data on pharmacokinetics from in vitro and animal studies to humans. However, it is not always necessary that a candidate drug would show the same response in humans as it showed in animal models. While using candidate drug in humans for the first time, there is always a concern that pharmacokinetic profile might be different from the animal studies.
Phase 0 Studies
The phase 0 or microdosing or exploratory investigational new drug (IND) studies are done for obtaining clinical information on a newly discovered molecule in the early clinical developmental phase. During pharmaceutical development, large numbers of molecules are generated with the goal of identifying the most promising candidates for further development. These molecules are generally structurally related, but can differ in several ways. Promising candidates are often selected using in vitro testing models that examine binding to receptors, effects on enzyme activities, toxic effects, or other in vitro pharmacologic techniques. Candidates that are not rejected during these early tests proceed to in vivo animal testing for efficacy and safety. Commonly, a single candidate is selected for an IND application and introduction into human subjects, initially healthy volunteers in most cases.

The microdosing studies help in identifying the best candidates for further development and eliminate those which do not hold promise. These studies are done at very early stage of Phase 1 clinical trial and involve very limited human exposure which have no therapeutic or diagnostic intent. Microdosing is a method for studying the in vivo behaviour of INDs through administration of doses so small that they are unlikely to produce whole-body effects, but large enough to elicit the cellular response to be studied. Thus, it is possible to see the pharmacokinetic profile of the IND with almost no risk of adverse effects. It is usually done before testing on animals to predict whether a drug is viable for the next phase of testing. This allows only best drug candidates to advance further, which is more expensive and extensive clinical development. Microdosing studies are conducted prior to the traditional dose escalation, safety, and tolerance studies and provide vital information on pharmacokinetics and bioavailability of a prospective drug.


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