View
215
Download
1
Category
Tags:
Preview:
Citation preview
M. Simpson1, G. Lappin2, C. Wagner3, O.Langer3, I. Morris4
1University of York, York, UK2Xceleron Inc, Gaithersburg, MD, USA
3Medical University of Vienna, Vienna, Austria 4Hull York Medical School, York, UK
Overview
Accelerator Mass SpectrometryPositron Emission TomographyCombining AMS/PETClinical DesignAMS/PET Data SummaryConclusions/Applications
Accelerator Mass Spectrometry Isotope ratio techniqueOriginally developed for radiocarbon datingExtremely sensitiveTypically used with 12C/14C
Accelerator Mass Spectrometry
Ion source
Injection magnet
Linearaccelerator
Analysingmagnet
12C13C
14C
High energyallows separationof rare 14C fromother isotopes99.8%
1.1%
10-11%
Positron Emission TomographyPET
Non-invasive nuclear imaging techniqueTissue distribution Drug labelled with positron emitting radionuclide (e.g. 11C or 18F)
Positron Emission Tomography
PET Camera
11C 11B + β+ + v + energy (97keV)
β+
11C
PET Camera
AMS & PETAMS
Prolonged PK dataLimitation – no distribution information
PETPK in tissueLimitation – short term PK only
CombinationLong term PK (AMS)Brain PK (PET)
IN THE SAME SUBJECTS
Clinical DesignAdministration of verapamil
Calcium channel inhibitorP-glycoprotein substrate, crosses blood-brain-barrierWell documented safety and PK profileIV dual labelled (R/S)-[14C], (R)-[11C] verapamil (50 µg)
Chiral centrePosition of dual label (11C and 14C)
Clinical Design (2)
IV Verapamil = 50 µg(R/S)-[14C] (4.1kBq), (R)-[11C] (407 MBq)PET scan/arterial plasma collection (0-60 minutes)Venous plasma collection (0-24 hours)MRI scan
Period 1 Period 2IV dual-labelled
verapamil (50 μg)
7 healthy male volunteers
IV dual-labelled
verapamil (50 μg)
7 healthy male volunteers
Oral verapamil (80 mg)
Aims
To establish a protocol for microdosing studiesR-verapamil in brain by PET R- and S-verapamil in plasma by AMS
Assess PK linearity between therapeutic dose and microdose
Quantification of R- and S-verapamil by HPLC-AMS
Separation of R- & S-verapamil by 2D C18-chiral HPLC
R-verapamilS-verapamil
Plasma Data Summary
R-verapamil
Microdose Microdose + therapeutic dose
Plasma PK Data SummaryParameter Enantiomer Microdose
Microdose + therapeutic
dose
t1/2 (h)R 6.3 ±1.9 6.9 ±1.6
S 7.2 ±2.5 7.1 ±2.2
Cmax (pg/mL)R 210.1 ±79.2 243.8 ±77.7
S 96.3 ±28.6 103.5 ±33.6
AUC(0-24) (hpg/mL)R 579.8 ±107.4 794.0 ±265.1
S 272.6 ±70.7 313.8 ±59.7
AUC(0-inf) (hpg/mL)R 624.5 ±131.6 843.2 ±281.1
S 308.6 ±79.3 343.3 ±58.9
CL (L/h)R 61.0 ±12.6 46.9 ±10.9
S 89.7 ±24.2 78.2 ±14.7
V (L)R 528.2 ±95.1 465.7 ±133.0
S 912.9 ±341.9 789.0 ±272.8
Vss (L)R 397.9 ±89.8 319.9 ±68.7
S 682.0 ±167.0 600.6 ±187.6
PET Data Summary
SUVPET therapeutic dosePET micro dose MRI
2.8
0
PET Data Summary
Arterial plasma Whole brain grey matter
Total 11C
11C-R-verapamil
PET Data SummaryParameter Microdose
Microdose +therapeutic
dose
K1 (mLmL-1min-1) 0.030±0.003 (10) 0.031±0.005 (8)
k2 (min-1) 0.099±0.006 (49) 0.095±0.008 (40)
k3 (min-1)
k4 (min-1)
0.100±0.001 (90)
0.092±0.029 (26)
0.101±0.000 (96)
0.159±0.063 (42)
DV (mLmL-1) 0.66±0.12 (4) 0.56±0.11 (2)
DV (Logan) (mLmL-1) 0.66±0.11 (2) 0.57±0.11 (1)
ConclusionsPrinciple of AMS/PET combination demonstratedLong term plasma PK obtained along with tissue
distribution informationVerapamil shown to be dose linear
Plasma (by AMS)Brain (by PET)
S-verapamil shows preferential clearanceProof of concept for combination studies
Applications in brain, tumour, cardiac therapy
Acknowledgements
PET team - Medical University of Vienna
University of York
Xceleron Ltd
Recommended