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Qps Preclinical And Clinical Radiolabel Adme Studies
 

Qps Preclinical And Clinical Radiolabel Adme Studies

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QPS Preclinical And Clinical Radiolabel ADME Studies

QPS Preclinical And Clinical Radiolabel ADME Studies

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  • Metabolite Identification and Profiling

Qps Preclinical And Clinical Radiolabel Adme Studies Qps Preclinical And Clinical Radiolabel Adme Studies Presentation Transcript

  • QPS – Xcellent Services is your Global LinkOverview of QPS’ full suite of linearly integrated preclinical and clinical ADME services
  • QPS – Xcellent Services is your Global LinkReasons why our Sponsors recommend performing their preclinical andclinical 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.
  • QPS – Xcellent Services is your Global Link Part I -QPS’PRECLINICAL ADME services
  • QPS is your Global Link 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 Compd #1(IV) Compd #1 o Quantitative Whole-Body Autoradiography (QWBA) 1000 (PO) Compd #2 (IV) Compd #2 o Microautoradiography (MARG) (PO) Compd #3 (IV) 100 o Discovery QWBA Compd #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 is your Global LinkQPS Delaware DMPK FacilityVivarium – 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 daysEight (8) BioAnalysis Labs for dose formulation, sample prep, and assaysMass 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 80.0In 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 30.0LIMS 20.0 o DEBRA and Watson 10.0 0.0 IV PO PO/BDC
  • QPS is your Global LinkQPS Delaware DMPK FacilityTwo (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 SystemsSupport 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 is your Global LinkQPS Delaware DMPK Bioanalysis FacilityDedicated 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 PenetrationRadio-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
  • QPS – Xcellent Services is your Global Link ADMEAbsorption Protein BindingDistribution *AutoradiographyMetabolismElimination * Radiolabelled Studies
  • QPS – Xcellent Services is your Global LinkQPS Autoradiography Technology Output Microtome Image Analysis, Presentation &Phosphor/Fluor Imager Summary Microscope
  • QPS – Xcellent Services is your Global Link 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 ParsleyCynomolgus Monkey Cockroach
  • QPS is your Global LinkWhole-Body Autoradiography – Study DesignsGLP 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.
  • QPS is your Global LinkExample: Definitive TD and Tissue PKAutoradiographs showing thetissue distribution in albino(Sprague-Dawley) andpigmented rats (Long Evans).Note the amount ofradioactivity in the eye of theLE rat vs. the SD rat
  • QPS is your Global LinkHuman DosimetryQPS has a standard set of calculations, which are based on MIRD and ICRPrecommendations to determine human radiation dosimetry estimatesQPS can also use equations suggested by the sponsor.QPS utilizes the true tissue concentration data obtained from QWBA analysisas opposed to organ homogenate data which can produce misleading resultsregarding 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)
  • QPS is your Global LinkRoutine Tissue ListAdipose (brown and white) Large Intestine Liver Spinal cordAdrenal Gland Lung TestisBlood Lymph node ThymusBone Ovary ThyroidBone Marrow Pituitary gland UterusBrain (cerebrum, Prostate gland Vaginacerebellum, medulla) Salivary gland Urinary BladderCecum Seminal vesicles Any other tissue asEpididymis Skeletal muscle needed; e.g., epiphysealEye (uvea and lens) Skin plate, knee joints,Harderian gland cartilage, specific brain Stomach regions, pampiniformHeart Small intestine plexus, vomero-nasalKidney Cortex Spleen gland, meninges, choroidKidney Medulla plexus
  • QPS is your Global LinkExample: Differential Distribution of MetabolitesIn this experiment, the goal as to track the tissue distribution of 2 knownmetabolites in the rat. Two batches of the parent molecule were prepared andeach was labeled with 14C at two different positions on the molecules so thatthe metabolites could be imaged and tissue concentrations determined usingQWBA.The goal being to determine specific tissue exposure to each metabolite toaddress safety concerns.Methods: 2 groups of animals were used and 1 animal/gp. at each of thefollowing time points were analyzed by QWBA at 1, 2, 4, 8, 24, 48, 72, 168, 240,and 336 hr post-dose.
  • QPS is your Global LinkExample: Definitive TD & PK (24hr) Label A Label B
  • QPS is your Global LinkExample: 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
  • QPS is your Global Link 125I-Labeled Biotherapeutics (peptides, mAbs, proteins) 125IData Interpretation:Whole-body autoradioluminograph of a rat after a single IVdose of an 125I-compound and co-administration of sodium Thyroid, stomach, kidneys, mammary gland, salivaryiodide (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
  • QPS is your Global Link Example: QPS Brain Surgeries Enable Specific DosingQPS can perform brain surgeries to specifically administer targeteddoses of test article directly into the brain of rats using stereotaxicframes and known anatomical brain coordinates.Examples of applications are CNS genetic diseases, Oncology andAlzheimers
  • QPS is your Global Link Example: QPS Brain Surgeries Enable Specific DosingBrain-cannulated rats can be maintained and infusedconstantly for up to 7 continuous days
  • QPS is your Global LinkExample: 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
  • QPS is your Global LinkMicro AutoradiographyProvides 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
  • QPS is your Global LinkExample: Micro Autoradiography Localization of drug molecules in brain tissue Thickness = 10m and the lumen of the epididymis
  • QPS is your Global LinkExample: Micro AutoradiographyRepresentative photomicroautoradiograph Representativeof 14C-AZT localization in rat kidney photomicroautoradiograph ofglomeruli. 14C-compound localization in rat hair sebacious gland Correlate possible tox findings to cellular distribution. If needed metabolite profiling/ID for mechanistic study.
  • QPS is your Global Link Example: QWBA, Micro Autoradiography& IHC Co-Localization14C-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.
  • QPS – Xcellent Services is your Global Link ADMEAbsorptionDistributionMetabolismElimination
  • QPS is your Global LinkMass Balance StudiesObjectives 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 studyNon-GLP or GLPSamples – urine, feces, bile, blood, plasma, tissues, expired airGenerally included in IND regulatory submissionTimelines: o Lead time – 2 weeks o Results – 3 to 4 weeks
  • QPS is your Global LinkExample: 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)
  • QPS is your Global Link 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 RadioactivityNumber Study Sex Route Level (mg/kg) (mL/kg) Conc. (mg/mL) Level (Ci/kg) Mass1 (Intact) Balance 3M PO TBD TBD TBD 50 Mass2 (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 RinseNumber Wipe Pre-dose,0-6, 6-24, Pre-dose, 24-h 24-h intervals to1 (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
  • QPS is your Global LinkExample: Mass Balance Studies in RatsRecovery – 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
  • QPS is your Global Link 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 70Collect bile, urine, feces 60 Cage Wash FecesAverage 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 StudySpot trend from a series of compounds Bile Duct-Cannulated Studies using 14C-labeled Compounds3H BDC study – inexpensive with respect 110to cost and time for 3H-labeling, and 100 Average Recovery 93.8%study cost 90 80 % Dose RecoveredWhat is consider to be unexpected 70 Cage Residue 60 Fecesdata? 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
  • QPS – Xcellent Services is your Global Link ADMEAbsorption Metabolic StabilityDistribution *Species Comparison Inhibition/InductionMetabolism *Reaction PhenotypingElimination *Metabolite Profiling/ID * Radiolabelled Studies
  • QPS is your Global LinkMetabolite Profiling and Identification
  • QPS is your Global Link 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 PathwayVersion 2010.03.19
  • QPS is your Global Link 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-quantitationVersion 2010.03.19
  • QPS is your Global Link 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 fromDevelopment 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 samplesMetabolite ID Molecular Ions Proposed Structures MSn spectra and Internal Review Final Report Accurate Mass (if needed) Metabolic Pathway Version 2010.03.19
  • QPS is your Global LinkExample: Radiochromatograms from TopCount® 7Plasma 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
  • QPS is your Global LinkExample: Radiochromatograms from TopCount® 7 6Urine . 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
  • QPS is your Global LinkExample: Radiochromatograms from TopCount® 0Fecal 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
  • QPS is your Global LinkExample: Mass Spectra of the Parent and Metabolite AFull Scan of Parent (top) and Metabolite A2008101703 #2826-2846 RT: 27.35-27.49 AV: 7 NL: 1.86E6F: 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 4502008101703 #2369 RT: 22.99 AV: 1 NL: 2.93E4 m/zF: 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
  • QPS is your Global Link 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: 3.66E3F: 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
  • QPS – Xcellent Services is your Global Link Part II -QPS’CLINICAL ADME services
  • QPS is your Global LinkAbbreviationsEC = 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
  • QPS is your Global LinkHuman Mass Balance StudyObjectives 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 studyGCPSamples – urine, feces, blood, plasma, expired airTimelines: 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
  • QPS is your Global LinkHuman Mass Balance study at QPS in 10 StepsStep 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
  • QPS is your Global LinkStep 1 – Ethics Committee & Competent Authority SubmissionThe application process for a radioactive phase I trial in the Netherlandsis essentially the same as for any other non-radioactive phase I trial!Written EC and CA approval is routinely obtained within 14 days aftersubmission 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 is your Global LinkHuman DosimetryQPS has a standard set of calculations, which are based on MIRD and ICRPrecommendations to determine human radiation dosimetry estimatesQPS can also use equations suggested by the sponsor.QPS utilizes the true tissue concentration data obtained from QWBA analysisas opposed to organ homogenate data which can produce misleading resultsregarding human tissue exposure during human radiolabeled studies (e.g.exposure of the fine melanized tissue of the eye).
  • QPS is your Global LinkStep 2 - Receipt and Release of 14C-labeled IMP14C-labeled IMP is sent from the Sponsor to the Radiopharmacy14C-labeled IMP is placed in quarantine at the Radiopharmacy untilrelease by QP.14C-labeled IMP is entered in IBC-606 (fully automated & validatedIsotope Book Keeping System) of the Radiopharmacy.
  • QPS is your Global LinkStep 3 – Individual Drug Preparation of 14C-labeled IMPIndividual drug preparation of 14C-labeled study medication is done bythe Radiopharmacy.Individual Drug Preparation Forms are prepared by the Clinical TrialPharmacy – documents are reviewed by the Radiopharmacy and theSponsor.Label specifications are prepared according to GMP Annex 13 by theClinical Trial Pharmacy – documents are reviewed by the Radiopharmacyand Sponsor.Labels are printed (without batch number) by the Clinical TrialPharmacy. Unique batch numbers will be added in handwriting on thelabels during each individual drug preparation.
  • QPS is your Global LinkStep 4 – Transport of 14C-labeled IMPIndividually prepared 14C-labeled study medication is picked up at theRadiopharmacy and transported in a closed perspex transport box to theCPU (i.e. the place where drug administration takes place) by ClinicalTrial Pharmacy personnel.
  • QPS is your Global LinkStep 5 – Drug Administration of 14C-labeled IMPDrug administration of the 14C-labeled study medication is always donein 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 radioactivecontamination of the CPU.
  • QPS is your Global LinkStep 6 – Collection, Sample Processing and Transport of Radioactive Human ExcretaAll necessary steps to ensure sample integrity (experience gained from preclinicalstudies) will be taken from sample collection, sample processing, storage, andshipping.Collection of blood, urine, feces and expired air takes place in the CPU.Sample processing of collected blood, urine and expired air samples takes placein the CPU as well.Sample processing (i.e. homogenization and aliquoting) of collected fecessamples takes place in the radionuclide laboratory.The volunteers are discharged from the clinic after at least 85 % (or more if thestudy protocol requires to do so) of the total dose of radioactivity has beenrecovered in the excreta from the volunteer.The radioactive human excreta and/or aliquots are stored in a designatedfreezer in the CPU until transport to the radionuclide laboratory.The radioactive human excreta and/or aliquots are picked up at the CPU bylaboratory technicians and subsequently transported in a closed perspextransport box to the radionuclide laboratory.
  • QPS is your Global LinkStep 7 - Return and/or Destruction of 14C-labeled IMPReturned/(partially) used 14C-labeled study medication is picked up atthe CPU (i.e. the place where drug administration takes place) andtransported in a closed perspex box to the Radiopharmacy by ClinicalTrial Pharmacy personnel.Returned/(partially) used 14C-labeled study medication, if any, is storedin a closed perspex box in a locked cabinet in the Radiopharmacy untilapproval for destruction has been received from Sponsor.Returned /(partially) used 14C-labeled study medication is treated aswell as disposed of as radioactive waste which will be handled accordingto the UMCG guidance on radioactive health and safety.
  • QPS is your Global LinkStep 8 – Measurement of the 14C-Radioactivity in Human ExcretaAll necessary sample pretreatments after the samples have beenprocessed and aliquoted until the measurement of 14C-radioactivity, aredone by laboratory technicians from the radionuclide laboratory whoare trained by in GLP and the particular Assays Instruction(s) as requiredby the Bioanalytical Protocol of the concerned study.The measurement of 14C-radioactivity in human study samples isperformed on a beta-counter (Tricarb 2500) in the radionuclidelaboratory.
  • QPS is your Global LinkStep 9 – Determination of the total 14C-Radioactivity Recovery RateDetermination of the total 14C-radioactivity recovery rate is done by theBiometrics Department using validated excel sheets.The total recovery rate from urine, feces and expired air samples will becalculated during the last 24-hour interval of hospitalization on the basisof quick count determinations since the percentage of 14C-radioactivityrecovery will be used as the discharge criterion for the volunteer in theclinic.The 14C-radioactivity recovery from all human excreta at all samplingtimes and intervals will be documented in a validated excel sheet.
  • QPS is your Global LinkStep 10 – Disposal of Radioactive Human ExcretaAll radioactive human excreta collected during mass balanced studieswill be treated as radioactive waste and handled according to the UMCGguidance on radioactive health and safety.
  • QPS is your Global LinkPhysical locations on the premises of the UMCG where activities take place duringthe 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
  • QPS is your Global LinkFunctions Involved – Roles & ResponsibilitiesFunctions Physical location/affiliation Roles & ResponsibilitiesRadiopharmacy 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 IMPClinical 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 13Clinical 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 ExcretaBiometrics Biometrics Department of QPS Determination of the total 14C-Radioactivity Recovery Rate