Microdosing
Encyclopedia
Microdosing is a technique for studying the behaviour of drugs in humans through the administration of doses so low ("sub-therapeutic") they are unlikely to produce whole-body effects, but high enough to allow the cellular response to be studied. (Note that while this is the most common definition, the term also is used to refer to instruments for dispensing full therapeutic amounts of active pharmaceutical ingredient (API), as in direct "API-into-Capsule" technology. http://capsugel.com/media/library/micro-dosing-equipment-fills-niche-in-randd-clinical-trial-materials.pdf) This allows us to see the Pharmacokinetics
of the drug with almost no risk of side effects. This is called a Phase 0 study and is usually conducted before clinical Phase I to predict whether a drug is viable for the next phase of testing. Human Microdosing aims to reduce the resources spent on non-viable drugs and the amount of testing done on animals.Different than microdispensing
.
The basic approach is to label
a candidate drug using the radioisotope
carbon-14
, and then administer the compound to human volunteers at levels typically about 100 times lower than the proposed therapeutic dosage (from around 1 to 100 microgram
s but not above). How the body responds – for example, its conversion of the original drug into other molecules, and how long they stay in the body. The amount of radioactivity administered is typically around 200 nano Curies, which is low as to be considered 'non-radioactive' by authorities.
As only microdose levels of the drug are used, analytical methods are limited. Extreme sensitivity is needed. AMS accelerator mass spectrometry
is the most common method for microdose analysis. AMS arose in the late 1970s from two distinct research threads with a common goal: an improvement in radiocarbon dating that would make efficient use of datable material and that would extend the routine and maximum reach of radiocarbon dating. AMS is routinely used in geochronology and archaeology, but biological applications began appearing in 1990 mainly due to the work of scientists of Lawrence Livermore National Laboratory. AMS service is now more accessible for biochemical quantitation from several private companies and non-commercial access to AMS is available at the National Institutes of Health (NIH) Research Resource at Lawrence Livermore National Laboratory, or through the development of smaller affordable spectrometers. AMS does not measure the radioactivity of carbon-14 in microdose samples. AMS, like other mass spectrometry methods, measures ionic species according to mass to charge ratio.
The technique has been developed commercially and in 2005, trials were conducted with several major pharmaceutical companies in the CREAM (Consortium for Resourcing and Evaluating AMS Microdosing) trials, in which microdosing was used to predict the behaviour of five drugs, each with idiosyncrasies that had proved problematic in animal testing. The results pointed to a 70 per cent correspondence between the results obtained using microdosing and those obtained from full-dose studies.
In 2006 an EU-funded Microdosing collaboration was formed to test the relationship between a microdose and therapeutic dose of another seven drugs.
It is reported that 15 of the 20 largest pharmaceutical companies have now used microdosing in drug development, and the use of the technique has been provisionally endorsed by both the European Medicines Agency
and the Food and Drug Administration
. Furthermore it is expected that by 2010, human microdosing will have gained a secure foothold at the discovery-preclinical interface driven by early measurement of candidate drug behavior in humans and by irrefutable economic arguments.
In January 2006, the European Union Microdose AMS Partnership Programme (EUMAPP) was launched. Ten organizations from five different countries (United Kingdom, Sweden, Netherlands, France and Poland) will study various approaches to the basic AMS technique. The study is set to be published in 2009.
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
of the drug with almost no risk of side effects. This is called a Phase 0 study and is usually conducted before clinical Phase I to predict whether a drug is viable for the next phase of testing. Human Microdosing aims to reduce the resources spent on non-viable drugs and the amount of testing done on animals.Different than microdispensing
Microdispensing
Microdispensing is the technique of producing liquid media dosages in volumes of less than one microlitre.The continuing miniaturization in almost all technical areas creates constant challenges for industry, development and research facilities. Microdispensing is one of those challenges...
.
The basic approach is to label
Label
A label is a piece of paper, polymer, cloth, metal, or other material affixed to a container or article, on which is printed a legend, information concerning the product, addresses, etc. A label may also be printed directly on the container or article....
a candidate drug using the radioisotope
Isotope
Isotopes are variants of atoms of a particular chemical element, which have differing numbers of neutrons. Atoms of a particular element by definition must contain the same number of protons but may have a distinct number of neutrons which differs from atom to atom, without changing the designation...
carbon-14
Carbon-14
Carbon-14, 14C, or radiocarbon, is a radioactive isotope of carbon with a nucleus containing 6 protons and 8 neutrons. Its presence in organic materials is the basis of the radiocarbon dating method pioneered by Willard Libby and colleagues , to date archaeological, geological, and hydrogeological...
, and then administer the compound to human volunteers at levels typically about 100 times lower than the proposed therapeutic dosage (from around 1 to 100 microgram
Microgram
In the metric system, a microgram is a unit of mass equal to one millionth of a gram , or 1/1000 of a milligram. It is one of the smallest units of mass commonly used...
s but not above). How the body responds – for example, its conversion of the original drug into other molecules, and how long they stay in the body. The amount of radioactivity administered is typically around 200 nano Curies, which is low as to be considered 'non-radioactive' by authorities.
As only microdose levels of the drug are used, analytical methods are limited. Extreme sensitivity is needed. AMS accelerator mass spectrometry
Accelerator mass spectrometry
Accelerator mass spectrometry differs from other forms of mass spectrometry in that it accelerates ions to extraordinarily high kinetic energies before mass analysis. The special strength of AMS among the mass spectrometric methods is its power to separate a rare isotope from an abundant...
is the most common method for microdose analysis. AMS arose in the late 1970s from two distinct research threads with a common goal: an improvement in radiocarbon dating that would make efficient use of datable material and that would extend the routine and maximum reach of radiocarbon dating. AMS is routinely used in geochronology and archaeology, but biological applications began appearing in 1990 mainly due to the work of scientists of Lawrence Livermore National Laboratory. AMS service is now more accessible for biochemical quantitation from several private companies and non-commercial access to AMS is available at the National Institutes of Health (NIH) Research Resource at Lawrence Livermore National Laboratory, or through the development of smaller affordable spectrometers. AMS does not measure the radioactivity of carbon-14 in microdose samples. AMS, like other mass spectrometry methods, measures ionic species according to mass to charge ratio.
The technique has been developed commercially and in 2005, trials were conducted with several major pharmaceutical companies in the CREAM (Consortium for Resourcing and Evaluating AMS Microdosing) trials, in which microdosing was used to predict the behaviour of five drugs, each with idiosyncrasies that had proved problematic in animal testing. The results pointed to a 70 per cent correspondence between the results obtained using microdosing and those obtained from full-dose studies.
In 2006 an EU-funded Microdosing collaboration was formed to test the relationship between a microdose and therapeutic dose of another seven drugs.
It is reported that 15 of the 20 largest pharmaceutical companies have now used microdosing in drug development, and the use of the technique has been provisionally endorsed by both the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
and the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
. Furthermore it is expected that by 2010, human microdosing will have gained a secure foothold at the discovery-preclinical interface driven by early measurement of candidate drug behavior in humans and by irrefutable economic arguments.
In January 2006, the European Union Microdose AMS Partnership Programme (EUMAPP) was launched. Ten organizations from five different countries (United Kingdom, Sweden, Netherlands, France and Poland) will study various approaches to the basic AMS technique. The study is set to be published in 2009.