Qps Preclinical And Clinical Radiolabel Adme Studies

QPS – Xcellent Services
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Overview of QPS’ full suite of linearly integrated
preclinical and clinical ADME services

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Reasons why our Sponsors recommend performing their preclinical and
clinical ADME studies at QPS and why you should consider QPS?
o QPS has extensive experience and expertise with the conduct of preclinical and clinical
studies (references will be provided upon request).
o The option of using QPS as a preferred provider - on a compound-by-compound basis -
for delivering both the preclinical radiolabeled studies and the human mass balance
study as one complete package enables QPS to transfer the knowledge obtained from
the preclinical studies smoothly to the clinical setting.
o Smooth knowledge transfer from preclinical to clinical becomes particularly important
when metabolism pathways are complex and ensuring sample integrity becomes
critical.
o The favorable regulatory environment in the Netherlands makes conducting human
mass balance studies at QPS an excellent choice.
o In addition, sponsors can take advantage of the fact that QPS uses state of the art
radiopharmaceutical facilities with a governmental Manufacturer’s/GMP license for
the (individual) preparation of 14C-labeled IMPs. Because of these outstanding
radiopharmaceutical facilities, the availability of only the 14C-labeled drug substance is
sufficient to carry out human mass balance studies at QPS.

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Part I
-
QPS’PRECLINICAL ADME services

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QPS Delaware Comprehensive Radiolabel Studies

Pharmacokinetics
o Single and multiple dose pharmacokinetics, dose proportionality, absolute bioavailability,
PK/TK modeling
o Mass Balance/Excretion/BDC
o Formulation optimization, intestinal permeability, and mechanistic studies
Protein Binding; RBC/Plasma Distribution Rat PK 3-in-1 IV/PO
o Covalent binding
10000

Tissue Distribution Comp'd #1(IV)
Comp'd #1
o Quantitative Whole-Body Autoradiography (QWBA) 1000 (PO)
Comp'd #2 (IV)
Comp'd #2
o Microautoradiography (MARG) (PO)
Comp'd #3 (IV)
100
o Discovery QWBA Comp'd #3
(PO)

Metabolism 10

o Metabolic stability
1
o CYP450 Inhibition/Induction 0 4 8 12 16 20 24

o Reaction Pathway Profiling
o Metabolite Profiling & Identification – in vitro, animals, and human

* Radiolabelled Studies


QPS Delaware DMPK Facility

Vivarium – focus on mouse and rat with nine (9) rodent rooms
o 1 Surgical Suite
o Triple cannulated animals for special models & in situ CSF
o Intracranial infusions for up to 7 days
Eight (8) BioAnalysis Labs for dose formulation, sample prep, and assays
Mass Balance Studies
100.0
o Mass Balance Cages (Plastic and Glass)
90.0
o Micro-Filter Cages for Nude Mice and Rats

Percent Dose Recovered
80.0

In vitro cell culture Lab 70.0
Rinse
60.0
o S9, microsomes, and hepatocytes 50.0
Urine
Bile
o Tumor cell-lines for xenografts 40.0
Feces
30.0
LIMS 20.0
o DEBRA and Watson 10.0
0.0
IV PO PO/BDC


QPS Delaware DMPK Facility

Two (2) Autoradiography Labs
o Leica CM 3600 Cryomacrotome (Whole-body)
o Leica Vibratome 9800 (Whole-body)
o Leica CM 3050 S Cryomicrotome (individual organ/tissue)
o Molecular Dynamics Typhoon 9410 Imager
o Six (6) Imaging Research MCID Elite Systems
Support Equipment:
o Snap-freezing equipment
o Photography equipment
o Sample Oxidizers
o Liquid Scintillation / Gamma Counters
o Microplate Scintillation Counter
o Radioactivity / LC Detectors


QPS Delaware DMPK Bioanalysis Facility

Dedicated LC/MS/MS
o Three (3) Bioanalysis Labs for sample prep and assays
o Six (6) Mass Spec (5 Sciex API 4000s, Finnigan LTQ ProteomeX)
o Waters UPLCs, Shimadzu VP-series LCs, Agilent 1100 LCs; LEAP HTC/PAL injectors
o Detectors – UV/Vis, Fluorescence, Electrochemical
o Tomtec Quadra 96 for 96-well sample prep
Tissue Penetration
Radio-Quantitation
o Two (2) Packard Model 307 Sample Oxidizers 35
Kidney
30
o Two (2) PE Tri-Carb 2800TR Scintillation Counters Liver

Tissue Concentration
Lung
25
o PE TopCount® NXT Microplate Scintillation Counter Spleen

20
o Parkard Cobra II Gamma Counter
15
o Four (4) Radioactivity Detectors 10

o ARC XFlow System; Off-line Fraction Collectors 5

0
A B C D

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ADME

Absorption
Protein Binding
Distribution *Autoradiography
Metabolism
Elimination

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QPS Autoradiography Technology

Output

Microtome

Image Analysis,
Presentation &
Phosphor/Fluor Imager Summary

Microscope

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QPS Autoradiography – Analyze All Types of Samples

QPS Autoradiographers have a broad depth of experience and
knowledge of anatomy across many Biological Species, Phyla,
and Kingdoms

Earthworm

Dog Rabbit Calf head
Clover

Tumor-Bearing Mouse
Rat

Sea Bass

Parsley
Cynomolgus Monkey Cockroach


Whole-Body Autoradiography – Study Designs

GLP Preclinical Studies
o Routinely designed to fulfill regulatory requirements to determine large and/or
small animal tissue distribution and Pharmacokinetic parameters to determine
human radioactive dosimetry estimates.
Non-GLP Preclinical Studies
o Routinely designed to fulfill regulatory and/or Sponsor requirements, but are not
audited by QPS QAU to determine large and/or small animal tissue distribution and
Pharmacokinetic parameters to determine human radioactive dosimetry estimates.
Discovery Studies
o Specifically designed to provide answers to specific questions and/or to provide
preliminary tissue distribution data to sponsors quickly and at a reduced cost.


Example: Definitive TD and Tissue PK

Autoradiographs showing the
tissue distribution in albino
(Sprague-Dawley) and
pigmented rats (Long Evans).

Note the amount of
radioactivity in the eye of the
LE rat vs. the SD rat


Human Dosimetry

QPS has a standard set of calculations, which are based on MIRD and ICRP
recommendations to determine human radiation dosimetry estimates
QPS can also use equations suggested by the sponsor.
QPS utilizes the true tissue concentration data obtained from QWBA analysis
as opposed to organ homogenate data which can produce misleading results
regarding human tissue exposure during human radiolabeled studies. (e.g.
exposure of the fine melanized tissue of the eye)
QPS NL supports First-in-Human Studies (SAD / MAD)


Routine Tissue List

Adipose (brown and white) Large Intestine Liver Spinal cord
Adrenal Gland Lung Testis
Blood Lymph node Thymus
Bone Ovary Thyroid
Bone Marrow Pituitary gland Uterus
Brain (cerebrum, Prostate gland Vagina
cerebellum, medulla) Salivary gland Urinary Bladder
Cecum Seminal vesicles Any other tissue as
Epididymis Skeletal muscle needed; e.g., epiphyseal
Eye (uvea and lens) Skin plate, knee joints,
Harderian gland cartilage, specific brain
Stomach regions, pampiniform
Heart Small intestine plexus, vomero-nasal
Kidney Cortex Spleen gland, meninges, choroid
Kidney Medulla plexus


Example: Differential Distribution of Metabolites

In this experiment, the goal as to track the tissue distribution of 2 known
metabolites in the rat. Two batches of the parent molecule were prepared and
each was labeled with 14C at two different positions on the molecules so that
the metabolites could be imaged and tissue concentrations determined using
QWBA.
The goal being to determine specific tissue exposure to each metabolite to
address safety concerns.
Methods: 2 groups of animals were used and 1 animal/gp. at each of the
following time points were analyzed by QWBA at 1, 2, 4, 8, 24, 48, 72, 168, 240,
and 336 hr post-dose.


Example: Definitive TD & PK (24hr)

Label A Label B


Example: Brains and Kidneys @ 1 hr post-dose

14C-Label A 14C-Label B 14C-Label A 14C-Label B

Time Brain (cerebellum) Brain (cerebrum) Kidney (cortex) Kidney (medulla)
Label A Label B Label A Label B Label A Label B Label A Label B
1 hr 0.088 0.229 0.070 0.201 7.820 6.036 4.917 8.296
2 hr 0.089 0.407 0.076 0.353 6.368 7.962 5.391 10.446
4 hr 0.072 0.600 0.074 0.526 5.477 7.596 4.512 12.891
8 hr 0.050 0.604 0.037 0.606 2.810 4.708 2.848 4.809
24 hr BQL 0.257 BQL 0.298 0.435 0.715 0.440 0.685
48 hr BQL 0.134 BQL 0.145 0.141 0.268 0.166 0.191
72 hr NI 0.094 NI 0.088 0.097 0.222 0.065 0.138
7 Day NI 0.046 NI 0.048 NI 0.093 NI 0.050
10 Day NI 0.030 NI 0.028 NI 0.056 NI 0.037
14 Day NI NI NI NI NI 0.040 NI BQL

125I-Labeled Biotherapeutics (peptides, mAbs, proteins)

125IData Interpretation:
Whole-body autoradioluminograph of a rat after a single IV
dose of an 125I-compound and co-administration of sodium Thyroid, stomach, kidneys,
mammary gland, salivary
iodide (NaI) Thyroid gland, thymus, epidermis,
and choroid plexus are
involved with excretion
and/or organification of
free 125I and can
concentrate it therefore
interpret data carefully.

Whole-body autoradioluminograph of a mouse after Dosing of “cold” Iodine
prior to radiolabeled
single PO dose of an 125I-compound only. compound can help reduce
that effect.

TCA Precipitation will help
to “correct” the data and
verify stability of the
radiolabel in vivo
Thyroid


Example: QPS Brain Surgeries Enable Specific Dosing

QPS can perform brain surgeries to specifically administer targeted
doses of test article directly into the brain of rats using stereotaxic
frames and known anatomical brain coordinates.
Examples of applications are CNS genetic diseases, Oncology and
Alzheimer's


Example: QPS Brain Surgeries Enable Specific Dosing
Brain-cannulated rats can be maintained and infused
constantly for up to 7 continuous days


Example: Quantitative Brain Distribution of siRNA

14C-siRNA studies – Couple autoradiography images
with rt-PCR results obtained from adjacent sections

TABLE: qRT-PCR analysis of transcript levels in Brain Tissue Punches using
the oligo dT primer for cDNA synthesis
Avg
Sample Detector Ct D Ct DCt DCt SD DCt %CV
Rat #1_300u_2 GAPDH 26.4692

Rat #1_300u_2 Htt 33.5393 7.0702

Rat #1_300u_2 GAPDH 26.4108

Rat #1_300u_2 Htt 34.9616 8.5509

Rat #1_300u_2 GAPDH 26.5414

Rat #1_300u_2 Htt 33.9178 7.3764 7.6658 0.7816 10.1961


Micro Autoradiography

Provides tissue/cellular level spatial resolution of the distribution of drug-
derived radioactivity
Requires tissue removal (necropsy) and sectioning
Qualitative, semi-quantitative and/or quantitative results
Different sample preparation methods influence results.
Compliment Immunohistopathology


Example: Micro Autoradiography

Localization of drug molecules in brain tissue Thickness = 10m
and the lumen of the epididymis


Example: Micro Autoradiography

Representative photomicroautoradiograph Representative
of 14C-AZT localization in rat kidney photomicroautoradiograph of
glomeruli. 14C-compound localization in rat hair

sebacious gland

Correlate possible tox findings to cellular
distribution.
If needed metabolite profiling/ID for
mechanistic study.


Example: QWBA, Micro Autoradiography& IHC Co-Localization
14C-Oligonucleotide Distribution
Liver MARG showing
Immunolabeled Kupfer
cells co-localized to 14C

Spleen showed
differential distribution
in White & Red pulp.
Quantified using Image
profile.
MARG shows cellular
distribution.

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ADME

Absorption
Distribution
Metabolism
Elimination


Mass Balance Studies

Objectives
o To determine the rate and extent of excretion of total radioactivity in urine, feces,
and/or bile following dose administration of radiolabeled test article in mice, rats,
dogs, or monkeys
o To evaluate the extent of absorption of radioactivity after dosing
o To examine the blood and plasma concentration profiles of total radioactivity
o To generate urine, feces, bile, and blood specimens for subsequent use in a
metabolite identification and profiling study
Non-GLP or GLP
Samples – urine, feces, bile, blood, plasma, tissues, expired air
Generally included in IND regulatory submission
Timelines:
o Lead time – 2 weeks
o Results – 3 to 4 weeks


Example: Mass Balance Studies in Rats

100.0
90.0

Percent Dose Recovered
80.0
70.0
Rinse
60.0
Urine
50.0
Bile
40.0
Feces
30.0
20.0
10.0
0.0
IV PO PO/BDC

Intact Rats IV 5 mg/kg Intact Rats PO 20 mg/kg Bile Duct-Cannulated
Rats PO 20 mg/kg
µg Equivalents/mL or µg/mL .

100.000 100.000 100
µg Equivalents/mL or µg/mL .

µg Equivalents/mL or µg/mL ,
10.000 10.000 10

1.000 1.000 1

0.100 0.100 0.1
Total Radioactivity,µg
Total Radioactivity, µg
equivalents/mL
0.010 equivalents/mL 0.010 Test Article, µg/mL 0.01
Total radioactivity, µg
Test Article, µg/mL equivalents/mL
Test Article (µg/mL)
0.001 0.001
0.001
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24

Time (h) Time (h) Tim e (h)


Mass Balance Studies – General Protocol

Three (3) group – Mass Balance, Bile Duct-Cannulated, PK
Total 11 Sprague-Dawley male rats
Collect bile to 72/96 hr, urine/feces to 72/96 and 168 hr, 10 plasma tp
Add female or additional dose gp as necessary
Target Dose Target
Group Number/ Dose Target Dose Volume Target Dose Radioactivity
Number Study Sex Route Level (mg/kg) (mL/kg) Conc. (mg/mL) Level (Ci/kg)
Mass
1 (Intact) Balance 3M PO TBD TBD TBD 50
Mass
2 (BDC) Balance 3M PO TBD TBD TBD 50
3 (JVC) PK 5M PO TBD TBD TBD 50

Group Cage Wash &
Bile Urine Feces Blood Cage Rinse
Number Wipe
Pre-dose,0-6, 6-24,
Pre-dose, 24-h 24-h intervals to
1 (Intact) N/A 24-h intervals to 168 N/A 168 h
intervals to 168 h 144 h
h
Pre-dose, 0-6, 6-24, Pre-dose, 0-6, 6-24, Pre-dose, 24-h 24-h intervals to
2 (BDC) N/A 72 h
24-48, 48-72 h 24-48, 48-72 h intervals to 72 h 48 h
Pre-dose, 5, 15, 30
3 (JVC) N/A N/A N/A N/A N/A
min., 1, 2, 4, 8, 24 h


Example: Mass Balance Studies in Rats

Recovery – No regulatory guidance, the common wisdom is to have ≥ 90%
Average dose recovered ≥ 90% (37/45 cpds ≥ 90%, 43/45 cpds ≥ 85%)
Mass Balance Excretion Studies in Rats using 14C-labeled Cpds

110
Average Recovery
100 93.8%

90
80
% Dose Recovered

Carcass
70 Air
60 Cage Wash
50 Feces
40 Urine

30 Bile

20
10
0
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45
# of Studies


Example: Bile Duct-Cannulation Studies in Rats
Bile Duct-Cannulated Studies using 3H-labeled Compounds

110
100
Average Recovery
87.4%

Simple Study design, n = 3
90
80

% Dose Recovered
70
Collect bile, urine, feces 60
Cage Wash
Feces

Average dose recovered 50 Urine
Bile
40
• 3H ≥ 85% 30
20
» 54/60 cpds ≥80% recovery
10
• 14C ≥ 90% 0
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59
» 55/62 cpds ≥85% recovery
# of Study
Spot trend from a series of compounds Bile Duct-Cannulated Studies using 14C-labeled Compounds
3H BDC study – inexpensive with respect
110
to cost and time for 3H-labeling, and 100
Average Recovery
93.8%

study cost 90
80
% Dose Recovered

What is consider to be unexpected 70 Cage Residue
60 Feces
data? 50 Urine
40 Bile

30
20
10
0
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61
# of Study

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ADME

Absorption
Metabolic Stability
Distribution *Species Comparison
Inhibition/Induction
Metabolism *Reaction Phenotyping
Elimination *Metabolite Profiling/ID



Metabolite Profiling and Identification

Workflow Diagram for Metabolic Stability and Species Comparison (Radiolabeled)
Test article incubated
No
with microsomes, S9 Samples LC/MS/RFD Method
Concentratio
fractions, or hepatocytes from in vitro Development.
n
of various species; Incubations HPLC Column Recovery
rodent, non-rodent, and
human

Yes

*Final HPLC/MS/RFD
Method Reconstitution Method and
Development Recovery Representative
metabolite profiles

Individual
Concentration No
Samples
? *HPLC-ARC
from in vitro
Metabolite Incubations
Profiling Yes Radio-quantitation
of parent compound
and metabolites
Selected samples
Reconstitution
Recovery
Selected samples

Metabolite ID Molecular Ions
MSn Spectra Internal Review Draft Report
Accurate Mass (if needed)

*The same HPLC
method is used. Spectra Interpretation. Final Report Sponsor Review
Proposed Structures,
and Metabolic Pathway

Version 2010.03.19

Workflow Diagram for Metabolite Profiling and ID of Preclinical Mass Balance Samples

Pool samples at different Urine/Bile *LC/MS/RFD method
time points from the same development. Metabolite Profiling
matrix LC column recovery
Method
Development
Metabolite ID Plasma/Feces

Molecular ions
Concentration, reconstitut MSn spectra
Urine, plasma, bile and Extraction Accurate mass (if needed)
ion recovery
fecal samples.
DPM data from Mass
Balance study

No >85% Yes
Radioactivity Spectra Interpretation.
Recovery Proposed Structures, and
Metabolite Profiling Metabolic Pathway
Radio-quantitation

Pool samples at the same Urine/Bile *Radio-analysis
time point from the same (LC/ARC) Draft Report Internal Review
matrix Radio-quantification

Plasma/Feces

Concentration, reconstitut
Extraction Sponsor Review Final Report
ion recovery

*The same LC/MS/RFD method
is used for both metab ID and
radio-quantitation

Version 2010.03.19

Workflow Diagram for Metabolite Profiling and ID of Human Mass Balance Samples

Selected samples ( early *Final HPLC/MS/RFD
Method Urine, Plasma, and and late time points) or Urine LC/MS/RFD Method method, Extraction
Fecal Samples. Pooled Samples from
Development DPM Data from Same Matrix
Development. method, and Column
LC Column Recovery recovery
Mass Balance Study

Plasma/Feces

Concentration, Reconstitu
Extraction
tion Recovery

No >85% Yes
Radioactivity
Recovery

Metabolite Individual samples
Plasma samples: >200 DPM/mL Urine Metabolite profiling
profiling *HPLC/Fractionation
(quantitation) of parent
Urine samples: >400 DPM/mL TopCount
(Quantitation Fecal Samples: >800 DPM/g and metabolites
) Selected
Plasma/Feces samples

Concentration, Reconstitutio
Extraction
n Recovery

Draft report Sponsor Review
Selected samples

Metabolite ID

Molecular Ions Proposed Structures
MSn spectra and Internal Review Final Report
Accurate Mass (if needed) Metabolic Pathway

Version 2010.03.19

Example: Radiochromatograms from TopCount®

7
Plasma

6
.
C P M

6
5 0 0 . 0

2
4 5 0 . 0

4 0 0 . 0

3 5 0 . 0

3 0 0 . 0

3
2 5 0 . 0

3
2 0 0 . 0

.
1 5 0 . 0

1
1 0 0 . 0

5 0 . 0 2

0 . 0
0 . 0 0 1 0 . 0 0 2 0 . 0 0 3 m
0 . n
i0 s0


7
6
Urine

.
C P M
1 1 0 0 . 0

0

1
1 0 0 0 . 0

0

2
9 0 0 . 0

.
8 0 0 . 0

2
7
7 0 0 . 0

1

0
6
6 0 0 . 0

0
0

0
7

.
5 0 0 . 0

0
0
3

0
0

6

.
2

4 0 0 . 0

.
3

0
.

1
0

1

3 0 0 . 0
.

7
8
.

.

2
2 0 0 . 0
0
.

2
5

9

1 0 0 . 0
7

1

0 . 0
0 . 0 0 1 0 . 0 0 2 0 . 0 0 3 m
0 . n
i0 s0


0
Fecal Homogenate

0
.
C P M
1 0 0 . 0

2

0
9 0 . 0

2
3

0
8 0 . 0

3

7
0

.
7 0 . 0

6
.
0

7
6 0 . 0
2

.

2
.

5 0 . 0
1

2
8

4 0 . 0

2
3 0 . 0

2 0 . 0

1 0 . 0

0 . 0
0 . 0 0 1 0 . 0 0 2 0 . 0 0 3 m
0 . n
i0 s0

Example: Mass Spectra of the Parent and Metabolite A

Full Scan of Parent (top) and Metabolite A
2008101703 #2826-2846 RT: 27.35-27.49 AV: 7 NL: 1.86E6
F: ITMS + c ESI Full ms [ 120.00-600.00]
268.1
100
198.3
90

80

70

60

50

40
270.0
30 200.2

20
290.1
10 155.3 209.2
125.3 196.3 292.1 314.3
210.3 247.9 352.4 382.3 425.8 448.3
0
150 200 250 300 350 400 450
2008101703 #2369 RT: 22.99 AV: 1 NL: 2.93E4 m/z
F: ITMS + c ESI Full ms [ 120.00-600.00]
444.0
100 184.6

90

80 268.3

70

60 202.8
130.6
50

40
446.1
30 542.3
184.0 224.5 301.4 368.4 468.1
20
366.5
171.6 228.6 370.4 543.5
10 259.4 400.3 488.3 548.2
571.0
0
150 200 250 300 350 400 450 500 550 600
m/z

Mass Spectra of Metabolite at Retention Time of 22 min

Product Ion Spectrum
(MS/MS of m/z 268 – parent and m/z 444 - metab)
2008101703 #2874 RT: 27.76 AV: 1 SB: 8 27.73-27.94 NL: 3.66E3
F: ITMS + c ESI Full ms2 268.00@19.00 [ 70.00-600.00]
207.0
100

90
198.0
80

70

60

50

40

30

20

10
77.0 124.5 155.2 224.1 267.3
0
100 150 200 250 300 350 400 450 500 550 6
2008081304 #2153-2175 RT: 22.16-22.34 AV: 6 NL: 2.88E5 m/z
F: ITMS + c ESI Full ms2 444.00@20.00 [ 120.00-600.00]
268.0
100

90

80

70

60

50

40

30

20 207.1 426.0
198.1
10
155.0 208.8 268.6 309.9 382.1 426.9 492.8 553.1
0
150 200 250 300 350 400 450 500 550 600
m/z

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Part II
-
QPS’CLINICAL ADME services


Abbreviations

EC = Ethics Committee
CA = Competent Authority
CPU = Clinical Pharmacology Unit
CTP = Clinical Trial Protocol
IB = Investigator’s Brochure
IMP = Investigational Medicinal Product
IMPD = Investigational Medical Product Dossier
ICF = Informed Consent Form
PI = Principal Investigator
UMCG = University Medical Center Groningen
QP = Qualified Person


Human Mass Balance Study

Objectives
o To determine the rate and extent of excretion of total radioactivity in urine, feces,
and/or expired air following dose administration of radiolabeled test article
o To evaluate the extent of absorption of radioactivity after dosing
o To examine the blood and plasma concentration profiles of total radioactivity
o To generate urine, feces and blood specimens for subsequent use in a metabolite
identification and profiling study
GCP
Samples – urine, feces, blood, plasma, expired air
Timelines:
o Clinical Protocol Approval – 2 weeks
o Total Radioactivity Recovery Results – 3 to 4 weeks
o Metabolite Identification and Profiling Results – 3 to 4 months


Human Mass Balance study at QPS in 10 Steps

Step 1: Ethics Committee & Competent Authority submission
Step 2: Receipt and Release of 14C-labeled IMP
Step 3: Individual Drug Preparation of 14C-labeled IMP
Step 4: Transport of 14C-labeled IMP
Step 5: Drug Administration of 14C-labeled IMP
Step 6: Collection, Sample Processing and Transport of 14C-labeled
Human Excreta
Step 7: Return and Destruction of 14C-labeled IMP
Step 8: Measurement of the 14C-Radioactivity in Human Excreta
Step 9: Determination of the total 14C-Radioactivity Recovery Rate
Step 10: Disposal of 14C-labeled Human Excreta


Step 1 – Ethics Committee & Competent Authority Submission

The application process for a radioactive phase I trial in the Netherlands
is essentially the same as for any other non-radioactive phase I trial!
Written EC and CA approval is routinely obtained within 14 days after
submission of the Clinical Trial Application (CTA).
Submission documents as part of the Clinical Trial Application are:
o Clinical Trial Protocol (CTP)
o Investigator’s Brochure (IB)
o Investigational Medical Product Dossier (IMPD)
o Informed Consent Form (ICF)
o Human Dosimetry Calculation


Human Dosimetry

QPS has a standard set of calculations, which are based on MIRD and ICRP
recommendations to determine human radiation dosimetry estimates
QPS can also use equations suggested by the sponsor.
QPS utilizes the true tissue concentration data obtained from QWBA analysis
as opposed to organ homogenate data which can produce misleading results
regarding human tissue exposure during human radiolabeled studies (e.g.
exposure of the fine melanized tissue of the eye).


Step 2 - Receipt and Release of 14C-labeled IMP

14C-labeled IMP is sent from the Sponsor to the Radiopharmacy
14C-labeled IMP is placed in quarantine at the Radiopharmacy until
release by QP.
14C-labeled IMP is entered in IBC-606 (fully automated & validated
Isotope Book Keeping System) of the Radiopharmacy.


Step 3 – Individual Drug Preparation of 14C-labeled IMP

Individual drug preparation of 14C-labeled study medication is done by
the Radiopharmacy.
Individual Drug Preparation Forms are prepared by the Clinical Trial
Pharmacy – documents are reviewed by the Radiopharmacy and the
Sponsor.
Label specifications are prepared according to GMP Annex 13 by the
Clinical Trial Pharmacy – documents are reviewed by the Radiopharmacy
and Sponsor.
Labels are printed (without batch number) by the Clinical Trial
Pharmacy. Unique batch numbers will be added in handwriting on the
labels during each individual drug preparation.


Step 4 – Transport of 14C-labeled IMP

Individually prepared 14C-labeled study medication is picked up at the
Radiopharmacy and transported in a closed perspex transport box to the
CPU (i.e. the place where drug administration takes place) by Clinical
Trial Pharmacy personnel.


Step 5 – Drug Administration of 14C-labeled IMP

Drug administration of the 14C-labeled study medication is always done
in the presence of the PI or a designated Research Physician.
Circumstances are again essentially the same as for any other non-
radioactive phase I trial.
Additional hygienic measures are used to prevent radioactive
contamination of the CPU.

Step 6 – Collection, Sample Processing and Transport of Radioactive Human Excreta

All necessary steps to ensure sample integrity (experience gained from preclinical
studies) will be taken from sample collection, sample processing, storage, and
shipping.
Collection of blood, urine, feces and expired air takes place in the CPU.
Sample processing of collected blood, urine and expired air samples takes place
in the CPU as well.
Sample processing (i.e. homogenization and aliquoting) of collected feces
samples takes place in the radionuclide laboratory.
The volunteers are discharged from the clinic after at least 85 % (or more if the
study protocol requires to do so) of the total dose of radioactivity has been
recovered in the excreta from the volunteer.
The radioactive human excreta and/or aliquots are stored in a designated
freezer in the CPU until transport to the radionuclide laboratory.
The radioactive human excreta and/or aliquots are picked up at the CPU by
laboratory technicians and subsequently transported in a closed perspex
transport box to the radionuclide laboratory.


Step 7 - Return and/or Destruction of 14C-labeled IMP

Returned/(partially) used 14C-labeled study medication is picked up at
the CPU (i.e. the place where drug administration takes place) and
transported in a closed perspex box to the Radiopharmacy by Clinical
Trial Pharmacy personnel.
Returned/(partially) used 14C-labeled study medication, if any, is stored
in a closed perspex box in a locked cabinet in the Radiopharmacy until
approval for destruction has been received from Sponsor.
Returned /(partially) used 14C-labeled study medication is treated as
well as disposed of as radioactive waste which will be handled according
to the UMCG guidance on radioactive health and safety.


Step 8 – Measurement of the 14C-Radioactivity in Human Excreta

All necessary sample pretreatments after the samples have been
processed and aliquoted until the measurement of 14C-radioactivity, are
done by laboratory technicians from the radionuclide laboratory who
are trained by in GLP and the particular Assays Instruction(s) as required
by the Bioanalytical Protocol of the concerned study.
The measurement of 14C-radioactivity in human study samples is
performed on a beta-counter (Tricarb 2500) in the radionuclide
laboratory.


Step 9 – Determination of the total 14C-Radioactivity Recovery Rate

Determination of the total 14C-radioactivity recovery rate is done by the
Biometrics Department using validated excel sheets.
The total recovery rate from urine, feces and expired air samples will be
calculated during the last 24-hour interval of hospitalization on the basis
of quick count determinations since the percentage of 14C-radioactivity
recovery will be used as the discharge criterion for the volunteer in the
clinic.
The 14C-radioactivity recovery from all human excreta at all sampling
times and intervals will be documented in a validated excel sheet.


Step 10 – Disposal of Radioactive Human Excreta

All radioactive human excreta collected during mass balanced studies
will be treated as radioactive waste and handled according to the UMCG
guidance on radioactive health and safety.

Physical locations on the premises of the UMCG where activities take place during
the conduct of your human mass balance study at QPS

University Medical Center Groningen

Radiopharmacy

Radionuclide Laboratory
Clinical Pharmacology Unit
Nuclear Medicine & Molecular Imaging

Clinical Trial Pharmacy

Biometrics


Functions Involved – Roles & Responsibilities

Functions Physical location/affiliation Roles & Responsibilities

Radiopharmacy Radiopharmacy of the UMCG Receipt and Release of 14C-labeled IMP
Individual Drug Preparation of 14C-labeled IMP
Return and/or Destruction of 14C-labeled IMP

Clinical Trial Pharmacy Clinical Trial Pharmacy of QPS Transport of 14C-labeled IMP
Preparation of Individual Drug Preparation Form
Preparation of Label Specifications according to GMP Annex
13

Clinical Pharmacology Unit Clinical Pharmacology Unit of Drug Administration of 14C-labeled IMP
QPS Sample Collection and Processing of Radioactive Human
Excreta (blood, urine, feces and expired air)

Radionuclide Laboratory Radionuclide Laboratory of the Processing of Radioactive Human Excreta (feces only)
UMCG Processing of samples for beta-counting
Measurement of the 14C-Radioactivity in Human Excreta

Biometrics Biometrics Department of QPS Determination of the total 14C-Radioactivity Recovery Rate

Qps Preclinical And Clinical Radiolabel Adme Studies

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