microdosing

Drug development is a time-consuming and expensive process. There is tremendous sense of urgency for the pharmaceutical industry to develop new tools to accelerate the drug development process and to reduce attrition rate on drug candidates.

Microdosing is a tool in the early drug development. The term Phase 0 is therefore often used to refer to such studies. Dose needs to administer in microdosing study is less than 1/100 of the test substance calculated to yield a pharmacologic effect, with a maximum dose of 100 μg.

The FDA in 2006 issued a guidance document on exploratory Investigative New Drug detailing the regulatory process for microdosing clinical studies (FDA Guidance ). These studies helps to understand the bioavailability and pharmacokinetic profiles of test compounds in human, to evaluate the metabolic profiles in human or to obtain the information on the tissue distribution of test compounds in human by using molecular imaging technology.

Microdosing can be useful in the discovery of endogenous biomarkers, which would assist in the quantitative evaluation of the in vivo effects of drugs. Since the dose is sub-therapeutic level, the potential for adverse side effect to a human subject in the clinical study is considered to be minimal. The preclinical toxicology required to support microdosing is minimal. Furthermore, if human screening of compounds is done earlier in the drug development process, fewer animal studies are required before Phase I clinical trials. Therefore, animal studies can be avoided with compounds having unsuitable pharmacokinetic (PK) profiles. Hence these studies can be used as a candidate selection tool to effectively eliminate drug candidates that show sub-optimal human PK before spending time and effort in the kind of extensive toxicology that is required prior to conventional Phase 1. Ultrasensitive bioanalytical equipment and techniques are obviously required, but the substantial cost and time savings from early elimination of unviable compounds may more than justify the investment. When the drug discovery process yielded a single molecule, microdosing can still be useful in such circumstance. It can quickly establish if it is worth taking the molecule forward prior to committing large-scale resources to a full Phase I study. Sometimes a metabolic pathway is identified in human hepatocytes or liver microsomes, which is not seen in animals. Microdosing may be used to establish if the metabolic pathway occurs in vivo.

 The fundamental strengths of microdosing, improved safety, reduced cost, and time to developmental decisions, are likely to get only stronger. The concept has been widened from a purely pharmacokinetic predictive method towards addressing other questions, such as drug-drug interactions, polymorphism and looking at whether a drug is likely to reach its site of action. Microdosing study data with modelling may lead to much more reliable predictions for drug candidate selection.

There are limitations in microdosing technique. At therapeutic dose level drug may exhibit limited solubility, and absorption becomes dependent on the rate and extent of dissolution, which cannot be predicted at microdose levels since drug candidate could dissolve readily at microdose, yielding good PK. Also this study may not be able to predict nonlinear pharmacokinetic characteristics of the drug at therapeutic dose level. Microdosing study needs very sensitive analytical methods to measure circulating drug levels in blood as a function of time.

FDA_IND

FDA Guidance

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