the microdose concept presenter: professor colin garner bpharm phd dsc frcpath ceo, xceleron ltd,...

THE MICRODOSE CONCEPT

Presenter: Professor Colin Garner BPharm PhD DSc FRCPath CEO, Xceleron Ltd, York, UK

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Xceleron Ltd – all rights reserved ©2004

A new product developmenttool kit ….is urgently neededto improve predictability andefficiency along the critical path

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SUB-OPTIMAL PHARMACOKINETICS IS A COMMONREASON FOR DRUG FAILURE

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OUR INDUSTRY CONTACTS STATE THAT HUMAN ADME/PK PREDICTION IS INCORRECT IN APPROXIMATELY

25-30% OF CASES!

THE AMS TECHNOLOGY

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AMS counts atoms and not radioactivity

For ease of understanding for biomedical researchers AMS data is expressed as DPMs

AMS is the most sensitive analytical technique ever developed andhas been used to measure drugs, metabolites, proteins, peptides

and endogenous molecules

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Carbon-14 = isotope of choicefor AMS drug analysis

Many other elemental isotopescan be analysed

Accelerator Mass Spectrometry (AMS) detects molecules at unprecedented levels of sensitivity

10-9 g

10-12 g

10-15 g

10-18 g

10-21 g

Liquid scintillation counting

Competitor immunoassay

Mass Spectrometry

Accelerator Mass Spectrometry

nanograms

picograms

femtograms

attograms

zeptograms

Only AMS has thenecessary analytical

sensitivity for microdosing and

ultralow label studies

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RADIOACTIVE DOSESRADIOACTIVE DOSES

Typical radioactive dose in a conventionalstudy = 80 to 100 µCi per person

Typical radioactive dose in an AMS study= 100 nCi per person

The average person containsca 400 nCi naturally-occurring 14C

The average person containsca 50 nCi naturally-occurring 40K

A banana contains about 1 nCi 40K ®


FDA Regulatory issue

‘Is there a de minimis level of 14C that can be administered to humans in the USA without animal dosimetry

studies under 21CFRPart361?’

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 SELECTIONCURRENT 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

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FDA regulatory issue

‘Is the Agency minded toupdate 21CFR361 to

include NCEs?’

WHAT IS A MICRODOSE?

EMEA definition1/100th of pharmacological dose based on animal data / in vitro systems OR a dose in or below the low microgram range but not to exceed 100 micrograms

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FDA Regulatory issue

‘Can 21CFRPart361 include specific mention of microdosing

as per the EMEA definition?’

TOXICOLOGY PACKAGE FOR MICRODOSESTUDIES

Single dose 7 day acute study in rat with histopathology3 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 factor

Ames test - abridged protocol or OECD

Abridged human lymphocyte chrom abs – abridged protocol or OECD

In vitro metabolism studies rat and human plus plasmaprotein binding

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FDA regulatory issue

‘What preclinical toxicologypackage could be used to

support microdosing studiesunder 21CFR Part 361?’

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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?

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 currentPhase I procedures?

NEXT STEPS?

the microdose concept presenter: professor colin garner bpharm phd dsc frcpath ceo, xceleron ltd,...

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