qps preclinical and clinical radiolabel adme studies

QPS – Xcellent ServicesQPS is your Global Link

Overview of QPS’ full suite of linearly integratedpreclinical and clinical ADME services


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.


Part I-

QPS’PRECLINICAL ADME services

QPS is your Global Link

Pharmacokineticso Single and multiple dose pharmacokinetics, dose proportionality, absolute bioavailability,

PK/TK modelingo Mass Balance/Excretion/BDCo Formulation optimization, intestinal permeability, and mechanistic studies

Protein Binding; RBC/Plasma Distributiono Covalent binding

Tissue Distributiono Quantitative Whole-Body Autoradiography (QWBA)o Microautoradiography (MARG)o Discovery QWBA

Metabolismo Metabolic stabilityo CYP450 Inhibition/Inductiono Reaction Pathway Profilingo Metabolite Profiling & Identification – in vitro, animals, and human

QPS Delaware Comprehensive Radiolabel Studies

* Radiolabelled Studies

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Comp'd #1(IV)

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Vivarium – focus on mouse and rat with nine (9) rodent roomso 1 Surgical Suiteo Triple cannulated animals for special models & in situ CSFo Intracranial infusions for up to 7 days

Eight (8) BioAnalysis Labs for dose formulation, sample prep, and assaysMass Balance Studieso Mass Balance Cages (Plastic and Glass)o Micro-Filter Cages for Nude Mice and Rats

In vitro cell culture Labo S9, microsomes, and hepatocyteso Tumor cell-lines for xenografts

LIMSo DEBRA and Watson

QPS Delaware DMPK Facility

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Two (2) Autoradiography Labso 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 Imagero Six (6) Imaging Research MCID Elite Systems

Support Equipment: o Snap-freezing equipmento Photography equipmento Sample Oxidizers o Liquid Scintillation / Gamma Counterso Microplate Scintillation Countero Radioactivity / LC Detectors

QPS Delaware DMPK Facility


Dedicated LC/MS/MSo Three (3) Bioanalysis Labs for sample prep and assayso Six (6) Mass Spec (5 Sciex API 4000s, Finnigan LTQ ProteomeX)

o Waters UPLCs, Shimadzu VP-series LCs, Agilent 1100 LCs; LEAP HTC/PAL injectorso Detectors – UV/Vis, Fluorescence, Electrochemical

o Tomtec Quadra 96 for 96-well sample prep

Radio-Quantitationo Two (2) Packard Model 307 Sample Oxidizerso Two (2) PE Tri-Carb 2800TR Scintillation Counterso PE TopCount® NXT Microplate Scintillation Countero Parkard Cobra II Gamma Countero Four (4) Radioactivity Detectorso ARC XFlow System; Off-line Fraction Collectors

QPS Delaware DMPK Bioanalysis Facility

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ADME

AbsorptionDistributionMetabolismElimination

Protein Binding*Autoradiography



Output

Image Analysis,Presentation & Summary

Microtome

Phosphor/Fluor Imager

Microscope

QPS Autoradiography Technology


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

Calf head

Cockroach

Tumor-Bearing Mouse

Rat

Cynomolgus Monkey

Dog Rabbit

Earthworm

Clover

Parsley

Sea Bass


GLP Preclinical Studieso 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 Studieso 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 Studieso Specifically designed to provide answers to specific questions and/or to provide

preliminary tissue distribution data to sponsors quickly and at a reduced cost.

Whole-Body Autoradiography – Study Designs


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

Example: Definitive TD and Tissue PK


QPS has a standard set of calculations, which are based on MIRD and ICRP recommendations to determine human radiation dosimetry estimatesQPS 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)

Human Dosimetry


Routine Tissue List

Adipose (brown and white) Adrenal GlandBlood Bone Bone Marrow Brain (cerebrum, cerebellum, medulla) CecumEpididymis Eye (uvea and lens)Harderian glandHeartKidney Cortex

Kidney Medulla

Large Intestine LiverLungLymph node Ovary Pituitary glandProstate glandSalivary glandSeminal vesiclesSkeletal muscleSkinStomachSmall intestineSpleen

Spinal cord Testis ThymusThyroid Uterus Vagina Urinary BladderAny other tissue as needed; e.g., epiphyseal plate, knee joints, cartilage, specific brain regions, pampiniform plexus, vomero-nasal gland, meninges, choroid plexus


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: Differential Distribution of Metabolites


Label A Label B

Example: Definitive TD & PK (24hr)


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

TimeLabel 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 8.2962 hr 0.089 0.407 0.076 0.353 6.368 7.962 5.391 10.4464 hr 0.072 0.600 0.074 0.526 5.477 7.596 4.512 12.8918 hr 0.050 0.604 0.037 0.606 2.810 4.708 2.848 4.80924 hr BQL 0.257 BQL 0.298 0.435 0.715 0.440 0.68548 hr BQL 0.134 BQL 0.145 0.141 0.268 0.166 0.19172 hr NI 0.094 NI 0.088 0.097 0.222 0.065 0.1387 Day NI 0.046 NI 0.048 NI 0.093 NI 0.05010 Day NI 0.030 NI 0.028 NI 0.056 NI 0.03714 Day NI NI NI NI NI 0.040 NI BQL

Brain (cerebellum) Brain (cerebrum) Kidney (cortex) Kidney (medulla)

Example: Brains and Kidneys @ 1 hr post-dose


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

Whole-body autoradioluminograph of a rat after a single IV dose of an 125I-compound and co-administration of sodium iodide (NaI)

Whole-body autoradioluminograph of a mouse after single PO dose of an 125I-compound only.

Thyroid

Thyroid

125I Data Interpretation: Thyroid, stomach, kidneys, mammary gland, salivary gland, thymus, epidermis, and choroid plexus are involved with excretion and/or organification of free 125I and can concentrate it therefore interpret data carefully.

Dosing of “cold” Iodine prior to radiolabeled compound can help reduce that effect.

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


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


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

Sample Detector Ct D CtAvg DCt DCt SD DCt %CV

Rat #1_300u_2 GAPDH 26.4692

7.0702

7.6658 0.7816 10.1961

Rat #1_300u_2 Htt 33.5393

Rat #1_300u_2 GAPDH 26.4108

8.5509Rat #1_300u_2 Htt 34.9616

Rat #1_300u_2 GAPDH 26.5414

7.3764Rat #1_300u_2 Htt 33.9178

Example: Quantitative Brain Distribution of siRNA


Provides tissue/cellular level spatial resolution of the distribution of drug-derived radioactivityRequires tissue removal (necropsy) and sectioningQualitative, semi-quantitative and/or quantitative resultsDifferent sample preparation methods influence results. Compliment Immunohistopathology

Micro Autoradiography


Thickness = 10mLocalization of drug molecules in brain tissue and the lumen of the epididymis

Example: Micro Autoradiography


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

Representative photomicroautoradiograph of 14C-compound localization in rat hair sebacious gland

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

Example: Micro Autoradiography


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.

Example: QWBA, Micro Autoradiography& IHC Co-Localization


ADME



Objectiveso 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 dosingo 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 GLPSamples – urine, feces, bile, blood, plasma, tissues, expired airGenerally included in IND regulatory submissionTimelines:o Lead time – 2 weekso Results – 3 to 4 weeks

Mass Balance Studies


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Example: Mass Balance Studies in Rats


Three (3) group – Mass Balance, Bile Duct-Cannulated, PKTotal 11 Sprague-Dawley male ratsCollect bile to 72/96 hr, urine/feces to 72/96 and 168 hr, 10 plasma tpAdd female or additional dose gp as necessary

Mass Balance Studies – General Protocol

Group Number Study

Number/ Sex

Dose Route

Target Dose Level (mg/kg)

Target Dose Volume (mL/kg)

Target Dose Conc. (mg/mL)

Target Radioactivity Level (mCi/kg)

1 (Intact)Mass

Balance 3 M PO TBD TBD TBD 50

2 (BDC)Mass

Balance 3 M PO TBD TBD TBD 503 (JVC) PK 5 M PO TBD TBD TBD 50

Group Number

Bile Urine Feces Blood Cage RinseCage Wash &

Wipe

1 (Intact) N/APre-dose,0-6, 6-24, 24-h intervals to 168

h

Pre-dose, 24-h intervals to 168 h

N/A24-h intervals to

144 h168 h

2 (BDC)Pre-dose, 0-6, 6-24,

24-48, 48-72 hPre-dose, 0-6, 6-24,

24-48, 48-72 hPre-dose, 24-h intervals to 72 h

N/A24-h intervals to

48 h72 h

3 (JVC) N/A N/A N/APre-dose, 5, 15, 30 min., 1, 2, 4, 8, 24 h

N/A N/A


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

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Air

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Urine

Bile

Average Recovery 93.8%


Example: Bile Duct-Cannulation Studies in Rats

Simple Study design, n = 3Collect bile, urine, fecesAverage dose recovered• 3H ≥ 85%

» 54/60 cpds ≥80% recovery• 14C ≥ 90%

» 55/62 cpds ≥85% recovery

Spot trend from a series of compounds3H BDC study – inexpensive with respect to cost and time for 3H-labeling, and study costWhat is consider to be unexpected data?

Bile Duct-Cannulated Studies using 3H-labeled Compounds

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Bile Duct-Cannulated Studies using 3H-labeled Compounds

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Bile Duct-Cannulated Studies using 14C-labeled Compounds

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Bile Duct-Cannulated Studies using 14C-labeled Compounds

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ADME


Metabolic Stability

*Species Comparison

Inhibition/Induction

*Reaction Phenotyping

*Metabolite Profiling/ID



Metabolite Profiling and Identification


Workflow Diagram for Metabolic Stability and Species Comparison (Radiolabeled)

Concentration

Yes

LC/MS/RFD Method Development.

HPLC Column Recovery

Samples from in

vitro Incubations

Draft ReportMolecular Ions MSn Spectra

Accurate Mass (if needed)

Reconstitution Recovery

Metabolite Profiling

Method Development

Concentration?

No

Selected samples

Test article incubated with microsomes, S9 fractions, or hepatocytes of various

species; rodent, non-rodent, and human

*Final HPLC/MS/RFD Method and

Representative metabolite profiles

Individual Samples from in

vitro Incubations

Radio-quantitation of parent compound

and metabolites

Spectra Interpretation.Proposed Structures,

and Metabolic Pathway

Selected samples

Metabolite ID

Sponsor Review

Internal Review

Concentration

*HPLC-ARC

ReconstitutionRecovery

No

Yes

*The same HPLC method is used. Final Report

Version 2010.03.19


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

Pool samples at the same time point from the same

matrix

>85% Radioactivity

Recovery

*LC/MS/RFD method development.

LC column recovery

Pool samples at different time points from the same

matrix

Urine, plasma, bile and fecal samples.

DPM data from Mass Balance study

Draft Report

Extraction

Plasma/Feces

Urine/Bile

Extraction

Metabolite Profiling

Molecular ions MSn spectra

Accurate mass (if needed)

Spectra Interpretation.Proposed Structures, and

Metabolic Pathway

*Radio-analysis(LC/ARC)

Radio-quantification

Concentration, reconstitution recovery

Concentration, reconstitution recovery

Plasma/Feces

Urine/Bile Internal Review

Sponsor Review

Metabolite ProfilingRadio-quantitation

Method DevelopmentMetabolite ID

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

YesNo

Final Report

Version 2010.03.19


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

>85% Radioactivity

Recovery

No Yes

LC/MS/RFD Method Development.

LC Column Recovery

Selected samples ( early and late time points) or Pooled Samples from

Same Matrix

Metabolite profiling (quantitation) of parent

and metabolites

Extraction

Plasma/Feces

Urine

Extraction

Molecular Ions MSn spectra

Accurate Mass (if needed)

*HPLC/FractionationTopCount

Concentration, Reconstitution Recovery

Concentration, Reconstitution Recovery

Plasma/Feces

Urine

Final Report

Draft report

Metabolite ID

Method Development

Individual samplesPlasma samples: >200 DPM/mLUrine samples: >400 DPM/mLFecal Samples: >800 DPM/g

Selected samples

*Final HPLC/MS/RFD method, Extraction

method, and Column recovery

Urine, Plasma, and Fecal Samples. DPM Data from

Mass Balance Study

Metabolite profiling

(Quantitation)

Selected samples

Proposed Structures and

Metabolic Pathway

Internal Review

Sponsor Review

Version 2010.03.19


Plasma

Example: Radiochromatograms from TopCount®

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.3

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26

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7

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CPM


Urine


5.33

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Fecal Homogenate


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Full Scan of Parent (top) and Metabolite A

Example: Mass Spectra of the Parent and Metabolite A

2008101703 #2826-2846 RT: 27.35-27.49 AV: 7 NL: 1.86E6F: ITMS + c ESI Full ms [ 120.00-600.00]

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268.1

198.3

270.0200.2

290.1209.2155.3

292.1196.3125.3 314.3247.9210.3 352.4 382.3 425.8 448.3

2008101703 #2369 RT: 22.99 AV: 1 NL: 2.93E4F: ITMS + c ESI Full ms [ 120.00-600.00]

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444.0184.6

268.3

202.8130.6

446.1542.3

224.5184.0 301.4 468.1368.4366.5

228.6 543.5370.4171.6259.4 400.3 488.3 548.2

571.0


Product Ion Spectrum (MS/MS of m/z 268 – parent and m/z 444 - metab)

Mass Spectra of Metabolite at Retention Time of 22 min

2008081304 #2153-2175 RT: 22.16-22.34 AV: 6 NL: 2.88E5F: ITMS + c ESI Full ms2 [email protected] [ 120.00-600.00]

150 200 250 300 350 400 450 500 550 600m/z

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207.1 426.0198.1

155.0 268.6 426.9309.9 382.1208.8 553.1492.8

2008101703 #2874 RT: 27.76 AV: 1 SB: 8 27.73-27.94 NL: 3.66E3F: ITMS + c ESI Full ms2 [email protected] [ 70.00-600.00]

100 150 200 250 300 350 400 450 500 550 600m/z

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224.1124.5 155.277.0 267.3


Part II-

QPS’CLINICAL ADME services


Abbreviations

EC = Ethics CommitteeCA = Competent AuthorityCPU = Clinical Pharmacology UnitCTP = Clinical Trial ProtocolIB = Investigator’s BrochureIMP = Investigational Medicinal ProductIMPD = Investigational Medical Product DossierICF = Informed Consent FormPI = Principal InvestigatorUMCG = University Medical Center GroningenQP = Qualified Person


Objectiveso To determine the rate and extent of excretion of total radioactivity in urine, feces,

and/or expired air following dose administration of radiolabeled test articleo To evaluate the extent of absorption of radioactivity after dosingo 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

GCPSamples – urine, feces, blood, plasma, expired airTimelines:o Clinical Protocol Approval – 2 weekso Total Radioactivity Recovery Results – 3 to 4 weekso Metabolite Identification and Profiling Results – 3 to 4 months

Human Mass Balance Study


Human Mass Balance study at QPS in 10 Steps

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


QPS has a standard set of calculations, which are based on MIRD and ICRP recommendations to determine human radiation dosimetry estimatesQPS 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).

Human Dosimetry


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

14C-labeled IMP is sent from the Sponsor to the Radiopharmacy14C-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.

QPS is your Global LinkPhysical 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

Clinical Trial Pharmacy

Clinical Pharmacology UnitRadionuclide Laboratory

Biometrics

Nuclear Medicine & Molecular Imaging


Functions Involved – Roles & Responsibilities

Functions Physical location/affiliation Roles & Responsibilities

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

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

Clinical Pharmacology Unit Clinical Pharmacology Unit of QPS

Drug Administration of 14C-labeled IMPSample Collection and Processing of Radioactive Human Excreta (blood, urine, feces and expired air)

Radionuclide Laboratory Radionuclide Laboratory of the UMCG

Processing of Radioactive Human Excreta (feces only)Processing of samples for beta-countingMeasurement 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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