Transcript Slide 1

“microdosing” in Google: first 4 hits
Gesponsorde Koppelingen
U.S. Microdosing Studies
www.acciumbio.com
FDA Exploratory-IND Services; Predict failure and success now!
Microdosing - Wikipedia, the free encyclopedia
Microdosing is a technique for studying the behaviour of compounds in vivo through
the administration of doses so low they are unlikely to produce ...
http://en.wikipedia.org/wiki/Microdosing - 19k
Xceleron - Microdosing
Human microdosing (Human Phase 0) is a new concept which relies on the
ultrasensitivity of accelerator mass spectrometry (AMS). ...
http://www.xceleron.co.uk/index.pl?id=2188 - 20k
Human microdosing proves its value in drug R&D
Human microdosing proves its value in drug R&D Xceleron has announced the
long-awaited results of the CREAM trial into human microdosing in drug development ...
http://www.drugresearcher.com/news/ng.asp?n=58575-human-microdosing-proves - 46k
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What is Microdosing ?
Microdosing
From Wikipedia, the free encyclopedia
Microdosing is a technique for studying the behaviour of compounds
in vivo through the administration of doses so low they are unlikely
to produce whole-body effects. . . . . 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 done before testing on
animals to predict whether a drug is viable for the next phase of
testing. This is lowering the cost spent on non viable drugs and the
amount of testing done on animals . . . .
...
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Conducting a human Phase 0
microdose study
Experiences at PRA EDS in The Netherlands
Berend Oosterhuis
Scientific Director EDS NL
PRA International
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workshop AGAH 19 April 2008
Selecting the human dose (1)
• EMEA / FDA definition of microdose:
“In the current context, the term ‘microdose’ would
be less then 1/100th of the dose calculated to yield
a pharmacological effect of the test substance based on
primary pharmacodynamic data obtained in vitro and in vivo
(typically doses in or below the low microgram range)
and at a maximum dose of 100 microgram.”
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Selecting the human dose (2)
• Difficulties with EMEA / FDA definition
– 100 microgram as upper limit is arbitrary
– calculation/prediction of human pharmacological dose often
uncertain
• Guiding suggestions:
– aim for (free) plasma concentrations ≤ 2 x EC50 or scaled dose
≤ 2x ED50 in most reliable pharmacological test/animal model
– include in pharmacology tests known related agonists as
“bench mark”
– bottom line: any dose acceptable if supported by “clean”
toxicology, including safety factor single dose tox study
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Supporting toxicity studies(2)
• Microdose tox program agreed between PRA and
Ethics Committee (late 2003)
• Single dose 100 x human microdose in rats with 8 days
observation
–
–
–
–
iv and intended human route (n=6 per route)
biochemistry on days 2 and 8
animals sacrificed on day 8
gross necropsy, limited histopathology
• Abridged genotoxicity (optional)
• Comparative in vitro metabolism; microsomes or hepatocytes
• Single i.v. dose CV safety in dogs (100 x microdose)
– 48h observation cardiovascular parameters
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Supporting toxicity studies(2)
• Microdose tox program agreed between PRA and
Ethics Committee (late 2003)
Human dose
Safety
(µg) in rats with
factor
• Single dose 100 x human microdose
8 days
observation
200
200
– iv and intended human route (n=6 per route)
300
300
– biochemistry on days 2 and 8
– animals sacrificed on day 8
400
400
– gross necropsy, limited histopathology
….
• Abridged genotoxicity (optional)
• Comparative in vitro metabolism; 1000
microsomes 1000
or hepatocytes
>1000x microdose)
1000
• Single i.v. dose CV safety in dogs (100
– 48h observation cardiovascular parameters
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Supporting toxicity studies(3)
• Varations accepted by Ethics Committee, e.g.
– 14 days observation with interim sacrifices on day 2
(doubling the number of animals)
– 1000x safety factor and hERG instead of CV safety in dogs
• What is a ‘clean’ tox study ?
– slight ‘no adverse’ effects in single dose tox study
acceptable, especially if 1000x safety factor
• Microdose-toxicology programs (GLP) often
outsourced by Sponsor
– lack of internal flexibility?
– most programs were conducted at NOTOX, Netherlands
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Supporting toxicity studies(3)
• Varations accepted by Ethics Committee, e.g.
– 14 days observation with interim sacrifices on day 2
(doubling the number of animals)
– 1000x safety factor and hERG instead of CV safety in dogs
total time for tox program:
• What is a ‘clean’ tox study ?
10-12 weeks from receipt
– slight ‘no adverse’ effects in single dose tox study
acceptable,
especially if 1000x safety factor
test substance/documentation
to draft
reports
• Microdose-toxicology programs (GLP) often
outsourced by Sponsor
– lack of~7
internal
gram flexibility?
of test substance required
– most programs were conducted at NOTOX, Netherlands
per compound
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CMC aspects and IMP “manufacturing”(1)
• Should drug substance (API) for human microdose
be manufactured under GMP?
– not addressed in EMEA position paper
– FDA exploratory IND allows same batch as in toxicology
studies
– MHRA (UK) allows “GLP quality”
– radiolabelled substance (for AMS): not drug substance but
(novel) excipient (CoA and some other data needed)
– don’t mix drug substance and radiolabelled substance
before manufacturing of IMP
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CMC aspects and IMP “manufacturing”(1)
• Should drug substance (API) for human microdose
be manufactured under GMP?
– not addressed in EMEA position paper
– FDA exploratory IND allows same batch as in toxicology
studies
– MHRA (UK) allows “GLP quality”
– -> no GMP but concise CMC description needed in IMPD
amounts needed for entire study:
– radiolabelled substance (for AMS): not drug substance but
“cold” compound
50-100
mgneeded)
(novel) excipient
(CoA and some
other data
– don’t compound
mix drug substance
and radiolabelled
labelled
corresponding
withsubstance
20-30 µCi
before shipment to PRA (ship separately)
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CMC aspects and IMP “manufacturing”(2)
• Manufacturing of “drug product” on site !
– manufacturing under GMP: manufacturing licence and QP
release at clinical site
– on the morning or day before dosing to subjects
– high risk of adsorption losses during preparation and dosing
– always run test preparations and mock administrations
– analytical testing of at least “hot” dose by LSC
– select best composition, procedures and materials for
vessels, syringes, infusion lines
– keep samples to assess actually administered doses during
study
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CMC aspects and IMP “manufacturing”(3)
• Keep the IMPD (and IB) lean and functional
– IMP documentation in CTA can be IB + “IMPD-Addendum”
containing the CMC data
– Drug Product section to describe how “product” will be
manufactured, control parameters for test batch, which
specifications should be met
– test batch preparation usually after CTA submission
– -> Drug Product section may need amendment based on outcome
of test preparation results
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CMC aspects and IMP “manufacturing”(3)
• Keep the IMPD (and IB) lean and functional
– IMP documentation in CTA can be IB + “IMPD-Addendum”
containing the CMC data
– Drug Product section to describe how “product” will be
manufactured, control parameters for test batch, which
specifications should be met
– test batch preparation usually after CTA submission
we have seen considerable delays
– -> Drug Product section may need amendment based on outcome
from
internal SOPs and
of test preparation
results
requirements by Sponsor’s
regulatory group
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Particulars about the clinical study
• For radioactive doses ≤ 1 μCi:
– “trivial” radiation burden ICRP-62 (<< 0.1 mSv)
– no (animal studies to support) dosimetry required
• Conduct study outside area for normal radiolabel studies
– to avoid contamination of subjects and samples
• Screening of subjects for background radioactivity ?
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Bioanalysis and role of AMS(1)
• LC-MS/MS
– >100 x more sensitive than ‘classical’ HPLC: picogram/mL range
– can provide parent vs. metabolite/structure information
– no 14C radiolabeled compound required
• Accelerator Mass Spectrometry (AMS)
– ultrasensitive: femtograms (10-15 g/mL) and below
– 14C radiolabeled compound required (50-200 nanoCurie)
• Only a few providers for AMS worldwide
–
–
–
–
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Xceleron, York UK and Gaithersburg USA
Accium Biosciences, Seattle, USA
Vitalea Sciences, USA
IAA, Tokyo, Japan
Bioanalysis and role of AMS (2)
• AMS “counts”
–
14C
14C-atoms
radiolabeled compound required (50-200 nanoCurie per dose)
• Samples converted to graphite before AMS
– direct AMS only gives total 14C content
– off-line HPLC separation of parent compound and metabolites
• Verification of HPLC separation by “fractionation”
– need certainty about full separation of parent !
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Bioanalysis and role of AMS (3)
LC-AMS parent vs. metabolite separation of diazepam
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Bioanalysis and role of AMS (4)
diazepam: total radioactivity and parent concentration-time profile
10.00
Diazepam IV microdose
Parent IV m icrodose
ng/mL
C-14 IV m icrodose
Profile
1.00
14C
Parent
0.10
0
20
40
80
60
Time (h)
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100
120
140
Concluding remarks
• planned human microdose supported primarily by
‘clean’ tox study with safety factor (100-1000x) single
dose in one species
• no clear rationale for 100 microgram upper limit
• pharmaceutical procedures to administer the right
dose are critical
• AMS is unique analytical tool; off-line separation of
parent is essential
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Conducting a human
Phase remarks
0 microdose study
Concluding
Time-critical activities
Parallel activities
Minimal
time
Amount of
substance
Reduced toxicity program
Radiosynthesis
CMC and IMPD
12 weeks
7 gram
Compilation CTA dossier
Writing IB, protocol,
subject information
3 weeks
CTA approval
Test batch IMP and QC
2 weeks
Clinical Study +
recruitment/screening
First samples to AMS
lab; setup LC-AMS
5 weeks
< 0.5 gram
20-30 µCi 14C
LC-AMS and assay of
samples
Initiate PK evaluation
6 weeks
< 0.1 gram
< 5 µCi 14C
Draft PK report
1 week
Total
29 weeks
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~ 7.5 gram
25-35 µCi 14C
Conducting a human
Phase remarks
0 microdose study
Concluding
Time-critical activities
Parallel activities
Minimal
time
Amount of
substance
Reduced toxicity program
Radiosynthesis
CMC and IMPD
12 weeks
7 gram
Compilation CTA dossier
Writing IB, protocol,
subject information
3 weeks
DoTestyou
consider
batch IMP and QC 2 weeks
microdosing?
Clinical Study + screening
First samples to AMS
5 weeks
lab; setup LC-AMS
! 4 weeks
LC-AMS and assay of
InitiateKISS
PK evaluation
CTA approval
samples
(keep it small and simple)
Draft PK report
1 week
Total
27 weeks
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< 0.5 gram
20-30 µCi 14C
< 0.1 gram
< 5 µCi 14C
~ 7.5 gram
25-35 µCi 14C