Clinical studies utilizing Accelerator Mass
Spectrometry: Opportunities and challenges
of 14C radiolabelled microtracer study delivery
Iain Shaw
Director, 14C Enabled Drug Development
Quotient Clinical, Nottingham, UK
IIS Conference,
Princeton NJ, June 7-11th 2015
Scope
• Brief introduction to Quotient Clinical
• Microtracer opportunity
• Case study examples
• Summary
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About Quotient Clinical
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Full service, early development provider founded in 1990
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Unique Translational Pharmaceutics platform
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Expert formulation development
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Real-time GMP manufacturing
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85 bed clinical pharmacology unit
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Highly integrated operations in the UK
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Approx. 250 employees – “full service” capability
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International client base (approx. 55% US, 40% EU, 5% RoW)
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Clients range from top pharma to emerging biotechs
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Quotient Clinical Experience
• >65 molecules administered in
microdose and microtracer studies
since 2007
• >30 client companies
• >20 publications
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Opportunity
• Integrated microdose and microtracer studies create scientifically rich
opportunities to generate data to support drug development
• ICH M3 R2 provides a regulatory framework
• AMS facilitates the quantitative and qualitiative analysis of low dose
radioactivity in biological samples
• Unlike conventional ADME studies
• Low radioactive doses can be administered without dosimetry data
• Intravenous microtracers can be administered without IV toxicology
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What is an IV microtracer ?
• Oral therapeutic dose
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Measured by LC/MS:MS
‘cold’ drug at therapeutic
dose
when oral dose is at Tmax
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Measured by AMS
• ivMicrotracer is a flexible
development tool
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•
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Standalone study
Add to any early development
study
Add to ADME study
Drug Concentration
• ivMicrotracer dose administered
14C
ivMicrotracer
administered at
Tmax
Time (hr)
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Why do we generate intravenous data ?
Pharmaceutical
development
Clinical
pharmacology
• Allometric scaling
• Simulation & modelling
• Input and output drivers of
availability
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Sub-optimal PK
Formulation strategy
Absolute bioavailability
IVIVC
Development support & Regulatory submission
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Stand alone 14C-IVMT
An open-label, single dose study in a single cohort
of 6-8 healthy male subjects
SINGLE
PERIOD
Oral reference product
with an intravenous
microtracer 14C drug
product
Define oral and IV PK to
determine absolute
bioavailability
200 to 1000+ fold dose PO:IV dose ratio
IVMT as 15min infusion at oral Tmax
Requires LC-MSMS analysis for
reference oral drug product and LC-AMS
for 14C intravenous parent drug product
as a minimum
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Single study report including
bioanalytical results
Case Histories – IVMT
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Onglyza absolute bioavailability: TGA driven
Study design
• Single period
• 8 subjects
• 5mg oral dose; 50µg 14C-IV dose
• LC-AMS & LC-MS/MS assays
• PK sampling for 24h
Deliverables
• IV PK of Onglyza
• Absolute oral bioavailability
Time
• Study completed in 4 months
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Utility of IV microtracer data
Decision making regarding
potential formulation “fix” for
poor and variable bioavailability
Absolute bioavailability and
absorption limited elimination....
“flip-flop” pharmacokinetics
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Assessment of biliary excretion
• Standard IV microtracer design
with use of Enterotest for bile
fluid collection
• Qualitative AMS analysis of
collected bile fluid
• Metabolite profile of bile
samples
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Case Histories – human ADME
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Mass balance – cytotoxic oncology molecule
• N=6 healthy volunteers
• Single oral suspension dose of
50µg 14C-elacytarabine containing
nmt 270nCi radioactivity
• Residency period 8 days plus 2
return visits of 24 hours for further
collections
• FDA protocol review
• Outcomes:
• Mass balance established
• Routes and rates of excretion
determined
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Integrated 14C IVMT/ tracer ADME study
An open-label, parallel group study in two cohorts
of 8 healthy male subjects
PART 1
Oral drug product with
an intravenous
microtracer dose of 14C
drug product
Define intravenous
pharmacokinetics, IV mass
balance, 14C in bile and absolute
bioavailability
PART 2
Oral drug product
incorporating oral 14C
tracer dose
Define oral mass balance, and
human metabolite profile and
characterise key metabolites
Unpublished study
Overall duration is dependent on halflife, dictating wash-out period between
Part 1 and Part 2 and residency period
to achieve mass balance
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Standalone clinical study
and metabolite investigation
reports
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Metabolism and IVMT in FIH
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Multi-part protocols with flexible design options
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Within protocol decision algorithms
IV
14C
tracer
Oral
14C
7 day
cycle timeDose
Part 1
(SAD)
Dose 1
tracer
1
Dose 21
Dose
Cohorts = 8 (6 active, 2 placebo)
Eight dose increments
9 study periods
FE group
2 nights residency except dose 5 + 6
PK sampling to 24hrDose 1
Part 2
Dose 5b
Dose 3
Dose 4
Dose 5a
Dose 7
MAD study interleaved with SAD
Precise starting point determined as study
progresses
Dose 1
(MAD)
Dose 6
Dose 2
Dose 3
Cohorts = 10 (7 active, 3 placebo)
Three dose increments
9 nights residency
PK sampling on day 1, and day 7-8
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Summary
• Technology advances in conventional methods are providing realistic
alternatives to AMS
• AMS provides a uniquely sensitive detection method enabling the use of
microtracer and microdose in drug development
• Integrated radiolabelled studies utilising conventional and AMS analysis
methods offer scientifically rich opportunities in drug development
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To transform drug development with science and innovation
Speed Quality Passion
[email protected]
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