Download What data can a 14C clinical study deliver?

What data can a 14C clinical study deliver? A
decade of innovative, integrated 14C study
designs to understand drug behaviour in
human subjects
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
• What’s it all about
• Conventional human ADME
• Integrated human ADME
• Final deliverables
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About Quotient Clinical
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•
Full service, early development provider founded in 1990
•
Unique Translational Pharmaceutics platform
•
Expert formulation development
•
Real-time GMP manufacturing
•
85 bed clinical pharmacology unit
•
Highly integrated operations in the UK
•
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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What are we trying to achieve?
Regulatory objectives
Regulatory-driven clinical metabolism studies
NDA/MAA/PMDA Submission requirements
Mass balance
Rates and routes of elimination
Metabolite profiling & identification
TGA Submission requirements
As above + Absolute bioavailability
Study requirements are many/varied and programs
are often complex
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What is required?
• “Nonclinical characterization of a
human metabolite(s) is only
warranted when that metabolite(s)
is observed at exposures greater
than 10% of total drug-related
exposure and at significantly
greater levels in humans than the
maximum exposure seen in the
toxicity studies
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The “regulatory package” plasma metabolites
Pooled plasma
Human
Rat
Dog
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2h plasma pool
across subjects
Human
8h plasma pool
across subjects
Rat
Dog
“AUC”pool,
Subject 1
Oral disposition dashboard
Input
Oral
Fraction absorbed
Drug in
Portal
Blood
Drug in
Intestine
Betaglucuronidase
Metabolism
in Liver
Phase 1
Phase 2
Bile
First Pass Loss %
Metabolites
in
Intestines
Fraction
unabsorbed
Drug and
metabolites
in
Blood
% Exposure, F
% Parent
% MET1, MET2, etc.
Mass balance recovery
Total
Recovery
% dose
8
=
Excretion
in Feces
% dose
+
Excretion
In expired air
% dose
+
Excretion
In Urine
% dose
% Total Recovery
% Parent
% MET1, MET 2, etc.
Conventional human ADME study
An open-label, single period study in a cohort
of 6-8 healthy male subjects
SINGLE
PERIOD
Oral
14C
drug product
Overall residence period is
dependent on radiochemical half-life,
dictating residency period to achieve
mass balance
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Define oral mass balance and
determine human metabolite
profile and characterise key
metabolites
Standalone clinical study
and metabolite
investigation reports
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Conventional ADME study
• N=6 healthy volunteers
• Single oral suspension dose of
300mg 14C-netupitant containing
nmt 60µCi radioactivity
• Residency period 14 days plus 2
return visits of 24 hours for further
collections
• Outcomes:
• Mass balance established
• Routes and rates of excretion
determined
• Key metabolites identified
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Pharmacokinetics and Pharmacodynamics
Netupitant PET Imaging and ADME Studies
in Humans
The Journal of Clinical Pharmacology
XX(XX) 1–12
© 2013 The Authors. The Journal of
Clinical Pharmacology Published by
Wiley Periodicals, Inc. on behalf of
The American College of Clinical
Pharmacology
DOI: 10.1002/jcph.198
Tulla Spinelli1, Selma Calcagnile1, Claudio Giuliano1, Giorgia Rossi1,
Corinna Lanzarotti1, Stuart Mair2, Lloyd Stevens2, and Ian Nisbet2
Abstract
Netupitant is a new, selective NK1 receptor antagonist under development for the prevention of chemotherapy‐induced nausea and vomiting. Two
studies were conducted to evaluate the brain receptor occupancy (RO) and disposition (ADME) of netupitant in humans. Positron emission tomography
(PET) imaging with the NK1 receptor‐binding–selective tracer [11C]‐GR205171 was used to evaluate the brain penetration of different doses of
netupitant (100, 300, and 450 mg) and to determine the NK1‐RO duration. A NK1‐RO of 90% or higher was achieved with all doses in the majority of the
tested brain regions at Cmax, with a long duration of RO. The netupitant minimal plasma concentration predicted to achieve a NK1‐RO of 90%, C90%, in
the striatum was 225 ng/mL; after administration of netupitant 300 mg, concentrations exceeded the C90%. In the ADME study, a single nominal dose of
[14C]‐netupitant 300 mg was used to assess its disposition. Absorption was rapid and netupitant was extensively metabolized via Phase I and II hepatic
metabolism. Elimination of >90% was predicted at day 29 and was principally via hepatic/biliary route (>85%) with a minor contribution of the renal
route (<5%). In conclusion, these studies demonstrate that netupitant is a potent agent targeting NK1 receptors with long lasting RO. In addition,
netupitant is extensively metabolized and is mainly eliminated through the hepatic/biliary route and to a lesser extent via the kidneys.
Keywords
NEPA, netupitant, palonosetron, metabolism, receptor occupancy
Nausea and vomiting represents one of the most feared
side effects of chemotherapy.1,2 Chemotherapy‐induced
nausea and vomiting, CINV, is described as acute, when it
Integrated study designs
•
Single and multi-part study designs can now provide a full and complete
metabolism and pharmacokinetic data package for regulatory
submission
•
Combinations of extravascular (oral, inhaled etc.) and iv administration
with therapeutic and/or tracer dosing can deliver an understanding of
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•
•
•
•
•
•
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Fraction absorbed
Absolute bioavailability
Intravenous pharmacokinetics
Mass balance
Routes and rates of elimination
Metabolic fate
All of the above are molecule specific and data driven
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Integrated 14C ivMicrotracer/ ADME study
An open-label, 2-way crossover study in a single
cohort of 6-8 healthy male subjects
PART 1
PART 2
Oral drug product with
an intravenous
microtracer dose of 14C
drug product
Oral
14C
drug product
Overall duration is dependent on halflife, dictating wash-out period between
Parts 1 and 2 and residency period to
achieve mass balance
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Defines intravenous
pharmacokinetics, mass balance
and absolute bioavailability
Defines oral mass balance,
human metabolite profile and
chemical structure of key
metabolites
Standalone clinical study
and metabolite
investigation reports
1
2
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Combination of 14C IVMT and 14C oral dosing
• N=6 healthy volunteers
• 2 period study
•
•
Period 1 IVMT collecting plasma urine
faeces and bile to 72/26hr post dose
Period 2 ADME collecting blood plasma
urine and faeces to 178hr post dose
• Sample analysis:
•
•
•
AMS (total radioactivity & C-14 parent
compound)
LSC (Total radioactivity)
LC/MS/MS (parent compound)
• Outcomes:
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•
•
•
13 •
IV and oral mass balance
Routes and rates of excretion
Absolute bioavailability
Fraction absorbed
Assessment of biliary excretion
Combination of 13C IVMT and 14C oral dosing
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•
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13C-Tofogliflozin
IV microtracer 0.1mg dose
14C-Tofogliflozin Oral 20mg therapeutic dose
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Radiolabelled intravenous and oral ADME study
An open-label, 2 period study in 2 cohorts of 6-8
healthy male subjects
COHORT 1
COHORT 2
14C
Intravenous
drug
product
Oral
14C
drug product
Define IV mass balance, IVPK,
determine human IV metabolite
profile and characterise key
metabolites
Define oral mass balance, Fa,
determine human oral metabolite
profile and characterise key
metabolites
Current unpublished example
IV and oral toxicology plus IV and oral
dosimetry required to support study design
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Standalone clinical study
and metabolite
investigation reports
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Integrated human ADME options
Study options
Data Analysis Requirements
Data
required for
NDA
submission
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ADME
IV:PO
cross/
ADME
IV
ADME/Oral
ADME
13C
ivMT/
ADME
14C
ivMT/
ADME
Mass balance – oral
dose
Y





Oral routes/rates of
elimination
Y





Met profiling
Y





Met ID
Y





(Y)
X

X


IV PK and clearance
N
X




Mass balance – IV dose
N
X
X

X

Fraction absorbed
N
X
X

X

IV routes/rates of
elimination
N
X
X

X

Absolute bioavailability
Study Delivery Complexity
Study design is driven by drug & client data requirements
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The final deliverable
Completed dashboard
% Exposure
0.5% Parent
2.2% Metab 1
57% Total Recovery
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30% Total Recovery
Opportunity from an ADME dashboard
• N=6 healthy volunteers
http://informahealthcare.com/xen
ISSN: 0049-8254 (print), 1366-5928 (electronic)
Xenobiotica, Early Online: 1–9
• Mass balance established
• Routes and rates of excretion
determined
• Key metabolites identified
• Review results alongside
corresponding in vitro
investigations
• Understanding of dominant CYP
enzyme involved in the
metabolism and DDI liability
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! 2013 Informa UK Ltd. DOI: 10.3109/00498254.2013.865856
RESEARCH A RTICL E
Absorption, metabolism and excretion of [14C]gemigliptin, a novel
dipeptidyl peptidase 4 inhibitor, in humans
Namtae Kim1, Lorna Patrick2, Stuart Mair2, Lloyd Stevens2, Gill Ford3, Vicky Birks3, and Sung-Hack Lee1
1
LG Life Sciences, Drug Metabolism and Pharmacokinetics, Daejeon, Republic of Korea, 2Quotient Clinical, Nottingham, UK, and 3Quotient
Bioresearch, Rushden, UK
Abstract
Keywords
1. Gemigliptin (formerly known as LC15-0444) is a newly developed dipeptidyl peptidase
4 inhibitor for the treatment of type 2 diabetes. Following oral administration of 50 mg
(5.4 MBq) [14C]gemigliptin to healthy male subjects, absorption, metabolism and excretion
were investigated.
2. A total of 90.5% of administered dose was recovered over 192 hr postdose, with 63.4% from
urine and 27.1% from feces. Based on urinary recovery of radioactivity, a minimum 63.4%
absorption from gastrointestinal tract could be confirmed.
3. Twenty-three metabolites were identified in plasma, urine and feces. In plasma, gemigliptin
was the most abundant component accounting for 67.2% rv 100% of plasma radioactivity.
LC15-0636, a hydroxylated metabolite of gemigliptin, was the only human metabolite with
systemic exposure more than 10% of total drug-related exposure. Unchanged gemigliptin
accounted for 44.8% rv 67.2% of urinary radioactivity and 27.7% rv 51.8% of fecal radioactivity. The elimination of gemigliptin was balanced between metabolism and excretion
through urine and feces. CYP3A4 was identified as the dominant CYP isozyme converting
gemigliptin to LC15-0636 in recombinant CYP/FMO enzymes.
DPP-4 inhibitor, human mass balance,
pharmacokinetics
History
Received 25 September 2013
Revised 8 November 2013
Accepted 11 November 2013
Published online 4 December 2013
Summary
• Requirements for NDA and MAA submission are addressed by the
conventional human ADME study
• Integrated studies can enhance the data generated depending on the
needs of the drug candidate
• Linking the human ADME and in vitro metabolism outcomes is key to help
understanding of DDI liability
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