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