THE MICRODOSE CONCEPT

Presenter: Professor Colin Garner BPharm PhD DSc FRCPath

CEO, Xceleron Ltd, York, UK

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A new product development
tool kit .is urgently needed
to improve predictability and
efficiency along the critical
path

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SUB-OPTIMAL PHARMACOKINETICS IS A COMMON
REASON FOR DRUG FAILURE

OUR INDUSTRY CONTACTS STATE THAT HUMAN ADME/PK

PREDICTION IS INCORRECT IN APPROXIMATELY
25-30% OF CASES!

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THE AMS TECHNOLOGY

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 AMS counts atoms and not radioactivity

Carbon-14 = isotope of choice

For ease of understanding
for AMS drugfor biomedical
researchers
analysis
AMS data is expressed as DPMs
Many other elemental isotopes
can be analysed
AMS is the most sensitive analytical technique ever developed and
has been used to measure drugs, metabolites, proteins, peptides
and endogenous molecules

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 Accelerator Mass Spectrometry (AMS) detects
molecules at unprecedented levels of sensitivity
Liquid scintillation counting 10-9 g nanograms

Competitor immunoassay

Mass Spectrometry 10-12 g picograms

Only AMS has the

necessary analytical
sensitivity for femtograms
10-15 g
microdosing and
ultralow label
studies
10-18 g attograms
Accelerator Mass
Spectrometry

10-21 g
zeptograms
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 RADIOACTIVE DOSES

Typical radioactive dose in a conventional

study = 80 to 100 Ci per person

Typical radioactive FDA

dose Regulatory issue study
in an AMS
= 100 nCi per person
Is there a de minimis level of 14C
that can be administered to humans
in theThe average
USA without person
animal contains
dosimetry
studies under 21CFRPart361?
ca 400 nCi naturally-occurring 14C

The average person contains

ca 50 nCi naturally-occurring 40K

A banana contains about 1 nCi 40K

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 HUMAN MICRODOSING GOING FROM
LAB BENCH TO CLINIC IN FOUR MONTHS

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 WHAT IS MICRODOSING?
Designed to obtain early human ADME/PK with
minimal preclinical toxicology

No pharmacological/toxic effect should be

manifest

No human safety/efficacy information obtained

Requires radioisotopes and ultrasensitive

analytical procedures eg AMS or PET

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 EARLY CANDIDATE SELECTION
CURRENT PROBLEM

Although many improvements in recent years,

still limited information from in vitro and animal
models to predict events in humans

Lack of predictivity of allometric scaling?

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CURRENT REGULATORY POSITION

FDA regulatory issue

Is the Agency minded to

update 21CFR361 to
include NCEs?

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 WHAT IS A MICRODOSE?

EMEA definition
FDA Regulatory
1/100th of pharmacological dose issue
based on animal
data / in vitro systems OR a dose
Can 21CFRPart361 in or below the low
include
microgram range but mention
specific not to exceed 100 micrograms
of microdosing
as per the EMEA definition?

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TOXICOLOGY PACKAGE FOR MICRODOSE
STUDIES

Single dose 7 day acute study in rat with histopathology

3 male, 3 female, iv & route of human exposure
Either 100 or 1000-fold safety factor

48 h, CVS in dog, 2 male 2 female, iv, telemetered or ECG,

100-fold safety factorFDA regulatory issue
What preclinical toxicology
package
Ames test - abridged couldorbe
protocol used to
OECD
support microdosing studies
under 21CFR Part 361?
Abridged human lymphocyte chrom abs abridged
protocol or OECD

In vitro metabolism studies rat and human plus plasma

protein binding

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 REGULATORY ISSUES
TO BE CONSIDERED

Can microdose studies on NCEs be covered by 21CFR

Part361

Is AMS a technology that meets the Critical Path initiative of

accelerating drug development?

NEXT STEPS?
Are there scientific/regulatory reasons why AMS should not
be used for all human volunteer radioactive studies
(ALARA or ALARP)

Are microdosing studies safer for FIH than current

Phase I procedures?

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